KEY INTERMEDIATES IN COMBINATORIAL CHEMISTRY - ACCESS TO VARIOUS HETEROCYCLES FROM ALPHA,BETA-UNSATURATED KETONES ON THE SOLID-PHASE

The value of alpha,beta-unsaturated ketones as key intermediates for t he combinatorial assembly of four different templates on the solid pha se, namely pyrimidines, dihydropyrimidinones, pyridines, and pyrazoles , was explored with individual syntheses of variably substituted model compounds. Starting from aldehydes grafted on polystyrene support, th e Wittig and the Claisen-Schmidt reaction conditions were adapted to e fficiently prepare alpha,beta-unsaturated ketones on the solid phase. Further derivatization of the alpha,beta-unsaturated ketones to form p yrimidines succeeded with a number of amidines. In a feasibility study , the potential to obtain, in a modular fashion, other small heterocyc les from the same intermediates was assessed. In this solid-phase appr oach alpha,beta-unsaturated carbonyl intermediates can act as a three- carbon component and a primary enamine is utilized to complement the s ystem for pyridine ring formation. Instead, with N-methylurea a dihydr opyrimidinone is obtained. As an alternative, substituted hydrazines a re incorporated in one orientation, providing pyrazoles with defined r egioisomerism. The study indicates that alpha,beta-unsaturated ketones grafted on the solid phase can take a pivotal role as branching point s in a number of synthetic diversity schemes and, therefore, represent versatile intermediates for the efficient preparation of combinatoria l small molecule libraries.