Technical Note 525

LITERATURE REVIEW: AN OVERVIEW OF MICROWAVE-ASSISTED ORGANIC SYNTHESIS USING POLYMER-SUPPORTED REAGENTS AND SCAVENGERS: PART 1

Microwave assisted organic synthesis has become an important tool to medicinal chemists for rapid organic synthesis. A huge number of research papers have appeared over the last decades on the application of microwave technology in organic synthesis.1 Some of the major advantages include spectacular decrease in reaction time, improved conversions, clean product formation and wide scope for the development of new reaction conditions. The use of polymer-supported reagents and scavengers is a powerful technique for expedited synthesis and purification.2 By using polymer-supported reagents and scavengers, excess reagents and byproducts can be selectively removed by a simple filtration rather than liquid-liquid extraction and chromatographic purification. In addition, polymer-supported reagents offer further advantages that include reaction of active intermediates by "catch-and-release", selectivity and immobilization of toxic intermediates. Rapid transformations using microwave technology has shifted the bottleneck from synthesis to the work-up and purification step. Therefore, chemists are increasingly looking for an expedited synthesis and purification strategy that would combine the use of microwave heating with polymer-assisted solutionphase organic synthesis. This overview3 covers the recent literature on the significant new applications of polymer-supported reagents and scavengers using microwave heating.

AMIDE SYNTHESIS USING PS-CARBODIIMIDE
Sauer and his group have recently reported4 the application of microwave-assisted organic synthesis using the polymer-supported carbodiimide, PS-Carbodiimide 1.5 A rapid, high-yielding protocol for the synthesis of amides by the coupling of various amines and carboxylic acids in the presence of PS-Carbodiimide and microwave heating was described (Scheme 1). The reaction was complete within 5 minutes at 100 °C under microwave irradiation. The scope of the protocol was evaluated using a broad range of primary, secondary and less reactive aromatic amines, and a host of carboxylic acids. The products were isolated in high yield and purity and the reaction conditions were found to be compatible with a number of organic solvents such as NMP, DMA, DME and MeCN.

www.argotech.com

Corporate Headquarters
220 Saginaw Drive | Redwood City, CA 94063 | (650) 716-1600 | Toll-free 1-877-655-4200

O

OH 1. + R1R2NH

O
1

N C N

O

NR1R2

N

HOBt, DMA, Microwave, 100 oC, 5 minutes 2. Si-Carbonate Ph Me N

N

R1R2NH =

BnNH2

O

NH

N H

NH Me

Scheme 1

SYNTHESIS OF CARBOXYLIC ESTERS USING P O LY M E R - S U P P O R T E D I S O U R E A S
In another study, Linclau et al6 have described the synthesis of a variety of carboxylic esters under microwave heating using polymer-supported isoureas 3. The reactions were carried out in MeCN under microwave heating at 125 °C for 3 minutes. The methyl, benzyl and allyl esters of a variety of carboxylic acids have been isolated in high yield and purity (Scheme 2). The polymer-supported isoureas 3 were synthesized by Cu(II)-catalyzed reaction of a polymer-supported carbodiimide 2 with the corresponding alcohols under ambient conditions.

ROH, Cu(OTf) 2 N C N 2 3, MeCN, R1COOH Microwave, 125 oC, 3 minutes R1COOR R = Me, Allyl, Benzyl

H N C N OR 3

R1COOH examples:

PhCH2CH2COOH, PhCH=CHCOOH,

HO

COOH NHBoc

Scheme 2

T H R E E S T E P A M I D E F O R M AT I O N F R O M POLMER-SUPPORTED CYCLOHEXANE-1,3-DIONE
Turner and his group have reported7 the synthesis of a polymer-bound cyclohexane-1,3-dione resin 5 in three steps from an aminomethyl functionalized polystyrene resin 4 (Scheme 3). The resin 5 was used for rapid synthesis of carboxamides under microwave conditions via a “capture and release” protocol. Thus, 5 was converted to the enol esters 6 which were cleaved by various amines to generate the corresponding amides in high yields.

