Pd-Catalyzed Freon-Enabled Aminocarbonylation of Aryl Iodides

Abstract

Abstract A palladium-catalyzed Freon-to-carbonyl transfer strategy has been developed for the CO-free aminocarbonylation of aryl and heteroaryl iodides with amines. Using chlorodifluoromethane (Freon-22) as both a difluorocarbene precursor and a carbonyl source, this protocol enables direct access to diverse benzamide derivatives without external CO gas or conventional CO-releasing reagents. The reaction exhibits a broad substrate scope and good functional-group tolerance, accommodating electronically diverse aryl iodides, polycyclic and heteroaryl iodides, and primary and secondary amines. Its synthetic utility is demonstrated by late-stage benzamidation of bioactive-molecule-derived substrates and concise synthesis of pharmaceutically relevant benzamide scaffolds, including trimethobenzamide and methyl tamibarotene. Mechanistic experiments involving benzimidazole trapping and H218O labeling support a difluorocarbene-derived carbonyl-transfer process in which water contributes to the oxygen atom of the amide carbonyl group. This work establishes Freon-22 as a practical carbonyl surrogate for CO-free amide synthesis.