Copper-Catalyzed Amide Synthesis via Transient Amine Activation with Isothiocyanates

Abstract

The development of catalytic amide synthesis strategies without carboxylic acid preactivation remains a formidable challenge. Herein, we report a copper-catalyzed method enabling direct amidation via transient activation of amines using isothiocyanates as traceless coupling agents. This approach exploits reversible amine-isothiocyanate coupling to generate thiourea intermediates that undergo copper-mediated desulfurization into carbodiimides, which react with non-activated carboxylic acids under ambient conditions (room temperature, air) to furnish amides. The protocol demonstrates broad functional group tolerance across pharmaceuticals and peptides, enabling late-stage functionalization of bioactive molecules. By merging catalytic efficiency with operational simplicity, this strategy provides a sustainable alternative to stoichiometric coupling methods.