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1 CHAPTER 1 Synthesis of amides using Lewis acid catalyst: Iodine catalyzed Ritter reaction Part-1 Chemistry of Lewis acids and amides

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Page 1: Synthesis of amides using Lewis acid catalyst: Iodine catalyzed Ritter reactionshodhganga.inflibnet.ac.in/bitstream/10603/51150/7/07... · 2015-10-16 · Synthesis of amides using

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CHAPTER 1

Synthesis of amides using Lewis acid catalyst: Iodine

catalyzed Ritter reaction

Part-1

Chemistry of Lewis acids and amides

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1.1.1. General overview of Lewis acids

Acid and base reactions are of tremendous importance in organic chemistry,

as they are also in inorganic and biochemistry. In 1884, Svante A. Arrhenius defined

acids as substances dissociating into protons (H+) and the corresponding anions (A‐)

in an aqueous medium.1

Correspondingly, bases were characterized as substances

dissociating into hydroxy‐anions (OH‐) and its respective cations (C+). Clearly this

concept is restricted to acids and bases like HBr or KOH in water. In 1923 Johannes

N. Brønsted and Thomas M. Lowry independently elaborated the extension of the

acid‐base theory by defining acids as proton‐(H+)‐donors and bases as

proton‐acceptors, no longer restricting the concept to specific substance classes or

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solvents.2

Following these ideas, a number of reactions could be interpreted

accordingly.

Since many reactions do not involve direct proton transfers, the

generalization of the acid base definition by Gilbert N. Lewis in 1938, was an

important step for the understanding of chemical compounds and their

transformations.3

A Lewis acid is a compound with electron demand, (i.e.) having an

unoccupied orbital which is able to accept an electron pair. On the other hand a

Lewis base donates an electron‐pair from an occupied orbital. The reaction products

of Lewis acids and bases are Lewis adducts, bound through a coordinative (or

dative) bond. By joining the two concepts it becomes clear, that a Brønsted acid is a

compound consisting of a Lewis base and a proton. This leaves the proton as the

smallest of all Lewis acids, bearing free space in its 1s‐orbital.

Further refined by Ralph G. Pearson in 1963, Lewis acids and bases are

categorized into hard and soft acids and bases (HSAB‐concept).

4 This approach

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describes the quality of a bond in a Lewis adduct by consideration of atomic or ionic

radii, charge distribution and polarizability.

Accordingly, moieties of small size, high charge density and high polarizing

potential are considered “hard”, whereas large radii, low charge densities and low

polarizing potential characterize “soft” acids or bases. The association of hard acids

with hard bases, and soft acids with soft bases is preferred. This preference is based

on the bond character present in these combinations. A bond between a hard acid

and a hard base, as in NaCl, has an ionic character, whereas the bond between a soft

acid and a soft base results in a combination exhibiting a covalent bond character.

With these concepts a manifold of chemical reactions and compounds can be

qualitatively described. Especially for the understanding of structure and reactivity

of transition metal complexes, the HSAB‐concept is of very high value (Scheme

1.1).

L A + LB LA LB L A LB

Lewis ad du ct bind ing through a coo rdinative (d ative ) bond

LA LB

Examples:

H + OH H2O

F3B + OEt2 BF3 OEt2

Cl4Si + OC(CH3)2 Cl4SiH OC(CH3)2

Hard acids: BF3+, H+, Na+, K+, Fe3+, Mg2+; Hard bases: OH-, F- , Cl-, NH3, NR3

Sof t acids: BH3, pd2+, Au+, Cu+, SiCl4; Soft bases: RSH, CN-, R2S, R3P,CO

LA=Lewis acid, LB=Lewis base

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Scheme 1.1: Interaction of Lewis acids and Lewis bases and the HSAB‐categorization.

A great potential of Lewis acids is their application in the activation of

molecules bearing Lewis basic sites. Thus Lewis acids play a key role for the

activation of σ‐and π‐systems. The formation of σ‐complexes is present in the

activation of substrates such as carbonyl compounds or imines.5

Due to the

interaction of the lowest unoccupied molecular orbital (LUMO) of the Lewis acid

with the highest occupied molecular orbital (HOMO) of the Lewis base, adjacent

bonds get polarized and a nucleophilic attack from external or internal nucleophiles

is facilitated. This mode of action can be summarized in a commonly accepted

catalytic cycle which accounts for this activation mode, “Lewis acid catalysis”

(Scheme 1.2).

L A

P

libe ration

S

activation

LA P Lewis adduct (intermediate II)

LA S

Lewis addu ct (intermediate I)

transformation

Scheme 1.2: General reactive principle of Lewis acid catalysis.

Together with Lewis base activation, Brønsted acid activation and Brønsted

base activation it represents the pillars of asymmetric catalysis.6

However,

Lewis acid activation is not restricted to σ‐electron donors. Some Lewis acids

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are very powerful catalysts for the activation of π‐electron‐systems as well. By

these interactions, nucleophilic attacks on allenes, alkenes and alkynes can be

efficiently triggered. Usually these catalysts are complexes bearing a “soft” metal

center.7

σ‐Lewis acids

Some archetypical Lewis acids for σ‐donor activations are group 3‐ and

4‐element halides, such as BF3, AlCl3, SnCl4 or SiCl4. Many other σ‐Lewis acids are

based on transition metals, such as TiCl4 and FeCl3. Based on the periodic table, a

vaguely defined borderline between (transition)‐metal and (transition)‐metal‐free

Lewis acids can be drawn. As a common example from the main group elements,

AlCl3 finds its application for various purposes.8

One important example is the

Friedel‐Crafts alkylation (see scheme 1.3). This reaction, first reported in 1877 by

French chemist Charles Friedel and American chemist James Crafts, is an

electrophilic aromatic substitution, occurring through an addition‐elimination

mechanism.9

The role of the Lewis acid is the interaction of its empty orbital with a

lone pair of electrons on chlorine. This interaction polarizes the halogen‐carbon

bond in RCl and results in a higher electrophilicity on carbon. Subsequently a

nucleophilic attack by the aromatic ring takes place. Upon rearomatization via

elimination of a proton, the product and the catalyst are liberated.

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HCl +

CH3

AlCl3 Cl

R

Me H

Cl AlCl3

R Cl

Cl

Al Cl

Cl

Scheme 1.3: Mechanism of the Friedel‐Crafts alkylation of benzene

π‐Lewis acids

As already mentioned, the activation of multiple carbon‐carbon bonds is

another domain of Lewis acid catalysis. Here the π‐systems of, for example, allenes,

alkenes and alkynes are activated. An extremely important reaction using this

slightly different mode of action is the Ziegler‐Natta polymerization of ethylene or

propylene.10

Z iegler-Aufbau:

R Al

R

n+1

R Al

R

R Al

R

( ) n

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Scheme 1.4: The Ziegler‐Aufbau reaction.

In early studies Ziegler developed the so‐called Aufbau‐reaction (Aufbau

(Ger.) = assembly), the multiple insertion of ethylene into the carbon‐aluminium

bond of trialkylaluminium compounds (Scheme 1.4).

1.1.2. Application of Lewis acid catalysts in organic synthesis

The use of Lewis acids in organic synthesis, especially in catalysis is one of

the most rapidly developing fields in synthetic organic chemistry. In addition, Lewis

acid catalysis is one of the key technologies for asymmetric synthesis, and

combinatorial chemistry as well as for large-scale production. Lewis-acid (LA)-

catalyzed reactions are of great interest because of their unique reactivities

and selectivities and mild reaction conditions used. A wide variety of reactions

using Lewis acids have been developed, and they have been applied to the

synthesis of natural and unnatural compounds. Some of the examples are given

below.

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Alkylation reactions

Friedel-Crafts alkylations are of great interest due to their importance and

common use in synthetic and industrial chemistry. In 1887 Charles Friedel and

James Mason Crafts11

isolated amylbenzene after the treatment of amyl chloride

with AlCl3 in benzene (Scheme 1.5). This was not only one of the first descriptions

of a Lewis acid used in organic synthesis but also the first example of what as later

to be called Friedel-Crafts alkylation after its inventors.

+ Cl AlCl3

-HCl

Scheme 1.5: Friedel-Crafts alkylation of amyl chloride with benzene

Over the intervening years many other Lewis acids including BF3, BeCl2,

TiCl4, SbCl5 and SnCl4 have been described as catalysts for the FC alkylation.12

Acylation reactions

Friedel–Crafts acylation is the acylation of aromatic rings with an acyl

chloride or acid anhydride using FeCl3 or AlCl3 as a strong Lewis acid catalyst.

Reaction conditions are similar to the Friedel–Crafts alkylation as mentioned above.

O

RCOCl or (RCO)2O R

FeCl3

Scheme 1.6: Friedel–Crafts acylation of benzene with acylchloride

The aldol reactions

The Lewis acid-catalyzed aldol reaction of silyl enol ethers, commonly

known as the Mukayama aldol reaction, was first reported in the early seventies.13

The titanium-tetrachloride was also used as Lewis acid catalyst for the cross-aldol

reactions.14

Kobayashi reported15

the first Lewis acid catalyzed cross-aldol reaction

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in aqueous solution. He examined the effects of lanthanide triflates in the reaction of

several silyl enol ethers with benzaldehyde.

