Combinatorial Synthesis of Heterocycles

Combinatorial Chemistry. Willi Bannwarth, Berthold Hinzen (Eds.) 

Copyright 2006 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-30693-5 

The generic building block 1 (cyanomethyl active ester) was coupled to ami-nomethylated polystyrene resin by reacting 2.0 g (1.04 mmol) of the solid phase with a solution of ester 1 (1.50 g, 2.10 mmol, 2 equiv), DMAP (256 mg, 2.10 mmol, 2 equiv), and DIPEA (365 pL, 3.15 mmol, 3 equiv.) in N- 

To the fully derivatized product on the solid support was then added TFA/ H20/dimethyl sulfide (15 mL 95 5 10) and the mixture was stirred for 12 h. The cleavage solution was removed by filtration through a caimula, and the resin was rinsed wfith an appropriate solvent (e. g., MeOH/CH2Cl2). Concentration of the combined filtrates then provided the crude product 6. The products could be purified by chromatography on siHca gel with hexane/ EtOAc (50-0/0.5-100%) as eluent to give the purified products in yields of 52-82%. 

Palladium black precipitates on the resin during Stille coupHng. After removal of the reaction solution and rinsing of the resin, a brief treatment with dilute KCN in DMSO clears the precipitate from the resin. 

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Combinatorial synthesis of heterocycles 96MI7, 97CRV449, 99AG(E)2494, 99CSR1. 

Westman, J. and Lundin, R., Solid phase synthesis of aminopropenones and aminopropenoates. Efficient and versatile synthons for combinatorial synthesis of heterocycles, Synthesis, 2003, 7, 1025-1030. 

Gopalsamy A, Pallai PV, Combinatorial synthesis of heterocycles solid phase synthesis of 2-arylquinoline-4-carboxylic acid derivatives, Tetrahedron Lett., 38 907-910, 1997. 

Gordeev MF, Patel DY, Gordon EM, Approaches to combinatorial synthesis of heterocycles a solid-phase synthesis of 1,4-dihydropyridines, J. Org. Chem., 61 924-928, 1996. 

Patel DV, Gordeev MF, England BP, Gordon EM, Solid-phase and combinatorial synthesis of heterocyclic scaffolds Dihydropyridines, pyridines, and pyrido[2,3-d]pyrimidines, in Molecular Diversity and Combinatorial Chemistry (Eds Chaiken IW, Janda KD), pp. 58-69, 1996, American Chemical Society, Washington. 

In an earlier investigation by the author [1] polystyrene-g-acrylamide, (I), was used in the combinatorial synthesis of heterocyclic amines as illustrated below. 

MF Gordeev, DV Patel, J Wu, EM Gordon. Approaches to combinatorial synthesis of heterocycles solid phase synthesis of pyridines and pyrido [2,3-d] pyrimidines. Tetrahedron Lett 37 4643-4646, 1996. 

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