One-Pot Synthetic Approach to 3-Carboxyl- and 3-Ketopyridines in Aqueous Media.

Abstract

We describe a one-pot strategy to access 3-carboxyl- and 3-ketopyridines from readily available alkynes and propargylamine via a hydroamination process. This one-pot protocol uses alkynes as starting materials, has a broad substrate scope, and operates in aqueous media and open-air conditions. A series of aryl- and alkyl-substituted pyridines were synthesized. This green methodology can be scaled to laboratory size and was used for the synthesis of the natural product core, 4-aza-fluorenone. Density-functional theory and control mechanistic studies support a domino hydroamination/pericyclic reaction, which includes the formation of the enaminone intermediate and its transformation through an aza-Claisen rearrangement to the desired pyridine product.