CHO OSiMe3

+

Yb(OTf)3 (10 mol%)

H2O-THF , RT

OH O

Scheme 1.7: Lewis acid-catalyzed aldol reaction of silyl enol ether

Allylation reactions

The synthesis of homoallylic alcohols via Lewis acid-catalyzed reaction of

organo-metallic reagents with a carbonyl compound has been widely studied.16

The

first example of such a Lewis acid-catalyzed allylation reaction in aqueous medium

was again reported by Kobayashi.17

In smooth reaction under the influence of 5

mol% of Sc(OTf)3, tetra allyltin reacted with several ketones and aldehydes. The

much cheaper Yb(OTf)3 was also used effectively and the Lewis acid could be re-

used without loss of activity.18

CHO

+

OH

Br Sc(OTf)3 (5 mol%)

H2O, RT

Scheme 1.8: Lewis acid-catalyzed allylation reaction of benzaldehyde with allylbromide

Diels-Alder Reaction

Davies et al.19

developed aluminum chloride induced reaction between

cyclopentadiene and α,β-unsaturated aldehydes resulting in the stereoselective

formation of the products of a formal [4 + 3] cycloaddition. The reaction proceeded

by a tandem Diels-Alder reaction/ring expansion. They also reported MeAlCl2 –

catalyzed hetero Diels-Alder reaction.20

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3

R2

AlCl + R1 R2

21-90%

O O R1

Scheme 1.9: Lewis acid-catalyzed Diels-Alder reaction of cyclopentadiene and α,β-unsaturated

aldehyde

Rearrangement

Lambert et al.21

have developed a new Lewis acid-catalyzed [3,3]-

Sigmatropic rearrangement and Allenote-Claisen rearrangement between benzyl 2,3-

pentadienoate and allyl pyrrolidines using Lewis acid catalyst.

Me Me C +

N Lewis Acid

Me NR2

CO 2Bn CH2Cl2 Me

syn

CO2Bn

Scheme 1.10: Lewis acid-catalyzed Rearrangement

Yb(OTf)3, Sn(OTf)2, Cu(OTf)2, TiCl4, AlCl3, FeCl3, Zn(OTf)2 were also

used as Lewis acid catalysts for this transformation.

Halogenations

Yamamoto et al.22

have reported asymmetric chlorination of ketones using

ZrCl4 as a Lewis acid catalyst.

OSi OSi

ZrCl4 Cl

CH2Cl2, -78 ºC

OSi

( )n

ZrCl4

O Si

Cl

( )n

Scheme 1.11: Lewis acid-catalyzed halogenation

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2

Hintermann, and Tongni, have developed chiral Lewis acid catalyzed

asymmetric chlorination and bromination.23

O O O

R1 OR2 + N X

5mol% A

O O

R1 OR2

Nph-1

Nph-1

O O

Cl

O

1-Nph

1-Nph

MeCN Me X M e O

Ti

O

X=Cl, Br

MeCN Cl

A

NCMe

Scheme 1.12: Lewis acid-catalyzed bromination

Oxidation

Michel Vatele et al.24

developed the method for the oxidative rearrangement

of tertiary allylic alcohols. Most of tertiary allylic alcohols studied were oxidized to

their corresponding transposed carbonyl derivatives in excellent to fair yields by

reaction with TEMPO in combination with PhIO and Bi(OTf)3 or copper(II)

chloride in the presence of oxygen.

R2

H O H

Bi(OTf)3/PHIO

O R4

4 R1 R3

R1

R3 R TEMPO , CH2Cl2

R

Scheme 1.13: Lewis acid-catalyzed oxidative rearrangement of tertiary allylic alcohol

Reduction

Stephan et al.25

have found that the Lewis acid B(C6F5)3 efficiently catalyzed

the direct hydrogenation of imines and the reductive ring-opening of aziridines with

H2 under mild conditions; addition of a bulky phosphine allows the reduction of

protected nitriles.

R1

N

R2 R3

5mol%, B(C6H6)3

H2

R1

NH

R2 R3

H

Scheme 1.14: Lewis acid-catalyzed reduction reaction of imines

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Addition reaction (Michael addition)

Feringa et al.26

observed that the large range of β-keto esters reacted

efficiently with various β-unsubstituted enones in the presence of a catalytic amount

of Yb(OTf)3, to give corresponding product with good yield.

O O

R1 O R2 +

R O

Yb(OTf)3

H2O

R2O O

R O

O R1

Scheme 1.15: Lewis acid-catalyzed Michael addition of β-keto esters with β-unsubstituted enones

Mannich-type reaction

For the synthesis of β-amino ketones the Mannich reaction is one of the most

attractive processes. A Lewis acid-catalyzed Mannich reaction can be carried out

conveniently in aqueous solution.27

An aldehyde, an amine and a vinyl ether reacted

in THF/water mixture in the presence of 10 mol% of Yb(OTf)3, to give β-amino

ketone in 55-100% yield.

R1CHO + R2NH2 +

OMe

R3

10 mol%, Yb(OT f)3

THF/H2O

R2

NH O

R1 R3

Scheme 1.16: Lewis acid-catalyzed Mannich-type reaction

1.1.3. General introduction of amides

The amides are a group of organic compounds derived from carboxylic acids

and nitrogen compounds, like ammonia and amines providing compounds that

contain the -CONH2, -CONHR, or -CONR2 groups. They have the ability to bond

very strongly to themselves, at other amide sites down the chain, or different chains

with amides through hydrogen bonding between the oxygen and the hydrogen from

the NH group elsewhere. These are very strong intermolecular bonds.

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Amide bonds play a major role in the elaboration and composition of

biological systems, representing for example the main chemical bonds that

link amino acid building blocks together to give proteins. Hermann Fischer

discovered the peptide bond (Amide bond) and won the Nobel Prize for Chemistry

in 1902 for groundbreaking work on the structure and properties of purines and

sugars.

The structure of amides

Amides are made by a chain of carbon atoms with one as a carbonyl bonded

to an amine group, which is then bonded to the next carbon to continue the chain.

O O

R R R N R N

H H A B

Scheme 1.17: Structure of amide

The lone pair of electrons on the nitrogen is delocalized into the carbonyl,

thus forming a partial double bond between N and the carbonyl carbon.

Consequently the nitrogen in amides is not pyramidal. It is estimated that acetamide

is described by resonance structure A for 62% and by B for 28%.28

1.1.4. Amide Formation

One or more of the hydrogens of the ammonia are replaced with organic acid

groups to produce primary, secondary, or tertiary amide. Primary amides are

prepared by reacting ammonia or amines with acid chlorides, anhydrides, or esters.

Secondary and tertiary amides are prepared by reacting primary amides or nitriles

with organic acids.

Amides are commonly synthesized via reactions of a carboxylic acid with an

amine.

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R

R1

O H O

R O H + H

N R R N

H

+ H2O

Scheme 1.18: Amide Synthesis

Many methods are known for driving the unfavorable equilibrium to

the right, because the unification of these two functional groups does not

occur spontaneously at ambient temperature, with the necessary elimination of water

only taking place at high temperatures (e.g. >200 ºC),29

conditions typically

detrimental to the integrity of the substrates. For this reason, it is usually necessary

to first activate the carboxylic acid, a process that usually takes place by converting

the –OH of the acid into a good leaving group prior to treatment with the amine

(Scheme 1.19).

O activation O

H O

R1 N R2 R1

R N R OH R Act

R2

Scheme-1.19: Principle of the activation process for amide-bond formation.

In order to activate carboxylic acids, one can use so-called coupling reagents,

which act as stand-alone reagents to generate compounds such as acid chlorides,

(mixed) anhydrides, carbonic anhydrides or active esters.

For the most part, these reactions involve "activating" the carboxylic acid

and the best known method, the Schotten-Baumann reaction which involves

conversion of the acid to the acid chlorides.

O

activation O

R O H R Cl

R1 NH2 O

NaO H R N H

Scheme 1.20: Schotten-Baumann reaction

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Many reviews on coupling reagents have been published.30–36

For example

DCC,37

HOBt,38,39

DIC40

HOAT,41

etc 42

have been effectively employed for this

purpose.

Amide can be synthesized from ketone with hydrogen azide using acid

catalyst (Schmidt Reaction).

O

R R1

HN3

H2SO4

O

R NHR1

Scheme 1.21: Schmidt Reaction

The use of magnesium nitride as a convenient source of ammonia allows a

direct transformation of esters to primary amides. Methyl, ethyl, isopropyl, and tert-

butyl esters are converted to the corresponding carboxamides in good yields.43

O Mg3N2 O

R= alkyl o r ar yl

R OR1

MeOH, 80 º C R NH2 R1= Me, Et, i- Pr, t-Bu

Scheme 1.22: Amide formation from esters

Gunanathan, et al.44

have prepared amides from amines and alcohols under mild

pressure and neutral, homogeneous conditions using a dearomatized bipyridyl-based

PNN Ru(II) pincer complex as a catalyst.

N H P

H

H

R O H

H

+ R1 N

H

N Ru CO O

R1 R N

Toluene, Ref lux, -2H2 H

Scheme 1.23: Synthesis of amides from amine and alcohol

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R N

R1

1.1.5. Applications of amides

Uses in organic synthesis

Recently, Matthias Beller and co-worker reported45

amine can be prepared

from amide using zinc acetate as catalyst.

O

R2 Zn(OAc)2 R2

R N Sila ne s, RT

R1

Scheme 1.24: Synthesis of amine from amides

Since Nahm and Weinreb first reported the use of N-methoxy-N-methylamides

as carbonyl equivalents, this functional group has rapidly become popular in organic

synthesis. The ease of preparation, the limitation of side reactions during

nucleophilic addition, and the selective reduction of this moiety to aldehydes has

propelled it to the forefront of synthetic utility.

