Green Chemistry MicrowaveAssisted Organometallic

Reaction

Green Chemistry

To promote innovative chemical

technologies that reduce or eliminate the

use or generation of hazardous substances

in the design manufacture and use of

chemical products

What does the Chemical Industry do for us

Green chemistry

is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally

Benign Solvent systems

Green Chemistry = Responsibility

Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo

Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo

- Ronald Breslow

Green Chemistry is also calledhellip A new approach to designing chemicals and chemical

transformations that are beneficial for human health and the environment

An innovative way to design molecules and chemical transformations for sustainability

Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs

Benign by design

Pollution prevention at the molecular level

What is Green Chemistry

bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment

bull Three components catalysis solvents non-toxic

bull 12 principles of green chemistry

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 115
• Slide 116
• Slide 117
• Slide 118

Green Chemistry

To promote innovative chemical

technologies that reduce or eliminate the

use or generation of hazardous substances

in the design manufacture and use of

chemical products

What does the Chemical Industry do for us

Green chemistry

is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally

Benign Solvent systems

Green Chemistry = Responsibility

Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo

Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo

- Ronald Breslow

Green Chemistry is also calledhellip A new approach to designing chemicals and chemical

transformations that are beneficial for human health and the environment

An innovative way to design molecules and chemical transformations for sustainability

Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs

Benign by design

Pollution prevention at the molecular level

What is Green Chemistry

bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment

bull Three components catalysis solvents non-toxic

bull 12 principles of green chemistry

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

What does the Chemical Industry do for us

Green chemistry

is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally

Benign Solvent systems

Green Chemistry = Responsibility

Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo

Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo

- Ronald Breslow

Green Chemistry is also calledhellip A new approach to designing chemicals and chemical

transformations that are beneficial for human health and the environment

An innovative way to design molecules and chemical transformations for sustainability

Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs

Benign by design

Pollution prevention at the molecular level

What is Green Chemistry

bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment

bull Three components catalysis solvents non-toxic

bull 12 principles of green chemistry

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 118

Green chemistry

is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally

Benign Solvent systems

Green Chemistry = Responsibility

Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo

Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo

- Ronald Breslow

Green Chemistry is also calledhellip A new approach to designing chemicals and chemical

transformations that are beneficial for human health and the environment

An innovative way to design molecules and chemical transformations for sustainability

Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs

Benign by design

Pollution prevention at the molecular level

What is Green Chemistry

bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment

bull Three components catalysis solvents non-toxic

bull 12 principles of green chemistry

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 117
• Slide 118

Green Chemistry = Responsibility

Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo

Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo

- Ronald Breslow

Green Chemistry is also calledhellip A new approach to designing chemicals and chemical

transformations that are beneficial for human health and the environment

An innovative way to design molecules and chemical transformations for sustainability

Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs

Benign by design

Pollution prevention at the molecular level

What is Green Chemistry

bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment

bull Three components catalysis solvents non-toxic

bull 12 principles of green chemistry

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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Green Chemistry is also calledhellip A new approach to designing chemicals and chemical

transformations that are beneficial for human health and the environment

An innovative way to design molecules and chemical transformations for sustainability

Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs

Benign by design

Pollution prevention at the molecular level

What is Green Chemistry

bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment

bull Three components catalysis solvents non-toxic

bull 12 principles of green chemistry

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 117
• Slide 118

What is Green Chemistry

bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment

bull Three components catalysis solvents non-toxic

bull 12 principles of green chemistry

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 117
• Slide 118

Green Chemistry Is About

Cost

Waste

Materials

Hazard

Risk

Energy

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 118

bull Chemistry is a very prominent part of our daily lives

bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products

bull A famous example is the pesticide DDT

Why do we need Green Chemistry

1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created

2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product

3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment

4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity

5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used

6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure

The 12 Principles of Green Chemistry (1-6)

The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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The 12 Principles of Green Chemistry (7-12)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 118

What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 118

Green Chemistry

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
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• Slide 118

The cost of usinghazardous materials

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 14
• Slide 15
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• Slide 17
• Slide 18
• Slide 19
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• Slide 21
• Slide 22
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• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
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• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
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• Slide 43
• Slide 44
• Slide 45
• Slide 46
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• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
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• Slide 79
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• Slide 81
• Slide 82
• Slide 83
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• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
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• Slide 97
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• Slide 99
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• Slide 101
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• Slide 116
• Slide 117
• Slide 118

