Solid-Phase Synthesis of 1,2,3,4-Tetrahydro-2-pyridones via Aza-Annulation of Enamines

Abstract

An efficient solid-phase approach has been developed to prepare nitrogen heterocycles with a 1,2,3,4-tetrahydro-2-pyridone core via aza-annulation of enamines. Immobilized enamines were prepared from the reaction of primary amines with propynoic acid derivatives or ketones. Aza-annulation reactions were carried out by reacting resin-bound enamines with symmetrical alpha,beta-unsaturated acid anhydrides or alpha,beta-unsaturated acids in the presence of DPPA and TEA. The annulation products were isolated in good to high crude yields. Influence of sterically hindered amines as well as alpha- and beta-substituted acrylic acid derivatives on the annulation reaction was also investigated.