Copper-Mediated Oxidative Coupling of Difluoromethyl Bromides/Chlorides with Primary Amines: Direct Synthesis of α-Ketoamides

Abstract

A practical and efficient protocol for one-pot synthesis of α-ketoamides has been developed through ligand-free copper-mediated using commercially available 2-bromo/chloro-2,2-difluorophenylethanones and primary amines as starting materials. The reaction exhibits moderate to good yields, broad functional group tolerance, and mild reaction conditions. Mechanistic studies indicate a plausible pathway involving copper-mediated oxidative elimination in DMSO to generate a key acyl fluoride intermediate, which subsequently reacts with aniline to afford the corresponding ketoamide. Notably, this methodology has also been applied to the synthesis of potent PARP1 inhibitors successfully, demonstrating its potential for the efficient preparation of bioactive molecules.