2

MeO + NH 4

O OMe 3 steps N OH

COOH 5 O O

R

1COCl

MeCOOH, DCM + 5 Microwave, 110 oC 10 minutes x 2

N

O O 6 O

R1

1. R 2R3NH, MeOH, Microwave, 125 oC, 30 minutes R2 2. SO3H

R3 N O

R1

+

5

R1, R2, R3 = Alkyl, Aryl

Scheme 3

P O LY M E R - A N D S I L I C A - S U P P O R T E D D I A M I N E S F O R S C AV E N G I N G EXCESS ACID ANHYDRIDES
Kappe and his co-workers have described8 rapid purification of a small library of N-acylated dihydropyrimidines 7 by scavenging of excess acid anhydrides using both polystyrene- and silica-supported diamines 89 under microwave irradiation (Scheme 4). The scavenging time for excess anhydrides were reduced from several hours to a few minutes under microwave heating.

R3 EtOOC R2 N R1 N H + O R4 O O O R
4

R3 1. TEA, DMAP EtOOC R2 N R1 7 N

O R4 O

2. Scavenger 8, MW, 5 minutes 80-100 oC N H NH2

8, PS- or Si-

Scheme 4

3

REFERENCES:
1. (a) Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light, CEM Publishing: Matthews, NC, 2002; (b) Loupy, A., Ed.; Microwaves in Organic Synthesis; Wiley – VCH, Weinheim, 2002; (c) Varma, R. S. Advances in Green Chemistry: Chemical Syntheses using Microwave Irradiation; AstraZeneca Research Foundation India, Bangalore, 2002. See for example: Bhattacharyya, S.; Rana, S.; Gooding, O. W.; Labadie, J. Polymer-supported triacetoxyborohydride; a novel reagent of choice for reductive amination. Tetrahedron Lett. 2003, 44, 4957-4960 and references 1-2 cited therein. Part 2 of this review will appear in the following issue of the Newsletter. Sauer, D. R.; Kalvin, D.; Phelan, K. M. Microwave-assisted synthesis utilizing supported reagents: a rapid and efficient acylation procedure. Org Lett 2003, 5, 4721-4724. PS-Carbodiimide is commercially available from Argonaut Technologies. PS-Carbodiimide
PART NUMBER 800369 800370 800371 800372 QUANTITY 10 g 25 g 100 g 1000 g

2.

3. 4. 5.

6.

Crosignani, S.; White, P. D.; Steinauer, R.; Linclau, B.: Polymer-supported O-Benzyl and O-allylisoureas: convenient preparation and use in ester synthesis from carboxylic acids. Org Lett 2003, 5, 853-856. Humphrey, C. E.; Easson, M. A. M.; Tierney, J.; Turner, N. J. Solid-supported cyclohexane-1, 3-dione (CHD): a "capture and release" reagent for the synthesis of amides and novel scavenger resin. Org Lett 2003, 5, 849-852. Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. High-throughput synthesis of N3-acylated dihydropyrimidines combining microwave-assisted synthesis and scavenging techniques. Org Lett 2003, 5, 849-852. PS-Trisamine and MP-Trisamine are similar scavenger resins available from Argonaut Technologies . PS-Trisamine
PART NUMBER 800228 800229 800230 800309 QUANTITY 10 g 25 g 100 g 1000 g QUANTITY 10 g 25 g 100 g 1000 g

7.

8.

9.

MP-Trisamine

PART NUMBER 800397 800398 800399 800400

© 2004 Argonaut Technologies, Inc. All rights reserved. 135-702 Japanese Headquarters
Itsuwa Bldg. 6F, 2-26-9, Nishigotanda, Shinagawa-ku, Tokyo, 141-0031, Japan T: +81-3-5719-1239 F: +81-3-5719-1203

European Headquarters
New Road, Hengoed, Mid Glamorgan United Kingdom, CF82 8AU T: +44 (0) 1443 811811 F: +44 (0) 1443 816552

Sign up to vote on this title
UsefulNot useful

Master Your Semester with Scribd & The New York Times

Special offer for students: Only $4.99/month.

Master Your Semester with a Special Offer from Scribd & The New York Times

Cancel anytime.