Conventional Heating vs Alternative Energy Source

Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 10
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• Slide 13
• Slide 14
• Slide 15
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• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
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• Slide 33
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• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
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• Slide 46
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• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
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• Slide 59
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• Slide 61
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• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
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• Slide 77
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• Slide 79
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• Slide 81
• Slide 82
• Slide 83
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• Slide 85
• Slide 86
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• Slide 88
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• Slide 90
• Slide 91
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Clean Chemical Synthesis UsingAlternative Reaction Methods

Alternative Energy SourcesMicrowaveUltrasoundSunlight UV

AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
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• Slide 118

Microwaves in Synthesis

bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied

bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power

The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937

Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a

diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of

Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz

A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar

1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production

History or how it all beganhellip

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
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• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71
• Slide 72
• Slide 73
• Slide 74
• Slide 75
• Slide 76
• Slide 77
• Slide 78
• Slide 79
• Slide 80
• Slide 81
• Slide 82
• Slide 83
• Slide 84
• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer

bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

History or how it all beganhellip

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 117
• Slide 118

bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413

bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279

bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 118

Energy Use in ConventionalChemical Processes

Heating Stirring Piping

Transporting Cooling

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 14
• Slide 15
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• Slide 115
• Slide 116
• Slide 117
• Slide 118

Problem of Conventional Heating

You heat what you donrsquot want to heat

Solvents for reactions apparatus

heated up and cool it down

Double energy penalty without any

apparent ldquobenefitrdquo

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Energy Consumptions

Three ways to get the reaction done but different energy bills to pay

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 116
• Slide 117
• Slide 118

Microwaves

bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash

10oCsec heating rate

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 7
• Slide 8
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• Slide 84
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• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Electromagnetic Spectrum

Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Schematic of a Microwave

E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 118

Microwaves Application in Heating Food

1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 8
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• Slide 116
• Slide 117
• Slide 118

Spectrum Electromagnetic

bull Electric field component

bull Responsible for dielectric heating

bull Dipolar polarization

bull Conduction

bull Magnetic field component

Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the

molecule some inertia

bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results

bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results

bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity

bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample

bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating

rates of 10 degC per second when powerful waves are used

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
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• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
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• Slide 27
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• Slide 30
• Slide 31
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• Slide 33
• Slide 34
• Slide 35
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• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
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• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71
• Slide 72
• Slide 73
• Slide 74
• Slide 75
• Slide 76
• Slide 77
• Slide 78
• Slide 79
• Slide 80
• Slide 81
• Slide 82
• Slide 83
• Slide 84
• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

MW Heating Mechanism

Alternating electric field Withhigh frequency

NoconstraintContinuous electric field

Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 91
• Slide 92
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• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Microwave Dielectric HeatingMechanisms

Dipolar PolarizationMechanism

Conduction Mechanism

Dipolar molecules try toalign to an oscillating fieldby rotation

Ions in solution will moveby the applied electricfield

Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
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• Slide 116
• Slide 117
• Slide 118

Microwave vs Oil-bath Heating

J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 115
• Slide 116
• Slide 117
• Slide 118

Conventional Heating byConduction

ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess

temperature on the outside surface isin excess of the boiling point of liquid

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
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• Slide 46
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• Slide 115
• Slide 116
• Slide 117
• Slide 118

Direct Heating by MicrowaveIrradiation

bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off

Inverted temperature gradients

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 2
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• Slide 49
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• Slide 54
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• Slide 83
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• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Molecular Speeds

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
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• Slide 118

Molecular Speeds

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 116
• Slide 117
• Slide 118

Microwave Ovens

Cooking Chemistry Cooking Food

Household MW ovens

The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
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• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
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• Slide 62
• Slide 63
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• Slide 91
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Publications on MW-AssistedOrganic Synthesis

7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 101
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• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Industrial Chemical Applications of Microwave Heating

Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization

Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls

Polymer Chemistry+ Rubber curing vulcanization+ Polymerization

CeramicsMaterials+ Alumina sintering+ Welding smelting gluing

Plasma+ SemiconductorsWaste Remediation+ Sewage treatment

Analytical Chemistry+ Digestion+ Extraction+ Ashing

Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing

Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 110
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• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Books on Microwave-Assisted Synthesis

1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety

Hayes B LCEM PublishingMatthews NC2002

(ACS Professional Reference Book) H M Kingston S J Haswell (eds)

Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Books on Microwave-Assisted Synthesis