M O

R1 OM e

LAH( or) DIBAL-H O

R N

O Me

R2M

M O

R1 OMe

R2 N Me

Me

1

R2 N

Me

R M = Li,Al

= alkyl, aryl, alkenyl, alkynyl.

heteroaryl M = Li,Mg

H3O

R2 = alkyl, aryl,alkenyl, alkynyl.

heteroary

H3O

O O

R H R R

Scheme 1.25: Synthesis of ketone and aldehyde from amides

The main synthetic use of Weinreb amides derives from their reactivity toward

nucleophiles. They can be useful for the addition of Grignard or alkyllithium reagents to

produce ketones. Other advantages are seen in the selective reduction of the Weinreb

amides to the corresponding aldehydes. The chelating ability of the amides provides a

stable intermediate that does not form the aldehyde until aqueous workup. This prevents

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the over reduction commonly seen with other functionalities. Several reviews and

numerous articles on the utility of Weinreb amides have been published.46

Schroeder et al.47

synthesized 1,5-disubstituted tetrazoles from amides using

diisopropyl azodicarboxylate (DIAD), diphenylphosphoryl azide (DPPA), and

diphenyl-2-pyridyl phosphine in THF.

O DPPA

R (2-pyridyl)PPh2 N N

NH DIAD, THF N

N

Scheme 1.26: Synthesis of tetrazole from amide

The amides such as dimethylacetamide, dimethylformamide, formamide,

N-methylformamide, methylpyrrolidone, 2-pyrrolidone and N-vinylpyrrolidone

are often used as very useful common solvents in organic synthesis. Several

articles and many reviews are available in literature regarding the use of amides

as starting materials or intermediates for the synthesis of several bioactive

molecules.

Uses in medicinal chemistry

Amide bonds are not limited to biological systems and are indeed present in

a huge array of molecules, including major marketed drugs. For example,

Atorvastatin,48

the top selling drug worldwide since 2003, blocks the production of

cholesterol, contains an amide bond (Fig. 1.1), as do Lisinopril49

(inhibitor of

angiotensin converting enzyme), Valsartan50

(blockade of angiotensin-II

receptors),51

and Diltiazem (calcium channel blocker used in the treatment of angina

and hypertension).52

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F

HO

COO H

OH

H2N N CO2H

O

N HO2C NH

H

H N

O

Atorvastatin Lisinopril

O

N

N N

HN N

CO 2H

H3CO

O

H O H

S O

N

N

Valsartan

Diltiazem

Figure 1.1: Examples of top drugs containing an amide bond.

Acetaminophen or Paracetamol, an amide is used as analgesic (pain-killer)

and antipyretic (fever reducer). It is commonly used for the relief of headaches,

other minor aches and pains, and is a major ingredient in numerous cold and flu

remedies. Another amide analgesic Phenacetin was introduced in 1887 by Harmon

Northrop Morse. It was one of the first synthetic fever reducers to go on the market.

It is also known historically to be one of the first non-opioid analgesics without anti-

inflammatory properties. Phenacetin was used in products such as Empirin and APC

(aspirin, phenacetin, and caffeine) tablets.

H H N N

O O HO O

Paracetamol Phenacetin

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O H N

N N

O

DEET Lidocaine

Figure 1.2: Amides with biological activity

Other commercially used amides include N,N-dimethyl-m-toluamide

(DEET) which is used as insect repellant and is intended to be applied to the skin or

to clothing, and is primarily used to repel mosquitoes. Lidocaine (Xylocaine) and

dibucaine (Nupercaine) were used as common local anesthetic and antiarrhythmic

drugs. Lidocaine is used topically to relieve itching, burning and pain from skin

inflammations, injected as a dental anesthetic or as a local anesthetic for minor

surgeries.

Uses in industry

Amides are used widely in industry. Amides are found in the plastic and

rubber industry, paper industry, water and sewage treatment and colour, in crayons,

pencils and inks. Acrylamide and polyacrylamide are the products most widely used

in these industries. However, acryl amide is a carcinogen, so can only be used if the

chemicals are not intended for consumption. Polyacrylamide is used in its place,

mainly therefore, in the treatment of drinking water and sewage, as these are

intended for consumption.

CH2 CH

C O

NH2

n

O

NH2 ]

O O

C C N N

H H n

Polyacrylamide Acryl amide Polyamides

Figure 1.3: Example of acrylamides and Polyamides

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OH

Acryl amides are a family of nylons, including Nomex and Kevlar. Kevlar, a

form of polyamide is a very strong material which is about five times as strong as steel,

weight for weight. It is used in composites for boat construction, in manufacture of

bulletproof vests, and in lightweight mountaineering ropes and skis and racquets.

Nylons are polyamides, first produced on February 28, 1935, by Wallace

Carothers at DuPont's research facility at the DuPont Experimental Station. It was

used for various purposes. Apart from textiles for clothing and carpets, nylon is also

used to make tyre cords.

1.1.6. Lewis acids catalyzed amide formation reactions

Yadav et al.53

have used FeCl3 as Lewis acid catalyst for the synthesis of

C-glycosyl amides from isocyanides in good yields with α-selectivity. The use of

FeCl3 makes this method simple, convenient and cost-effective. This is the first

report on carbon-Ferrier rearrangement using isonitriles as nucleophiles.

O

RO + R-NC

RO

OR

FeCl3

CH2Cl2, RT

O

O R RO N

H

RO

Scheme 1.27: FeCl3 catalyzed amide synthesis

Jae Nyoung Kim and co-workers reported InCl3 has efficiently catalyzed the

synthesis of amides from nitriles.54

The reaction was carried out in toluene at

refluxing temperature with the aid of acetaldoxime as an effective water surrogate to

produce amides in high yields.

H

Ph-CN + H3C N

InCl3 ,(5 mol%)

Tolune, ref lux

O

H Ph N

H

Scheme 1.28: InCl3 catalyzed amide synthesis

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Recently, rare-earth metal triflates have enjoyed extensive applications in a

variety of Lewis acid catalyzed organic reactions. Kumar and co-workers developed

Yb(OTf)3-catalyzed amidoalkyl naphthols from aldehyds in ionic liquids.55

O H O

+ R' NH2 +

CHO

O

R' R"

HN

Yb(OTf)3

R R" [bmim] [BF4]

R

Scheme 1.29: Yb(OTf)3 catalyzed amide synthesis

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CHAPTER 1

Synthesis of amides using Lewis acid catalyst: Iodine

catalyzed Ritter reaction

Part-2

Iodine-catalyzed synthesis of amides from nitriles via Ritter

reaction

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1.2.1 Introduction

During the last several decades, Lewis acid catalyzed carbon-nitrogen bond

formation has been extensively studied for organic synthesis. Amide formation

reaction between nitriles and alcohols or alkenes is one of the most important

methods for forming new carbon-nitrogen bond.

1.2.1.1. Ritter reaction

In 1948, J.J. Ritter and P.P. Minieri reported that, treatment of nitriles with

alkenes or tertiary alcohols under acidic conditions resulted in the formation of N-

tert-alkylamides (scheme 1.30).56

The formation of N-alkyl carboxamides from

aliphatic or aromatic nitriles and carbocations is known as the Ritter reaction. Since

its discovery, the Ritter reaction has enjoyed an enormous success and is widely

used for the preparation of acyclic amides as well as heterocycles (e.g. lactams,

oxazolines, etc.). The general features of this reaction are i) the carbocation can be

generated in variety of ways from tertiary, secondary, or benzylic alcohols, alkenes

or alkyl halides; ii) the classical reaction conditions involve the dissolution of the

nitrile substrate in the mixture of acetic acid and concentrated sulfuric acid followed

by the addition of the alcohol or alkene at slightly elevated temperature (50-100 ºC);

iii) alcohols that are easily ionized (e.g. 2˚, and 3˚ alcohols, benzylic alcohols) give

the best results; iv) besides protic acids, Lewis acids (e.g. SnCl4, BF3.OEt2, AlCl3,

etc.) have been successfully employed in the Ritter reaction to generate the required

carbocations; v) the structure of the nitrile compound can be varied widely and most

of the substrates containing a cyano group will undergo the reaction, so, for

example, besides aliphatic and aromatic nitriles, compounds like cyanogen and

cyanamide will also react; and vi) the nitrile substrate may not contain acid sensitive

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H

R

functional groups that would be destroyed under the strongly acid conditions, but

modifications (Ritter-type reactions) that proceed under neutral conditions expanded

the scope of the substrates.

+ R CN

H2SO 4 /AcO H

O R1

R2

R1 R2 H2O R N Me H

R1 2

OH + R CN

H2SO4 / AcOH

O R1

R2

3

R3 H2O R N R

Scheme 1.30: Ritter reaction

The Ritter reaction is most useful in the formation of new carbon-nitrogen

bonds, especially in the formation of amides in which the nitrogen has a tertiary alkyl

group. Real world applications include Merck’s industrial-scale synthesis of anti-HIV

drug Crixivan (indinavir);57

the production of the falcipain-2 inhibitor PK 11195; the

synthesis of the alkaloid aristotelone;58

and synthesis of Amantadine, an antiviral and

antiparkinsonian drug.59

Other applications of the Ritter reaction include synthesis of

dopamine receptor ligands and production of amphetamine from allylbenzene.60

1.2.1.2. Iodine

Iodine was discovered in 1811 by French chemist Bernard Courtois (1777-

1838). Iodine is one of the most abundant elements and its toxicity is relatively low. The

element occurs primarily in seawater and in solids formed when seawater evaporates. It

also exist in nature from many sources such as iodide ions in brines, as an impurity in

chile saltpeter and main natural source of iodine is kelp (2000kg seaweed=1kg iodine).

