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Combinatorial ChemistrySeminar 2006

Carolin Ruß

Table of Contents

1. Introduction

2. Preparation of PSRs

Covalent Linkage between the Active Species and

Support

1. Solid-Phase Chemistry, 2. Copolymerisation

Immobilisation Using Intermolecular Interactions

3. Ion-exchange, 4. Microencapsulation

Table of Contents

3. Examples

• Amide Bond Formation, Wittig-Reagents

• Schiff Base Zinc Complexes

• Reduction, Oxidation, Halogenation

4. Scavengers

5. Simultaneous Multistep Synthesis

6. Literature

1. Introduction

The use The use of polymerof polymer--supported reagents supported reagents ((PSRsPSRs) ) can combine can combine

the benefits the benefits of solidof solid--phase chemistry with the advantages phase chemistry with the advantages

of of solutionsolution--phase synthesisphase synthesis..

reagent

(insoluble)

reaction conditions

A

starting material (dissolved)

B

product(dissolved)

B

product(dissolved)

reagent

(insoluble)

+filtration

1.1 Definitions

•• PolymerPolymer--supported Reagentsupported Reagent (PSR):(PSR):Reagents that are either covalently or ionically Reagents that are either covalently or ionically

boundbound to to the supportthe support

••SupportSupport

InorganicInorganicmaterialsmaterials e.g. Oxides, e.g. Oxides, glassesglasses

Organic Organic polymerspolymers e.g. linear, e.g. linear, crosscross--linkedlinked

1.2 Advantages

•Simplification of Product Work-up,Separation, and Isolation

•Automation•Excess of Reagents

•Potential of Recovery of Reagents

•Higher Stability•Reduction of Toxicity•One-pot Reactions

1.2 Disadvantages

•Change in Reactivity•Additional Time and Cost in Synthesis•Slow Reaction and Low Yields•Limited Chemical and Mechanical Stability

of the Support

2. Preparation of PSRs

1. Solid-Phase Chemistry

X + reactive moietyY

solid phase organic chemistry

X reactive moietyY

2. Preparation of PSRs

2. Copolymerisation

reactive moiety polymerization

+ reactive moietycovalent

bond

2. Preparation of PSRs

3. Ion-exchange

NMe3+X-

M reagent

ion exchangechromatography

NMe3+X- reagent

ionicinteraction

2. Preparation of PSRs

4. Microencapsulation

3. Examples1. Covalent Linkage- Amide Bond Formation

Cl O

ClNO2

NO2OH

O+

NO2O

O O

Et1) AlCl3, Ph-NO2, 60 °C, 5h Et

O

pyridine2) BnMe3N+OH-, H2O, dioxane, 90 °C, 8h A

OCO2Me

NH2 O

MeO2CNH

O

ACHCl3, Et3N, 15 min,quant. yield

3. Examples1. Covalent Linkage- Wittig Reagents

Ph H

O

PhPh+

P PhPh

O

1) NaOMe, MeOH, THF, rt, 3h

2) MeOH, THF, rt (16 h), 70 °C (2 h) 89 %

Polystyrene

Br2, Tl(OAc)3,CCl4

Br1) n-BuLi, toluene2) ClPPh2, THF or LiPPh2, THF

PPh2 P PhPh

PhBr

DMF, 70 °C, 48 h, 93 %

PhBr

3. Examples

2. Copolymerisation- Schiff Base Zinc Complexes

O

Ph

PhOH

H2N

+AIBN, benzene,THF, 75 °C

O OO

cross-linkingagent

O

Ph

PhOH

H2N

n

n n

Crosslinkage

A

3. Examples2. Copolymerisation- Schiff Base Zinc Complexes

CHO

Cl Cl

HOA, Et2Zn,toluene, hexane, 0 °C, 6h, 92%, 94% ee

N

OHPh

Ph

Cl Cl

O

HN Ph

Ph

Intermediates

3. Examples3. Ion-Exchange- Reduction

NMe3 +ClH2O

NMe3NaBH4 BH4

R1 R2 (H)

O NMe3 BH4

R1 R2 (H)

OH

MeOH

O OH

NMe3 BH4

MeOH

90 %

3. Examples3. Ion-Exchange- Oxidation

OHCHO

NMe3

2

Cr2O72-

75 %

3. Examples

3. Ion-Exchange- Halogenation

O

NMe3 Br3

O

Br

OHNH Br3

OH

Br

4. Scavengers

A + B A-B + side products A-B

XY A-B+

filter

Some Solid-Supported Scavenger Reagents

4. Scavengers

Urea Library Using Scavenger Reagents

5. SimultaneousMultistep Synthesis

OH O O

Br

O

O

NH+ HCr2O7

cyclohexane, 65 °C,12 h, 55 %

NMe3+ Br3

NMe3+

N N

HOCl

CF3

N N

Cl

CF3

cyclohexane, 65 °C,12 h, 78 %

cyclohexane, 65 °C,12 h, 98 %

a b

c

a, b, ccyclohexane, 65 °C, 16 h, 48 %

"one-pot reaction"

6. Literature

• A. Akelah, D.C. Sherrington, Application of Functionalized Polymers in Organic

Synthesis, Chem. Rev. 1981, 81, 557-587.

• Bannwarth W. and Felder E. (eds.): Combinatorial chemistry, A Practical Approach,

Wiley-VCH, Weinheim, 2000 (86/VK 5500 B219).

• Hodge P. and Sherrington D. C. (eds.): Polymer-supported Reaction in Organic

Synthesis, John Wiley & Sons, New York, 1980 (86/VK 5500 H688).

• D. H. Drewry, D. M. Coe, S. Poon, Solid Supported Reagents in Organic Synthesis,

Medicinal Research Reviews, Volume 19, Issue 2, Pages 97-148.

• Kobayashi, New methods for high-throughput synthesis, Pure Appl. Chem., Vol. 73,

No. 7, pp. 1103–1111, 2001.

That´s

It!

Many Thanks!