Lidstoumlm PTierney J P(Eds)BlackwellScientific2005

Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs

Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 83
• Slide 84
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• Slide 86
• Slide 87
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• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom

Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols

Edition - 2009 X 310 Pages Hardcover Monograph

Books on Microwave-Assisted Synthesis

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Microwave Ovens

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
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• Slide 90
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• Slide 95
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• Slide 101
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• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Monomodal instrument

Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005

Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
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• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
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• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
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• Slide 83
• Slide 84
• Slide 85
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• Slide 87
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• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Multimodal instrument

+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Monomodal Vs Multimodal

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Monomodal Vs Multimodal

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Thermal Effects

bullMore efficient energetic coupling of solvent with microwaves

promotes higher rate of temperature increase

bull Inverted heat transfer volumetric

bull ldquoHot spotsrdquo in monomode microwaves

bull Selective on properties of material (solvents catalysts

reagents intermediates products susceptors)

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 117
• Slide 118

Recent Applications of Microwave-Assisted Synthesis-MAOS

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 10
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• Slide 118

Hydrolysis of benzamide

thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)

The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions

R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 101
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Reactions or Solid-Solid Reactions

ldquoNo reaction proceeds without solventrdquo

Aristotle

Solventless syntheses

Green chemistry enabled advancement

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 14
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Organic Synthesis

Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed

i n t o a p o w e r f u l m e t h o d o l o g y a s i t

reduces the amount of toxic waste produced and therefore becomes less harmful to the

e n v i r o n m e n t

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71
• Slide 72
• Slide 73
• Slide 74
• Slide 75
• Slide 76
• Slide 77
• Slide 78
• Slide 79
• Slide 80
• Slide 81
• Slide 82
• Slide 83
• Slide 84
• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
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• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Organic Synthesis

bull Clean and efficient synthesis

bull Economic and environmental impact

bull Fast reaction kinetics

Best solvent is no solvent

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Adolf von Baeyer

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Synthesis of Indigo

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Towardsbenign

synthesiswith

remarkableVersatility

G W V Cave C LRaston J L ScottChemCommun

2001 2159

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 116
• Slide 117
• Slide 118

Solid-State General Oxidation with with Urea H2O2 Complex

R S Varma and K P Naiker Org Letters 1999 1 189

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71
• Slide 72
• Slide 73
• Slide 74
• Slide 75
• Slide 76
• Slide 77
• Slide 78
• Slide 79
• Slide 80
• Slide 81
• Slide 82
• Slide 83
• Slide 84
• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Oxidative Preparation of Heterocycles

Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 2
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• Slide 101
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• Slide 103
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• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones

Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Reduction

F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
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• Slide 8
• Slide 9
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• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Carbon-Carbon Bond Formation

Toda Tanada Iwata J Org Chem 1989 54 3007

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
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• Slide 61
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• Slide 66
• Slide 67
• Slide 68
• Slide 69
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• Slide 71
• Slide 72
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• Slide 81
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• Slide 83
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• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solventless Photo Coupling and Photo Rearangements

Y Ito S Endo J Am Chem Soc 1997 119 5974

Shin Keating Maribay J Am Chem Soc 1996 118 7626

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
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• Slide 39
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• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
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• Slide 54
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• Slide 81
• Slide 82
• Slide 83
• Slide 84
• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent - Free Condensation

Z Gross et al Org Letters 1999 1 599

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 14
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• Slide 117
• Slide 118

Solid-State Preparationof Dumb-bell-shaped C120

Wang Komatsu Murata Shiro Nature 1997 387 583

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
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• Slide 30
• Slide 31
• Slide 32
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• Slide 39
• Slide 40
• Slide 41
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• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
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• Slide 71
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• Slide 73
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• Slide 75
• Slide 76
• Slide 77
• Slide 78
• Slide 79
• Slide 80
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• Slide 88
• Slide 89
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• Slide 91
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• Slide 115
• Slide 116
• Slide 117
• Slide 118

Advantages of Solid Mineral Supports(Alumina Silica and Clay)

Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area

The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity

Solids are generally easier and safer to handle than liquids or gaseous reagents

Inexpensive recyclable and environmentally benign nature

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 104
• Slide 105
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• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solid-supported Solventless Reactions

bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation

R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 115
• Slide 116
• Slide 117
• Slide 118

Supported ReactionsUsing Microwaves

E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 13
• Slide 14
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Microwave-Assisted Deacetylationon Alumina

Varma et al J Chem Soc Perkin Trans 1 999 (1993)