World demand for iodine and organic iodine compounds is as follows: X-ray

contrast media (21 %), disinfectants and biocides (20 %), medium of organic reactions

(19 %), medicines and pharmaceuticals (16 %), animal feeds (9 %), herbicides (4 %),

and photographics (3 %). Chemical functional ability of iodine as disinfectant or biocide

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R N R

2

comes from the oxidizing ability of iodine itself, especially for SH groups to disulfides,

iodination of aromatic rings in tyrosine and histidine in proteins. Thus, iodine is one of

the most simple, less expensive, less toxic oxidants. Today, iodine is an old reagent;

however, in view of various functionalizing abilities, it is important as an

environmentally benign reagent for organic functional group conversions. The reports

on the recent synthetic utility of iodine in organic synthesis are discussed in the

literature section.

1.2.2. Review of literature

1.2.2.1. Ritter reactions

To date several methods have been reported in literature for synthesis of

amides via Ritter reaction using various catalysts.

Barton et al. (1974)61

: N-alkylated amides were prepared from nitrile and

alcohols. Chlorodiphenylmethylium hexachloroantimonate was used as catalyst for

the activation of primary and secondary alcohols.

R1 OH + RCN

1) Ph2CClSbCl6

2) H2O

Scheme 1.31

H R1 N R

O

Martinez et al. (1989)62

: They synthesized amide from alcohols and nitriles.

Here they have used triflic anhydride for activation of alcohols to obtain good yield.

3

R2 1) Tf 2O, CH2Cl2 R1 H

R1 OH + RCN

2) NaHCO3

R R3 O

Scheme 1.32

Lebedev et al. (2002)63

: N-Primary-alkyl amides were obtained by a Ritter-type

reaction of nitriles with lower primary alcohols or their esters in the presence of acid.

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CO CO

1) alkyl donor, acid H

RCN R1

N R

2) H2O O

Acids: H2SO4, PPA, Tf OH,ClSO3H

alkyl donors: MeCO OR1 B(OR) , R1SO Me, OP(OR)

, 3 2 3

Scheme 1.33

Reddy et al. (2003)64

: Aromatic and aliphatic nitriles react with tert-butyl

acetate in the presence of a catalytic amount of sulfuric acid to give the

corresponding N-tert-butyl amides in excellent yields.

CN O

+ Me O

X

H2SO4 (cat)

42 °C

O Me Me

N Me H

X

X : H, OMe, CF3, CF3O, CO2Me, F, Br, SMe

Ar : phenyl, naphthyl, pyridyl and thiophenyl

Scheme 1.34

Jaouen et al. (1981)65

: Benzyl alcohol derivatives reacted with nitriles in the

presence of chromium tricarbonyl complexes to give corresponding amides and the

complex provided stereochemical controlled product.

R1

R

Cr OH

OC CO CO

R2CN

H2SO4

R : Me, OMe, H, R1 : H, Me, Ph

R2 : Me, Ph

R1

R O

Cr HN

OC CO R2

CO

O

HO Me

MeCN

H2SO4

Cr Cr OC CO OC CO

racemic mixture 89 % Yield

optically pure

Scheme 1.35

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H

H

R

Warren et al. (2002)

66: They reported electrophilic activation of Ritter

reaction for alkenes with nitriles.

R + E

E M eCN

R H2O

O E

HN Me +

E R

H N M e

O

Scheme 1.36

Lewis acid catalyzed Ritter reactions:

Callens et al. (2006)67

: N-tert-Alkyl and aryl amides were obtained by a

Ritter reaction of various nitriles with tertiary alcohols in the presence of a catalytic

amount of bismuth triflate.

RCN + HO

Me 1) Bi(OTf)3

Me

Me 2) H2O

R= alkyl, aryl

Me O

Me

Me N R

Scheme 1.37

Reymond and Cossy et al. (2009)68

: A safe and inexpensive synthesis of

amides, from benzylic alcohols and nitriles and from t-butyl acetate and nitriles,

using a Ritter reaction catalyzed by FeCl3·6H2O was described.

RCN

FeCl3.6H2O O

t-Bu

t-BuOAc, H2O, 150 °C R N

RCN +

OH FeCl3.6H2O NHCOR

Ar R1 H2O , 150 °C Ar R1

Scheme 1.38

Varma et al. (2008)69

: They have developed an atom-economic solvent-free

synthesis of amides by the Ritter reaction of alcohols and nitriles under microwave

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irradiation. This green protocol was catalyzed by solid-supported Nafion®

NR50 with

improved efficiency and reduced waste production.

OH

CN O

Nafion®NR50 N + H

MW, 130 °C

R1 R2

R1 R2

R1= H, OMe, Cl R2= H, Cl, Me, O Me, naphthyl, etc

Scheme 1.39

Tamaddon et al. (2007)70

: Tertiary alcohols as well as primary and

secondary benzylic alcohols react efficiently with nitriles to give the corresponding

amides in good to excellent yields in the presence of P2O5/SiO2 (60% w/w).

O

P2O5/SiO2 (60% w/w) R C N + R1 O H R N R

1

Heat or MW H

R= Ph, Me, C=C, R1= Ph, t-Bu

Scheme 1.40

1.2.2.2. Iodine catalyzed transformations

Iodine has been attracting much attention in synthetic organic chemistry since its

discovery in 1811. It is the weakest oxidizer among the halogens and a poor electrophile

that often needs the assistance of strong acid. Iodine has several advantages over the

vast majority of the other Lewis-acid catalysts, especially the metallic catalysts. Its

catalytic potential is intriguingly broad.

Many Iodine-catalyzed transformations have been reported in literature. The

reports on the recent synthetic utility of iodine in organic synthesis are discussed below.

In the C–C bond formation reactions

A mild, metal-free, and environmentally benign iodine-promoted regioselective

C−C and C−N bonds formation of N-protected indole derivatives giving 2,3′-biindoles

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and 4-(1H-indol-2-yl)morpholines has been successfully demonstrated. Various

bioactive 2, 3′-biindoles and 4-(1H-indol-2-yl) morpholines, bearing electron-rich to

moderately electron-poor substituents, can be prepared in moderate to good yields.71

R1

1equiv I2

N NaHCO3, Rt

R2

R2

N R1

N

R2

R1= H, M e, Br, OMe

R2= H, M e, allyl, Bn

HN O

R1

R1

R1 N O

N I2 , Cs2CO3, Rt N

R2 R2

Scheme 1.41: Iodine catalyzed carbon-carbon bond formation

Intramolecular cyclization of enamines

The synthesis of 3H-indoles was achieved via the iodine-mediated

intramolecular cyclization of enamines. A wide variety of 3H-indole derivatives

bearing multifunctional groups were obtained in good to high yields under transition

metal-free reaction conditions.72

R3 R2

I2

R

R3 R2

R R1

N R1

H

base N

Scheme 1.42: Iodine catalyzed indole synthesis

Treatment of olefins bearing an active methylene group, such as allyl ethyl

malonate and α-alkenyl β-ketoesters with iodine in benzene or CH2Cl2 results in

fused cyclopropane lactone and fused cyclopropane β-ketoester respectively.73

O O I2 (1.2 equiv)

K2CO3 (2.4 equ iv)

O OEt T oluene

I2 (4 equiv) O O

O

EtO2C

O

O

OEt

Et3N (2 .5 equ iv) M g(ClO4)2 (2.0 equiv

CH2Cl2, rt

CO 2Me

Scheme 1.43: Iodine catalyzed fused cyclopropane lactone synthesis

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Iodine as acetylation catalyst

While the catalytic activity of iodine in the acetylation of alcohols with

acetic anhydride was being studied by Deka and co-workers,74

the following

conversion was observed in more than 90% yield in a short reaction time.

I2

RCHO + Ac2O RCH(O Ac)2 CHCl3

R = alkyl, aryl

Scheme 1.44: Iodine catalyzed acetylation

Protection of carboxylic acids as esters using iodine catalyst

Carboxylic acids with a catalytic amount of iodine in methanol provides the

corresponding methyl esters smoothly.75

The reaction is not possible with acidic

aromatic carboxylic acids and iodine is assumed to oxidize methanol partly during

the course of this reaction.

R COOH

I2 (1.0 equiv)

MeOH,

R COOM e

Scheme 1.45: Iodine catalyzed ester synthesis

Iodine in one-pot three-component synthesis

Iodine has been found to be an effective catalyst for one-pot synthesis of

homoallyl benzyl ethers under mild reaction conditions.76

Various homoallyl benzyl

ethers were synthesized in moderate to high yields by three-component condensation

of aldehydes, benzyloxytrimethylsilane, and allyltrimethylsilane in presence of

iodine (10 mol %) in dichloromethane at 0 °C.

