microwave-assisted combinatorial chemistry. examples of high-speed solid-phase organic synthesis

C. Oliver Kappe,* Alexander Stadler, Gernot A. Strohmeier

The 12th European Symposium on Organic Chemistry (ESOC-12), July 13-18, 2001, Groningen, The Netherlands

Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austriaemail: oliver.kappe@uni-graz.at

Introduction:

(A) Isourea-Method

(B) Anhydride-Method

(1:2)

DCM / DMF0°C, 30 min

PhO

O

Ph

O

+N C NPh

O

HO

O

O

PhP

P OH DMAP (cat.)NMP, 200°C

99 %500 W, 10 min

DCM / DMF 9:1

DMAP (cat.)+N C N

NH

N O

O

PhPhHO

O

O

O

PhP

P OH

NH

O N

O

Ph

58 %

thermodynamicallymore stable

http://www.milestonesci.com

„open vessel“ system

T (°C) Time (PhCO)2O Conversion

10 min10 min

10 min10 min

10 min10 min

5080

120150200200

3 eq3 eq3 eq3 eq3 eq5 eq

27 %39 %48 %53 %74 %99 %

open vessel

T (°C) Time Conversion

15 min15 min15 min15 min

68 (50W)89 (100W)

132 (200W)153 (400W)

48 %73 %53 %50 %

sealed vessel

HO2C

99% (5 min) 98% (10 min)

HO2CMe

93% (10 min)

HO2C Me

98% (3 min)

HO2C

Me87% (15 min)

HO2CMe

Me

95% (10 min)

HO2C

Br92% (15 min)

HO2CCl

Cl99% (5 min)

HO2C

Cl88% (10 min)

HO2CI

95% (10 min)

HO2C

I99% (3 min)

HO2C

Cl

Cl

94% (3 min)

HO2COMe

99% (10 min)

HO2C

OMe

85% (3 min)

HO2C

NO2

97% (10 min)

HO2C NO2

NO2

88% (3 min)

HO2C

NO293% (3 min)

HO2C

CN

73% (10 min)

HO2C

CO2Me

87% (10 min)

HO2C

2a 2b 2c 2d 2e

2i 2j 2k 2l 2m 2n

2o 2p 2q2r 2s

2t 2u

2vSHO2C

92% (10 min)

3a 3b

NHO2C

84% (10 min) 86% (10 min)

NHO2C

3c

HO2C

99% (10 min)

4aHO2C

Me

91% (10 min)

4b 4c

88% (10 min)

HO2CMe

4d

89% (10 min)

HO2CCl

4e

87% (10 min)

HO2C

OMe

4f

93% (10 min)

HO2C

OMe

HO2C

84% (10 min)

HO2C C5H11

74% (10 min)

4g 4h

2g2f

HO2CBr

88% (10 min)

HO2CCl

95% (15 min)

98% (10 min)

HO2C Br

2h

NMP, 700 W, 5-10 min

Cs2CO3 (2.0 eq) O

O

ArP

(Merrifield)

PC l

Ar-CO2H (1.5 eq)

Esterification of Polymer-Supported Alcohol

Acknowledgement:This work was supported by the Austrian Science Fund (FWF, Project P-11994-CHE)

Microwave Equipment

Acid Attachment to Merrifield Resin (NMP, 200°C)

PTFA/DCM = 1:1

500 W, 30 min>99%

120°C, 7 bar

OO

O

PhP h

O

H

(Merrifield)

Employing microwave irradiation, acidolysis of the Merrifield linker can furthermore be carried

out quantitatively using a conventional TFA/DCM mixture under elevated pressure.

Stadler A., Kappe C.O., Eur. J. Org. Chem., 2001, 919-925

Microwave-Assisted Combinatorial Chemistry.Examples of High-Speed Solid-Phase Organic Synthesis

One of the most common solid-phase reactions in combinatorial synthesis involves the coupling of an acid ( i.e. an amino acid) to polystyrene solid supports (i.e. Wang or Merrifield resin).

A number of publications have reported the coupling of carboxylic acids to Merrifield resin via the cesium salt method and the esterification of Wang resin using carbodiimide either via the

isourea method or the symmetrical anhydride method. Since the reaction times using conventional conditions have been reported to be rather long (16-48 h) we have investigated the

effects of microwave irradiation towards both of these reactions using benzoic acid derivatives.

Milestone MLS 1600 Multimode Batch Reactor

GrazGrazMicrowave & Combichem

Institutfür Chemie Institutfür Chemie

Conclusion

Esterifications to solid support in 3-15 min instead of

24-72 hours

Isourea method causes byproduct due to rearrangement

of the thermolabile intermediate

Significant rate enhancement for coupling of benzoic

anhydride derivatives using microwave flash heating

Stadler A., Kappe C.O., Tetrahedron, 2001, 3915-3920

shielded thermocouple