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 115
• Slide 116
• Slide 117
• Slide 118

Deprotection of Benzyl Esters viaMicrowave Thermolysis

A practical alternative to traditional catalytic hydrogenation

Varma et al Tetrahedron Lett 34 4603 (1993)

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
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• Slide 24
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• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
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• Slide 57
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• Slide 83
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• Slide 86
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• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of

Carbonyl Compounds Using Microwaves

Varma Meshram Tetrahedron Lett 38 5427 (1997)

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm

PersulfatendashClay using Microwave and Ultrasonic Irradiation

Varma Meshram Tetrahedron Lett 38 7973 (1997)

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
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• Slide 103
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solid Supported Solvent-freeOxidation under MW

Varma et al Tetrahedron Lett 1997 38 2043 and 7823

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Reduction Using MW

Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction

Varma et al Tetrahedron Lett 1997 38 4337

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
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• Slide 21
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• Slide 40
• Slide 41
• Slide 42
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• Slide 45
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• Slide 49
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• Slide 52
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• Slide 54
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• Slide 87
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• Slide 91
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• Slide 94
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• Slide 96
• Slide 97
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• Slide 100
• Slide 101
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• Slide 103
• Slide 104
• Slide 105
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• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Hydrodechlorination under continuous MW

Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Synthesis of Heterocyclic Compounds

Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
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• Slide 94
• Slide 95
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• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Synthesis of Heterocyclic Compounds

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 7
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Organometallic Reactions

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 97
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• Slide 100
• Slide 101
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• Slide 103
• Slide 104
• Slide 105
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Rearrangements

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 7
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Rearrangements

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

INDOLIZINES

Heterocyclic systems 10- electronics

Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine

Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds

N

1

2

34567

8R2

R3

R1

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 7
• Slide 8
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• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Why interest for indolizinic products

Strong fluorescent properties luminiscent products luminiscent products

Potentially fluorescents marker Potentially laserldquoscintillatersrdquo

bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999

Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )

Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2

ldquoCalcium-entryrdquo blockers

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Indolizines by irradiation with microwaves in MCR

RBr

O+

N

R1 R2+N

R2

R1

COR

AcOAl2O3 Mw

R=Ph p-Tolil Stiril

R1= H COOMeR2= COOEt COOMe

Asymmetric indolizines by irradiation with microwaves in MCR

R1

O

Cl+ R2

N NEtOOC

OOMe

Br BrN N

EtOOC

COR1

R2COR1

R2

OOMe

2 [Pd(PPh3)2Cl24 CuI

20 echiv Et3N THF tc 2h

R1=Ph 4-OMe-C6H4R2= Ph

U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003

A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Synthesis of new indolizines

[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical

II

IHH

COORCOOR

N C C

O

R2NCC

O

R1

(B)

(A)

R1

O

C C N R2

O

CCN

H H

ROOC COOR

R1

O

C C N R2

O

CCN

COOR COOR

ROOC COOR

2

2 ROOC C C COOR

R1

O

C CH N R2

O

CCHN

H H

N NCH CHC C

O O

R1 R2

- 2 HX TEAanhydrous solvents

X-

X-

N NCH2 CH2C C

O O

R1 R2

C C COORH

R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5

Y=H NO2 OCH3 CH3 Cl BrX=Br Cl

bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998

bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001

bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004

bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Synthesis of new substituted pyridinium-indolizines

Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate

COO NO2CHC

N NH3C

OR

I IN NH3C

OR

IN NH3C

OR

I

H

KFNMP

-HI

NMP

95oC 30 min

N NH3CO

RN NH3C

O

R

O OO

NO2

O

NO2

-2[H]-2[H]

II

I II

N NH3CO

R

O O

NO2

IN NH3C

O

R

O O

NO2

I

(9a-d)(10a-d)

(15a-d)

(A) (B)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

12

34

56

78 9

10

11

12 3

4

56

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
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• Slide 64
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• Slide 84
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• Slide 86
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• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
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• Slide 97
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• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
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• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

C N

R1

CN

R1

R2

R2R1R2 CC

microunde KF alumina

2

R R

N NR X

+2

CH2

N X

CH2

NX

C

NR1

C

N

R1

R2

R2

R1

R2

C

C+

a) (C2H5)3N in C6H6sau N-metilpirolidona

b) microunde KF alumina

2

R

R

R

R

Indolizine synthesis in solid phase under microwaves

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 94
• Slide 95
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• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Monoindolizine synthesis in solid phase under microwaves

