Microwave-assisted Paal-Knorr reaction - Three-step regiocontrolled synthesis of polysubstituted furans, pyrroles and thiophenes

An efficient and highly versatile synthesis of furans, pyrroles and thiophenes is described. Starting from commercially available or easily prepared P-keto esters, functional homologation provides differently substituted 1,4-diketones that can be transformed, through a microwave-assisted Paal-Knorr condensation, into the corresponding methoxycarbonyl heterocycles. The methoxycarbonyl moiety can be directly transformed into an NH2 group by hydrolysis to carboxylic acid and Curtius rearrangement or into an amide by reaction with a primary amine in the presence of Me3Al. The method is compatible with the presence of a CbzNH group so that the final heterocycle can be inserted into a peptide sequence as a turn inducer. By using this procedure, a collection of more than 60 different tetrasubstitued pyrroles or trisubstituted thiophenes has been prepared. (c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.