O

+ OSiMe3 +

SiMe3 I2 (10 mol%) O

R H DCM, 0 °C R

Scheme 1.46: Iodine catalyzed homoallyl benzyl ether synthesis

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Iodine catalyzes efficiently the three-component condensation of aldehydes,

benzyl carbamate, and allyltrimethylsilane to afford the corresponding protected

homoallylic amines in excellent yields.77

O

R H +

Cbz NH2 +

SiMe3 I2 (10%), CH3CN

RT

NHCbz R

Scheme 1.47: Iodine catalyzed homoallylic amines synthesis

Iodine-catalyzed oxidation reactions

Aromatic and aliphatic thiols can be smoothly oxidized to the corresponding

disulfides by iodine in the presence of pyridine at room temperature as shown in

Scheme 1.48.78

I2, pyridine

RSH RSSR rt

Scheme1.48: Iodine catalyzed oxidation

Yadav et al.79

demonstrated the aromatization of 4-substituted Hantzsch 1,4-

dihydropyridines to the corresponding pyridines in high yields by iodine in

methanol.

R

ErO2C CO2Et

I2 (1.0 equiv)

M eOH

R

ErO2C CO2Et

Me N Me

H

Me N Me

Scheme 1.49: Iodine catalyzed aromatization

Jun Ji and co-workers reported,80

the electrophilic substitution reactions of

indoles with various aromatic aldehydes using a catalytic amount of I2 under

solvent-free conditions. The corresponding bis(indolyl)methanes were obtained in

excellent yields.

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+ Ar C HO

N H

I2

r.t., So lve nt F re e

Ar H

N N H H

Scheme 1.50: Iodine catalyzed bis(indolyl)methane synthesis

Panneer Selvam et al. have described a convenient and efficient one-pot

synthesis of substitutedamidophenols using iodine as catalyst at room temperature

under neat condition.81

CHO

OH

R +

R1

O H

I2 (4 mol%)/ CH3CN

AcCl, rt, R

NHAc

R1

Scheme 1.51: Iodine catalyzed amidophenol synthesis

Iodine was established as a good mediator and reagent in organic synthesis.82

For a long time iodine has been recognized as a good catalyst and reagent in

carbohydrate chemistry also.83

Recently Marjan Jereb et al.84

reported many

transformations of molecules containing oxygen functional groups using iodine as

catalyst.

1.2.3. Present work

In recent years there has been considerable interest in the one-pot reaction

using Lewis acid as catalyst due to their diversity, efficiency and rapid access to

complex and highly functionalized organic molecules. Pioneering work by several

research groups in this area has already established the versatility and uniqueness of

one-pot synthetic protocols as a powerful methodology for the synthesis of diverse

structural scaffolds required in the search of novel therapeutic molecules. In the past

decade there have been tremendous developments in the iodine catalyzed one-pot

reactions and great efforts have been paid to find and develop newer methodologies.

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Several iodine catalyzed transformations have been reported in literature

using alcohols such as benzyl, allyl, and propargyl alcohols as starting materials that

reacted with various nucleophiles in the presence of 2-20 mol % of I2 to form the

corresponding products. The property of iodine to catalyze the elimination of water

from hydroxy compounds has been known for almost a century85

while primary and

secondary benzylic alcohols furnished ethers at elevated temperatures under solvent

free reaction conditions. Benzylic and aliphatic alcohols were converted into nitriles

in the presence of a twofold excess of iodine in aqueous NH4OAc and many such

transformations were reported but there is no report found in literature for the

synthesis of amides from alcohols and nitriles using iodine as catalyst. Therefore, we

have planned to study the iodine catalyzed Ritter reaction for the synthesis of

amides. In this work, we have developed a simple and practical method for the

synthesis of amides and N-tert-butyl amides starting from nitriles and alcohols

(Scheme 1.52).

OH

R

(I,II,III)

+ R1-CN

I2 (20 mol %)

H2O (2 equiv), 110 ºC

O

HN R1

R

O

+ R-CN O

O I2 (20 mol %)

R N H2O (2 equiv), 110 ºC H

R = R1= alkyl, aryl

Scheme 1.52: Iodine catalyzed Ritter reaction

1.2.4. Results and discussion

The activation of alcohols to generate the carbocation is thought to be

difficult due to the poor leaving ability of the -OH group in the absence of any

catalyst. In the present study, alcohols I–IV and the tert-butyl acetate were used

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with a variety of aromatic/aliphatic nitriles for the synthesis of the corresponding

amides.

Reaction of 1-phenylethanol (I) with acetonitrile was taken as a model

reaction to optimize the reaction conditions.

After several trials, iodine with two equivalents of water was found to be the

best to provide the desired amide in good yield. To optimize other reaction

conditions, the reaction was performed using different solvents and toluene was

found to be superior to others. The reaction was also monitored to find out the

influence of different concentration of the catalyst using toluene as solvent and 20

mol% of iodine was found to be the optimum. To find out the optimum temperature,

the reaction was carried out at different temperatures and even at reflux conditions

the conversion was found to be only 50% and this prompted us to study the reaction

using sealed tubes. The reaction worked in a much better way at 110 ˚C in a sealed

tube (Table 1.1).

Table 1.1 Iodine - catalyzed Ritter reaction of I with MeCN in different solvents.

O

OH HN

CH3

CH3 +

I

CH3CN

I2 (20 mol %)

H2O (2 equiv),

CH3

Entry Solventa

Temp (˚C )

Time (h) Conversion (%)b

Yield (%)c

1 MeNO2 100 8 50 -

2 MeNO2 50 8 10 -

3 Toluene 110 4 100 85

4 Xylene 150 4 100 80

5 THF 80 6 30 - a Alcohol I (1 mmol ), nitrile (1.1 mmol), solvent (10 volume), sealed tube

b Conversion of I monitored by LC-MS

c Isolated yield

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The conditions described in the entry 3 of Table 1.1 were found to be

suitable for the synthesis of various other amides in good yields, and the results are

summarized in Tables 1.2 and 1.3.

The generality and scope of this protocol was evaluated for both aromatic

and aliphatic alcohols, and a variety of nitriles. In all these cases, the Ritter reaction

proceeded and yielded the desired amides in good to excellent yields including some

novel amides (entries 3, 7, 9, 10, 11, 15, 19). When secondary benzyl or tert-butyl

alcohols are used as substrates, amides are produced in good yields. On the other

hand primary benzyl alcohol on treatment with phenyl cyanide under the same

conditions, disappointingly, resulted in a very low conversion (10%).

Table 1.2 Ritter reaction of various alcohols and nitriles catalyzed by iodine

OH

R + R1-CN

I2 (20 mol %)

H2O (2 equiv), 110 ºC

O

HN R1

R

Entrya Alcohol Nitrile Amide Time Yield

(h)b

(%)c

1 4.0 8568

2 4.0 8468

3 4.0 60†

4 5.0 62

86

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Br HN

5 5.0 6487

O

6 HN

6

4.0 75

88,89

7 3.0 91†

Br OH

8

II

6.0 4490

Br OH

9

4.0 66 †

II

Br OH

10

4.0 88

II

Br OH O

11 6.0 82†

II 11

12 5.0 8068

13 6.0 85

68

CN

14 5.0 6051

Cl

15 6.0 70†

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16 6.0 6691,92

17 5.0 9593

18 6.0 4091

F

O

19 HN

7.0 76 †

19

20 8.0 6064

21 8.0 6364

a alcohol (1 mmol ), Nitrile (1.1 mmol), Solvent ( 10 volume), 110 ˚C, sealed tube b

Reactions were monitored by LC-MS c Isolated yield

† Novel compounds

1.2.5. Plausible mechanism

In the mechanism proposed, we invoke the formation of ether as suggested in

the Ritter reaction of alcohols catalyzed by FeCl3. 6H2O.70

The ether leads to the

formation of carbocation which attacks the nitrile to give the amide. When the

reaction was carried out in the absence of water, it has been observed that, ether B

was the major product and no amide was formed. While ether formation was

observed at low temperatures (60 ˚C), at higher temperatures (110 ˚C) amide was

found to be the only product (Scheme 1.53).

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OH

I2 (20 mol %)

o

MeCN,

O 110 oC

NHAc

MeCN, 60 C

I

I2 (20 mol%), B H

2O (2 equiv)

1

Scheme 1.53

In one of the experiments, ether B was isolated and confirmed by NMR. The

plausible mechanism for the iodine catalyzed Ritter reaction is given in Scheme

1.54. It is presumed that iodine catalyzes the reaction as a mild Lewis acid.71

The

molecular iodine is believed to activate the alcoholic OH to give intermediate A,

which on combination with another alcohol molecule yields the ether B. In the

presence of iodine, B may afford C which may then be converted to the carbocation

D. The attack of the carbocation on the nitrile followed by water addition may

provide the amide.

I2

I Ph O Ph I

OH I2 OH B

Ph Ph

I A

2

Ph O Ph

Ph I2

D C

O MeCN

HN Me

Ph

H2O

Ph

N C Me

1 E

Scheme 1.54

Next, we turned our attention to the synthesis of N-tert butyl amides from

tert- butyl acetate and nitriles under the reflux conditions. As the yields with the

tert-butyl alcohol are less, tert-butyl acetate has been used as the carbocationic

source. In an earlier report, synthesis of tert-butyl amides has been achieved using

H2SO4 and acetic acid at room temperature54

where they describe the convenient

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H

synthesis of only the tert-butyl amides but the present protocol can be effectively

used for the synthesis of both benzyl and tert-butyl amides.

Though the reaction was carried out at high temperature (110 ˚C), our

method avoids the use of corrosive H2SO4 and uses only catalytic amount of iodine.