N

N

CH3

OR

I

I

b)Et3NNMP

50-60oC 6-9h

(9a-d)

+ HC C COOC2H5

a) KFAl2O3

MW

10 min 95oC

c)KFAl2O3

95oC 10 min

N

N

CH3

O

R

I

O

OC2H5

(12a-d)

a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2

Reaction conditions and the yelds for synthesized compounds (12a-d)

Comp

Solution Solid phase Microwaves

Time

(min)

T

(degC)

Time

(min)

T

(degC)

Time

(min)

T

(degC)

12a 480 50 63 10 95 57 10 95 84

12b 480 50 61 10 95 50 10 95 77

12c 480 55 71 10 95 52 10 95 85

12d 480 60 53 10 95 47 10 95 71

bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 13
• Slide 14
• Slide 15
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• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Benefits of MW-Assisted Reactions

bull Higher temperatures (superheating sealed vessels)

bull 1048707 Faster reactions higher yields any solvent (bp)

bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts

specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do

conventionallybull 1048707 Automation parallel synthesis ndash combichem

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
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• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
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• Slide 49
• Slide 50
• Slide 51
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• Slide 54
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• Slide 56
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• Slide 81
• Slide 82
• Slide 83
• Slide 84
• Slide 85
• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

MW-Assisted Solvent-free Three Component Coupling

Formation of Propargylamines

Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Solvent-free Synthesis of Ionic Liquids

Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

MW Synthesis ofTetrahalideindate(III)-based IL

Kim and Varma J Org Chem 2005 70 7882

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable

J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
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• Slide 18
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• Slide 22
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• Slide 40
• Slide 41
• Slide 42
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• Slide 60
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• Slide 79
• Slide 80
• Slide 81
• Slide 82
• Slide 83
• Slide 84
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• Slide 86
• Slide 87
• Slide 88
• Slide 89
• Slide 90
• Slide 91
• Slide 92
• Slide 93
• Slide 94
• Slide 95
• Slide 96
• Slide 97
• Slide 98
• Slide 99
• Slide 100
• Slide 101
• Slide 102
• Slide 103
• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves

V Namboodiri R S Varma Green Chemistry 2001 3 146

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Advantages of Present Approach

PEG offers a convenient recyclable reaction medium

Good substitute for volatile organic solvents The microwave heating offers a rapid and clean

alternative at high solid concentration and reduces the reaction times from hours to minutes

The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Water as a ldquocleanerrdquo solvent

bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Cu (I) Catalyzed Click Chemistry

P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

N-alkylation of Aminesusing Alkyl Halides

Ju Y Varma R S Green Chem 2004 6 219-221

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
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• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Aqueous N-alkylation of Aminesusing Microwave Irradiation

Ju Y Varma R S Green Chem 2004 6 219-221

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Why Amines and Heterocycles

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

MW Synthesis of N-Aryl Azacycloalkanes

Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Choice of Reaction Media

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

MW -assisted one-pot synthesis of triazoles

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
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• Slide 104
• Slide 105
• Slide 106
• Slide 107
• Slide 108
• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy

ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups

bull Consider greener solventsbull Minimize number of purifications

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 113
• Slide 114
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• Slide 116
• Slide 117
• Slide 118

Take Awaysbull ldquoGreen chemistryrdquo is not so far away from

what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications

bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of

reagents and solvents

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Green Chemistry OpportunitiesConferences

ndash Annual ACS Green Chemistry and Engineering Conference

ndash Annual Gordon Conferenece Green Chemistry

bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Conclusion

Green chemistry Not a solution

to all environmental problems But the most fundamental approach to preventing pollution

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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• Slide 2
• Slide 3
• Slide 4
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• Slide 109
• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature

bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
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• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Lead References

bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225

bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002

bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005

bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
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• Slide 110
• Slide 111
• Slide 112
• Slide 113
• Slide 114
• Slide 115
• Slide 116
• Slide 117
• Slide 118

Lead Referencesreviews

A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_

Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M

Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl

Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255

R S Varma Advances in Green Chemistry Chemical Syntheses Using

Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K

Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27

18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K

Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J

Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash

96 C R Strauss

References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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References books

Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)

Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)

Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P

Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)

A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002

B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing

Matthews NC 2002

P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell

Publishing Oxford 2005

For online resources on microwave-assisted organic synthesis (MAOS) see

wwwmaosnet

118

THANK YOU

FOR YOUR ATTENTION

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118

THANK YOU

FOR YOUR ATTENTION

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