Construction of indole- and isoquinoline-fused nitrogen-containing heterocycles through copper-catalyzed multi-component reaction

Abstract

A copper-catalyzed synthesis of 2-(aminomethyl) indole through domino three-component coupling-cyclization has been developed. This reaction proceeds through Mannich-type coupling of 2-ethynylanilines, aldehydes, and secondary amines, followed by hydroamination. This indole formation was applicable to the synthesis of 4-methylene-2,3,4,9-tetrahyro-1H-pyrido [3,4-b] indoles and 5,6,7,8-tetrahydrobenzo [e] indolo [2,3-c] azepines via palladium-catalyzed C-H functionalization at the 3-position of indole. A combination of the three-component indole formation with nucleophilic cyclization promoted by t-BuOK or MsOH provides an effective access to β-carboline scaffolds. Indole-fused 1,4-diazepines were also synthesized through deprotection/N- arylation at the nitrogen atom of indole by one-pot addition of MeONa after the formation of 2-(aminomethyl) indoles. In relation to the three-component indole formation, a novel four-component synthesis of isoquinolines has been developed. This isoquinoline formation includes Mannich-type reaction of 2-ethynylbenzaldehyde with (HCHO)n and secondary amine, imine formation with t-BuNH2, isoquinoline formation, and elimination of t-butyl group to directly afford 3-(aminomethyl) isoquinolines in good yields. By the use of an alkane diamine instead of t-BuNH2, fused 3-(aminomethyl) isoquinoline derivatives were obtained by cascade cyclization and oxidation. © 2010 The Pharmaceutical Society of Japan.