Therefore this is an eco-friendly reaction. This reaction is useful to prepare bulky

amides, which may be useful in the preparation of the hindered amines by

hydrolysis.61

O

+ R-CN O

I2 (20 mol %) O

H2O (2 equiv), 110 ºC R N

Scheme 1.55

The scope of this reaction was investigated by examining a variety of nitriles

and in most of the cases, using the same conditions, the reaction proceeded smoothly

in a few hours with good yields and the results are summarized in Table 1.3.

Table 1.3 Ritter reaction of various nitriles with tert-butyl acetate catalyzed by

iodine

O

O + ArCN

I2 (20 mol %)

H2O (2 eq uiv), 110 ºC

O

Ar N

H

Entrya

Nitrile Amide Time (h) Yield (%)c

O

1 CN N H

6.0 6564

20

2 CN

Cl

O

N 6.0 4496

H

C l

22

O

3 CN N H

5.0 87†

23

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O

4 O2N CN

O

O 2N N H

7.0 81†

24

CN

5 MeO NO 2

MeO

O

N H

NO 2

6.0 86†

2 5

O

6 N CN N

N H

6.0 7294

2 6

7 CN

F3C

O

N H

CF 3 27

6.0 8664

8 CN

MeO

O

N H

Me O 28

4.0 8364

CN H N

9 O

F F 29

6.0 80†

H N

CN

10 Br Br

30

5.0 8295

a Nitrile (1.1 mmol), tert-butyl acetate (2 mmol ), Solvent ( 10 volume), 110 ˚C,

b Reactions were monitored by LC-MS

c Isolated yield after column chromatography

† Novel compounds

1.2.6. Conclusion

In conclusion we have developed a simple, convenient and efficient protocol

for the synthesis of amides and N-tert-butyl amides from alcohols, tert-butyl acetate

and nitriles by Ritter reaction using catalytic amount of iodine in a sealed tube. This

catalytic reaction is an inexpensive and eco-friendly process.

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1.2.7. Experimental section

General experimental procedure for the synthesis of amides: A mixture of

alcohol (1 mmol), nitrile (1.1 mmol), iodine (20 mol%) and water (2 equiv) were

placed in a sealed tube and heated to 110 ˚C for the appropriate time as mentioned in

Table 1.2. After completion of the reaction (reaction monitored by TLC), saturated

sodium thiosulfate in water was added and extracted with EtOAc. The organic layer

was separated and washed with water, brine and dried over sodium sulfate,

concentrated to furnish the desired amides. When ever necessary, the obtained

amides were purified by crystallization using petroleum ether/ethyl acetate (8:2).

General experimental procedure for the synthesis of tert-butyl amides: A

mixture of tert-butyl acetate (2 equiv), nitrile (1 mmol), iodine (20 mol%) and water

(2 equiv) were placed in a RB flask and heated to110 ˚C for the appropriate time as

mentioned in Table 1.3. After completion of the reaction (reaction monitored by

TLC), saturated sodium thiosulfate in water was added and extracted with EtOAc,

the organic layer was separated and washed with water, brine and dried over sodium

sulfate and concentrated. The obtained tert-butyl amides were purified by flash

chromatography.

1.2.8. Characterization of the products

Melting points, IR, LC-MS and 1H,

13C, NMR, data of some unknown

compounds are given below. All other known compounds data were cross checked

with reported data in literature.

4-Isopropyl-N-(1-phenylethyl)benzamide (3): Off-white solid. Isolated yield:

60%, mp 129-130 ˚C. IR (neat): 3335, 1632 cm-1

.1H NMR (DMSO-d6): δ (ppm)

8.73 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H) 7.3-87.41 (m, 2H), 7.30–7.34 (m,

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4H), 7.20-7.24 (m, 1H), 5.18 (m, 1H), 2.96 (m, 1H), 1.48 (d, J=7.2 3H), 1.23 (d, J =

6.8 Hz, 6H). 13

C NMR (DMSO-d6): δ 165.93, 152.18, 145.51, 132.70, 128.66,

127.98, 126.99, 126.55, 126.50, 48.81, 33.83, 24.14, 22.75. MS: m/z Calcd for

C18H21NO: 267.16; Found: 268.2 (M+). Anal. Calcd for C18H21NO: C, 80.86; H,

7.92; N, 5.24; O, 5.98%. Found: C, 80.80; H, 7.99, N, 5.22%.

2-(4-Bromophenyl)-N-(1-phenylethyl)acetamide (7): Isolated yield: 91%, mp

111-112 ˚C. IR (neat): 3285, 1644 cm-1

.1H NMR (DMSO-d6): δ (ppm) 8.56 (d, J =

7.6 Hz, 1H), 7.49 (m, 1H), 7.29–7.33 (m, 4H), 7.20-7.20 (m, 3H), 4.92 (m, 1H), 3.44

(s, 2H), 1.36 (d, J = 6.8 Hz, 3H). 13

C NMR (DMSO-d6): δ 169.17, 145.02, 136.37,

131.71, 131.48, 128.71, 127.09, 126.38, 119.98, 48.43, 42.01, 22.97. MS: m/z Calcd

for C14H16BrNO: 318.22; Found: 320 (M+2). Anal. Calcd for C14H16BrNO: C,

60.39; H, 5.07; Br, 25.11; N, 4.40; O, 5.03%. Found: C, 60.37; H, 5.09; N, 4.25%.

N-(1-(2-Bromophenyl)ethyl)benzamide (9): White solid. Isolated yield: 66%, mp:

168-169 oC. IR (neat): 3296, 1630 cm

-1.

1H NMR (DMSO-d6): δ (ppm) 8.98 (d, J =

7.2 Hz, 1H), 7.89–7.91 (m, 2H), 7.53-7.60 (m, 3H), 7.47–7.50 (t, 2H), 7.36–7.39 (t,

1H), 7.16–7.20 (m, 1H), 5.4 (m, 1H) 1.45 (d, J = 7.2 Hz, 3H).

13C NMR (DMSO-

d6): δ 166.11, 144.60, 134.78, 132.94, 131.74 129.10, 128.70, 128.53, 127.90,

127.46, 122.48, 49.06, 21.53. MS: m/z Calcd for C15H14 BrNO: 304.18; Found: 330

(M+2).Anal. Calcd for C15H14BrNO: C, 59.23; H, 4.64; N, 4.60; O, 5.26%. Found:

C, 59.20; H, 4.67; N, 4.55%.

N-(1-(2-Bromophenyl)ethyl)-4-isopropylbenzamide (10): White solid.Isolated

yield: 88%, mp: 183-184 ˚C. IR (neat): 3337, 1632 cm-1

. 1H NMR (DMSO-d6): δ

(ppm) 8.98 (d, J = 7.6 Hz, 1H), 7.852 (d, J = 8.0 Hz 2H), 7.52-7.59 (m, 2H), 7.33–

7.38 (m, 3H), 7.15–7.19 (m, 1H), 5.36-5.40 (m, 1H), 2.5–2.51 (m, 1H) 1.44 (d, J =

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6.8 Hz 3H), 1.23 (d, J = 6.8 Hz, 6H). 13

C NMR (DMSO-d6): δ 166.04, 152.33,

144.71, 132.91, 132.47, 129.03, 128.47, 128.05, 127.46, 126.57, 122.50, 49.02,

33.85, 24.14, 21.54. MS: m/z Calcd for C18H20BrNO: 345.07; Found: 346 (M

+).

Anal. Calcd for C15H14BrNO: C, 62.44; H, 5.82; Br, 23.08; N, 4.05; O, 4.62%.

Found: C, 62.40; H, 5.84; Br, 23.10; N, 4.0%.

N-(1-(2-Bromophenyl)ethyl)-2-phenylacetamide (11): White solid. Isolated yield:

82%, mp: 158–159 ˚C. IR (neat): 3236, 1638 cm-1

. 1H NMR (DMSO-d6): δ (ppm)

8.74 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz 1H), 7.14–7.41 (m, 8H), 5.09-5.16 (m,

1H), 3.4 (s, 2H), 1.32 (d, J = 6.8 Hz, 3H). 13

C NMR (DMSO-d6): δ 169.67, 144.28,

136.75, 132.95,129.44, 129.08, 128.60, 128.42, 127.24, 126.76, 122.45, 48.43,

42.65, 21.75. MS: m/z Calcd for C16H16BrNO: 318.21; Found: 320 (M+2). Anal.

Calcd for C15H14BrNO: C, 60.39; H, 5.07; Br, 25.11; N, 4.40; O, 5.06%. Found: C,

60.28; H, 5.12; N, 4.2%.

N-Benzhydryl-4-isopropylbenzamide (15): White solid. Isolated yield: 70%, mp:

166–168 ˚C. IR (neat): 3333, 2959, 1493 cm-1

. 1H NMR (DMSO-d6): δ (ppm) 9.21

(d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.33–7.39 (m, 10H), 7.25–7.30 (m,

2H), 6.4 (d, J = 8.8 Hz, 1H), 2.96 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H). 13

C NMR

(DMSO-d6): δ 166.35, 152.38, 142.89, 132.52, 128.52, 128.28, 127.41, 126.56,

56.75, 33.86, 24.13. MS: m/z Calcd for C23H23NO: 329.4; Found: 330 (M+). Anal.

Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25; O, 4.86%. Found: C, 83.98; H,

7.09; N, 4.21%.

