Modular Synthesis of Arylpyridylmethylamines via Visible-Light-Driven Reductive Coupling of Amines, Aldehydes and Pyridines.

Abstract

The arylpyridylmethylamine motif is a privileged scaffold in drug discovery. However, rapidly creating these valuable molecules with structural diversity by directly leveraging readily available, yet simple chemical feedstocks remains a challenge. Herein, we describe a versatile and modular photochemical method for the straightforward construction of arylpyridylmethylamine skeleton utilizing widely accessible starting materials, including amines, aldehydes, and pyridines. This multicomponent coupling proceeds under very mild conditions without the need for any transition-metal catalysts, photocatalysts, and acid additives and displays a broad substrate scope and excellent functional-group tolerance. The potential utility of this methodology in pharmaceutical development is demonstrated through late-stage modification of pharmaceutically relevant compounds, concise synthesis of bioactive compounds, and rapid construction of pyridyl analogue of drug molecules. Combined experimental and computational studies unveiled that this reaction proceeds through radical-radical cross-coupling between persistent pyridylphosphonium radicals and α-amino radicals.