NHC-catalyzed generation of difluorocarbene and its application to difluoromethylation of oxygen nucleophiles

Controlled generation of difluorocarbene was effected by an NHC catalyst under mild conditions starting from trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate (TFDA). Cyclohexenones and tetralones were treated with TFDA in the presence of catalytic amounts of N,N′-dimesitylimidazolium chloride and sodium carbonate. The ketones were difluoromethylated with the generated difluorocarbene to afford enol difluoromethyl ethers without difluorocyclopropanation. The ethers thus obtained were dehydrogenated with DDQ to furnish aryl difluoromethyl ethers in high yield. Under similar conditions, secondary amides underwent difluoromethylation selectively on the oxygen atom to give difluoromethyl imidates, which allows the formation of 2-difluoromethoxypyridines.

Controlled generation of difluorocarbene was effected by NHC-catalyst under mild conditions starting from TFDA. Cyclohexenones and tetralones were difluoromethylated with the generated difluorocarbene to afford enol difluoromethyl ethers. The ethers were then dehydrogenated with DDQ to furnish aryl difluoromethyl ethers in high yield. Secondary amides also underwent difluoromethylation selectively on the oxygen atom to give difluoromethyl imidates, which allows the formation of 2-difluoromethoxypridines.Figure optionsDownload as PowerPoint slideHighlights
► Controlled generation of difluorocarbene was effected by NHC catalyst starting from TFDA.
► The difluorocarbene reacted with cyclohexenones to give enol difluoromethyl ethers.
► The enol ethers were dehydrogenated with DDQ to give aryl difluoromethyl ethers.
► The difluorocarbene reacted with secondary amides to give difluoromethyl imidates.