N-Benzhydryl-2-(3-fluorophenyl) acetamide (19): White solid. Isolated yield:

76%, mp: 147–148 ˚C. IR (neat): 3293, 1650 cm-1

. 1H NMR (DMSO-d6): δ (ppm)

9.07 (d, J = 8.8 Hz, 1H), 7.34-7.37 (m, 5H), 7.24–7.32 (m, 6H), 7.04–7.13 (m, 3H),

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6.12 (d, J = 8.4 Hz, 1H), 3.60 (s, 2H), 13

C NMR (DMSO-d6): δ 169.32, 163.69,

161.28, 142.86, 139.64, 139.57, 130.4, 128.83, 127.81, 127.43, 125.63, 116.3, 113.7,

113.49, 56.56, 42.17. MS: m/z Calcd for C23H23NO: 319.37; Found: 320.2 (M

+).

Anal. Calcd for C23H23NO: C, 78.98; H, 5.68; F, 5.95; N, 4.39; O, 5.01%. Found: C,

78.76; H, 5.73; N, 4.21%.

N-tert-butyl-4-isopropylbenzamide (23): White solid. Isolated yield: 87 %, mp:

148-149 ˚C. IR (neat): 3333, 1633 cm-1

. 1H NMR (DMSO-d6): δ (ppm) 7.70–7.72

(m, 2H), 7.6 (s, 1H), 7.30-7.28 (m, 1H), 2.90-2.96 (m, 1H), 1.37 (s, 9H), 1.22 (d, J =

8.0 6H). 13

C NMR (DMSO-d6): δ 166.76, 151.67, 134.10, 127.90, 126.32, 51.10,

33.78, 29.08. 24.17. MS: m/z Calcd for C14H21NO: 219.32; Found: 220.2 (M+).

Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N, 6.39; O, 7.29%. Found: C, 76.12;

H, 9.83; N, 6.2%.

N-tert-butyl-2-methyl-5-nitrobenzamide (24): White solid. Isolated yield: 81%, mp:

100–102 ˚C. IR (neat): 3386, 1650 cm-1

. 1H NMR (DMSO-d6): δ (ppm) 8.15-8.18 (m,

2H), 8.02 (s, 1H), 7.54 (d, J = 8.4 1H), 2.43 (s, 3H), 1.38 (s, 9H). 13

C NMR (DMSO-d6):

δ 167.15, 145.63, 143.81, 139.78, 132.07, 123.81, 122.04, 51.47, 28.86, 19.70. MS: m/z

Calcd for C12H16N2O3: 236.27; Found: 237.0 (M+). Anal. Calcd for C12H16N2O3: C,

61.00; H, 6.83; N, 11.86; O, 20.32%. Found: C, 61.12; H, 7.55; N, 11.74%.

N-tert-butyl-4-methoxy-2-nitro-benzamide (25): White solid. Isolated yield: 86%, mp:

101–102 ˚C. IR (neat): 3232, 1626 cm-1.

1H NMR (DMSO-d6): δ (ppm) 8.13 (s, 1H),

7.47–7.52 (m, 2H), 7.27–7.30 (m, 1H), 3.87 (s, 3H), 1.34 (s, 9H). 13

C NMR (DMSO-d6):

δ 165.31, 160.24, 148.63, 130.85, 126.47, 119.02, 109.36, 56.59, 51.31, 28.71. MS: m/z

Calcd for C12H16N2O4: 252.26; Found: 253.2 (M+). Anal. Calcd for C12H16N2O4: C, 57.13;

H, 6.39; N, 11.10; O, 25.37%. Found: C, 57.05; H, 6.45; N, 11.13%.

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N-tert-butyl-2-(3-fluorophenyl)acetamide (29): White solid. Isolated yield: 86%,

mp: 105–106 ˚C. IR (neat): 3280, 1644 cm-1

. 1H NMR (DMSO-d6): δ (ppm) 7.73 (s,

1H), 7.30–7.36 (m, 1H), 7.02–7.08 (m, 3H), 3.38 (s, 2H), 1.25 (s, 9H). 13

C NMR

(DMSO-d6): δ 169.48, 163.68, 161.26, 140.21, 130.38, 125.47, 116.15, 113.48,

50.55, 43.02, 28.90. MS: m/z Calcd for C12H16FNO: 209.26; Found: 210.2 (M+).

Anal. Calcd for C12H16FNO: C, 68.88; H, 7.71; F, 9.08; N, 6.69; O, 7.65%. Found:

C, 68.92; H, 7.67; N, 6.65%.

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1.2.8.1. Spectras

O

HN

1H NMR (400 MHz, DMSO-d6) of Compound 3

O

HN

13C NMR (100 MHz, DMSO-d6) of Compound 3

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Br

O

H N

1H NMR (400 MHz, DMSO-d

6) of compound 7

Br

O

H N

13C NMR (100 MHz, DMSO-d

6) of compound 7

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O

Br HN

1H NMR (400 MHz, DMSO-d

6) of compound 9

O

Br HN

13C NMR (100 MHz, DMSO-d

6) of compound 9

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O

Br HN

1H NMR (400 MHz, DMSO-d6) of compound 10

O

Br HN

13C NMR (100 MHz, DMSO-d6) of compound 10

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O

N H

1H NMR 400 MHz, DMSO-d

6) of compound 15

O

N H

13C NMR (100 MHz, DMSO-d

6) of compound 15

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F

O

HN

1H NMR (400 MHz, DMSO-d

6) of compound 19

F

O

HN

13C NMR (100 MHz, DMSO-d

6) of compound 19

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O

N H

1H NMR (400 MHz, DMSO-d

6) of compound 23

O

N H

13C NMR 100 MHz, DMSO-d

6) of compound 23

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O

O2N N H

1H NMR (400 MHz, DMSO-d6) of compound 24

O

O2N N H

13C NMR (100 MHz, DMSO-d

6) of compound 24

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O

MeO

N H

NO2

1H NMR (400 MHz, DMSO-d

6) of compound 25

O

MeO

N H

NO2

13C NMR (100 MHz, DMSO-d

6) of compound 25

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H N

O

F

1H NMR (400 MHz, DMSO-d

6) of compound 29

H N

O

F

13C NMR (100 MHz, DMSO-d

6) of compound 29

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O

Br HN

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O

HN

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1.3. References

1. Arrhenius, S. A. in PhD‐Thesis, Norstedt, P. A. Stockholm, 1884.

2. (a) Lowry, T. M. J. Soc. Chem. Ind. 1923, 42, 1048. (b) Brönsted, J. N. Recl. Trav. Chim.

Pay. B. 1923, 42, 718.

3. (a) Lewis, G. N. J. Franklin Inst. 1938, 226, 293. (b) Lewis, G. N.; Seaborg, G. T. J. Am.

Chem. Soc. 1939, 61, 1886.

4. Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533.

5. Engberts, J. B. F. N.; Feringa, B. L.; Keller, E.; Otto, S. Recl. Trav. Chim. Pay. B. 1996, 115,

457.

6. Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.

7. Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.

8. Helmboldt, O.; Keith Hudson, L.; Misra, C.; Wefers, K.; Heck, W.; Stark, H.; Danner, M.;

Rösch, N. in Ullmann's Encyclopedia of Industrial Chemistry, Wiley‐VCH Verlag GmbH &

Co. KGaA, 2000.

9. Friedel, C.; Crafts, J. M.; Hebd. C. R. Séances Acad. Sci. 1887, 84, 1392.

10. (a) Ziegler, K.; Holzkamp, E.; Breil, H.; Martin, H. Angew. Chem., Int. Ed. 1955, 67, 541. (b)

Natta, G. Angew. Chem. 1964, 76, 553.

11. Friedel, C.; Crafts, J. M. J. Chem. Soc. 1877, 32, 725.

12. Rueping, M.; Nachtsheim, B. J. Beilstein. J. Org. Chem. 2010, 6, 6.

13. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. (b) Mukayama, T.;

Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.

14. (a) Kobayashi, S. Chem. Lett. 1991, 2187. (b) Kobayashi, S. Hachiya, I. J. Org. Chem. 1994,

59, 3590.

15. Kobayashi, S. Chem. Lett. 1991, 2087.

16. Yamamoto, Y.; Asoa, N. Chem. Rev. 1993, 93, 2207.

17. Hachiya, I.; Kobayashi, S. J. Org. Chem. 1993, 58, 6958.

18. Kobayashi, S.; Hachiya, I.; Yamanoi, Y. Bull. Chem. Soc. Jpn. 1994, 67, 2342.

19. (a) Davies, H. M. L.; Dai, X. J. Am .Chem. Soc. 2004, 126, 2692. (b) Niess, B.; Hoffmann, H.

M. R. Angew. Chem. Int. Ed. 2005, 44, 26.

20. Davies, H. M. L.; Dai, X. J. Org. Chem. 2005, 70, 6680.

21. Lambert. T. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 13646.

Page 60: Synthesis of amides using Lewis acid catalyst: Iodine catalyzed Ritter reactionshodhganga.inflibnet.ac.in/bitstream/10603/51150/7/07... · 2015-10-16 · Synthesis of amides using

60

22. Zhang, Y.; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038.

23. Hintermann, L.; Tongni, A. Helv, Chim. Acta, 2000, 83, 2425.

24. Vatele, M. J. Tetrahedron 2010, 66, 904.

25. Preston, A.; Jurca, C. T; Stephan, D. W. Chem. Commun. 2008, 1701.

26. Keller, E.; Feringa, B. L. Tetrahedron Lett. 1996, 37, 1879.

27. Kobayashi, S.; Ishitani, C J. Chem. Soc. Chem. Commum. 1995, 1379.

28. Carl R. Kemnitz C. R.; Loewen, M. J. J. Am. Chem. Soc. 2007, 129, 2521.

29. Jursic, B.S.; Zdravkovdki, Z. Synth. Commun. 1993, 23, 2761.

30. Bodanszky, M. Int. J. Pept. Protein. Res. 1985, 25, 449.

31. Bodanszky, M. Int. J. Pept. Protein. Res. 1992, 5, 134.

32. Han, S. Y.; Kim, Y. K. Tetrahedron 2004, 60, 2447.

33. Humphrey, J. M.; Chamberlin, A. R.; Chem. Rev. 1997, 97, 2243.

34. Katritzky, A. R.; Suzuki, K; Singh, S. K. Arkivoc, 2004, 12.

35. Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827.

36. Najera, C. Synlett 2002, 1388.

37. Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.

38. Koenig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.

39. Koenig, W.; Geiger, R. Chem. Ber. 1970, 103, 2024.

40. Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589.

41. Carpino, L. A.; J. Am. Chem. Soc. 1993, 115, 4397.

42. EricValeur, W.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.

43. Veitch, G. E.; Bridgwood, K. L.; Ley, S. V. Org. Lett. 2008, 10, 3623.

44. Gunanathan, C; Ben-David, Y; Milstein, D, Science 2007, 317, 790.

45. Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770.

46. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.

47. Schroeder, G. M; Marshall, S; Wan, H; Purandare, A. V. Tetrahedron Lett. 2010, 51, 404.

48. Graul, A.; Castaner, J.; Drugs Future, 1997, 22, 956.

49. Patchett, A. A. J. Med. Chem. 1993, 36, 2051.

50. Gasparo, M. D.; Whitebread, S.; Pept, R. 1995, 59, 303.

51. Ananthanarayanan, V. S.; Tetreault, S.; Saint-Jean, A. J. Med. Chem. 1993, 36, 1324.

52. Morse, H. N. "Ueber eine neue Darstellungsmethode der Acetylamidophenole". Berichte der

deutschen chemischen Gesellschaft, 1878, 11 232.

53. Yadav, J. S.; Subba Reddy B. V.; Narasimha Chary, D; Madavi, C.; Kunwar, A. C.

Tetrahedron Lett. 2009, 50, 81.

54. Sun Kim, E.; Seung Lee, H.; Hwan Kim, S.; Nyoung Kim, J. Tetrahedron Lett. 2010, 51,

1589.

55. Anil kumar, Sudershan Rao, M.; Israr Ahmad, Bharti Khungar, Can. J. Chem. 2009, 87, 714.

56. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. (b) Ritter, J. J.; Kalish, J. J.

Am. Chem. Soc, 1948, 70, 4048.

Page 61: Synthesis of amides using Lewis acid catalyst: Iodine catalyzed Ritter reactionshodhganga.inflibnet.ac.in/bitstream/10603/51150/7/07... · 2015-10-16 · Synthesis of amides using

61

57. Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry; Oxford Press: New

York, 2001.

58. Vardanyan, R.; Hruby, V. J. Synthesis of Essential Drugs, 1st Ed. Amsterdam: Elsevier,

2006,137.

59. Kurti, L.; Czako, B. Strategic Applications of Named in Organic Synthesis. Burlington, MA

Elsevier Academic Press. 2005.

60. Fujisawa, Deguchi, Chemical Abstracts 1958, 52, 11965.

61. Barton, D. H. R.; Magnus, P. D.; Garbarino, J. A.; Young, R. N. J. Chem. Soc. Perkin Trans.

1974, 1, 2101.

62. García Martínez, A.; Alvarez, R. M.; Teso Vilar, E.; García Fraile, A.; Hanack, M.;

Subramanian, L. R.; Tetrahedron Lett. 1989, 30, 581.

63. Lebedev, M. Y.; Erman, M. B.; Tetrahedron Lett. 1989, 43, 1397.

64. Reddy, K. L.; Tetrahedron Lett. 2003, 44, 1453.

65. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78.

66. Eastgate, M. D.; Fox, D. J.; Morley, T. J.; Warren, S. Synthesis 2002, 2124. and references

therein.

67. Callens, E.; Burtonb, A. J.; Barretta, A. G. M. Tetrahedron Lett. 2006, 47, 8699.

68. Anxionnat, B.; Guerinot, A.; Reymond, S.; Cossy, J. Tetrahedron Lett. 2009, 50, 3470.

69. Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 2661.

70. Tamaddon, F.; Khoobi, M.; Keshavarz, E. Tetrahedron Lett. 2007, 48, 3643.

71. Li, X. Y.; Ji, K. G.; Wang, H. X.; Ali, S.; Liang, Y. M. J. Org. Chem. 2011, 76, 744.

72. He, Z.; Li, H.; Li, Z. J. Org. Chem. 2010, 75, 4636.

73. (a) Toke, L.; Szabo, G. T.; Hell, Z.; Toth, G. Tetrahedron Lett. 1990, 31, 7501. (b) Toke, L.;

Hell, Z.; Szabo, G. T.; Toth, G.; Bihari, M.; Rockenbauer, A. Tetrahedron 1993, 49, 5133. (c)

Faigl, F.; Devenyi, T.; Lauko, A.; Toke, L. Tetrahedron 1997, 53, 13001. (d) Hell, Z.; Finta,

Z.; Grunvald, T.; Bocskei, Z.; Balan, D.; Keseru, G. M.; Toke, L. Tetrahedron 1999, 55, 1367.

(e) Yang, D.; Gao, Q.; Lee, C.; Cheung, K. Org. Lett. 2002, 4, 3271.

74. Deka, N.; Dipok J.; Kalita, J.; Borah, R.; Jadab C. Sarma, J. Org. Chem. 1997, 62, 1563.

75. (a) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Tetrahedron Lett. 2002, 43, 879. (b)

Chavan, S. P.; Kale, R. R.; Shivasankar, K.; Chandake, S. I.; Benjamin, S. B. Synthesis 2003,

2695.

76. Kataki, D.; Phukan, P. Tetrahedron Lett. 2009, 50, 1958.

77. Phukan, P. J. Org. Chem. 2004, 69, 4005.

78. (a) Higuchi, T.; Gensch, K. H. J. Am. Chem. Soc. 1966, 88, 5486. (b) Gensch, K. H.; Pitman,

I. H.; Higuchi, T. J. Am. Chem. Soc. 1968, 90, 2096. (c) Young, P. R.; Hsieh, L. J. Am. Chem.

Soc. 1978, 100, 7122. (d) Young, P. R.; Hou, K. C. J. Org. Chem. 1979, 44, 947. (e) Eiki, T.;

Tagaki, W. Chem. Lett. 1980, 1063. (f) Doi, J. T.; Musker, W. K.; Leeuw, D. L.; Hirschon, A.

S. J. Org. Chem. 1981, 46, 1239. (g) Doi, J. T.; Musker, W. K. J. Am. Chem. Soc. 1981, 103,

1159.

Page 62: Synthesis of amides using Lewis acid catalyst: Iodine catalyzed Ritter reactionshodhganga.inflibnet.ac.in/bitstream/10603/51150/7/07... · 2015-10-16 · Synthesis of amides using

62

79. Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.; Reddy, G. S. K. K. Synthesis 2000, 1532.

80. Ji, S. J.; Wang, S. Y.; Zhang, Y.; Loh, T. P. Tetrahedron Lett. 2004, 60, 2051.

81. Selvam, N. P.; Perumal, P. T. Tetrahedron Lett. 2008, 64, 2972.

82. Togo, H.; Iida, S. Synlett 2006, 2159.

83. Vaino, A. R.; Szarek, W. A. Adv. Carbohydr. Chem. Biochem. 2001, 56, 9.

84. Jereb M.; Vrazic, D.; Zupan, M. Tetrahedron 2011, 67, 1355.

85. (a) Hibbert, H. J. Am. Chem. Soc. 1915, 37, 1748. (b) Reeve, W.; Reichel, D. M. J. Org.

Chem. 1972, 37, 68. (c) Conant, J. B.; Tuttle, N. Org. Synth. 1941, 1, 345.

86. Ramesh naidu, V.; Kim, M. C.; Suk, J-M.; Kim, H-J.; Lee, M.; Sim, E.; Jeong, K-S.Org. Lett.

2008, 10, 5373.

87. Suttsuo, F.; Kato, K.; Mukaiyama, T. Chemistry Lett. 2008, 37, 506.

88. Luigino, T.; Emanuela, P.; Valentina, S.; Piera, T. Tetrahedron: Asymmetry 2009, 20, 368.

89. Nordstrom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672.

90. Stemmler, R. T.; Bolm, C. Tetrahedron Lett. 2007, 48, 6189.

91. Vincent, A. C.; Sci, F. P.; Nigeria, U.; Nigeria, N. J. Chem and Eng data. 1984, 29, 231.

92. Tignibidina, L. G.; Filimonov, U. D.; Pustovotitiv, A. V.; Gorshkova, V. K.; Saratikov, A. S.;

Krasnov, V. A. Khimiko-Farmatsevticheskii zhurnal. 1989, 23, 1455.

93. Salehi, P.; Khodaei, M.M.; Zolfigol, M.A.; Keyvan, A. Synth. Commun. 2001, 31, 1947.

94. Londregan, A.; T. Storer, G.; Wooten, C.; Yang, X.; Warmus, J. Tetrahedron Lett. 2009, 50,

1986.

95. Deganan, W. M.; Shoemaker, C. J. J. Am. Chem. Soc. 1946, 68, 104.

96. Wan, X.; Ma, Z.; Li, B.; Zang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128,

7416.