Copper-Catalyzed Cross-Coupling of Organozincs with Carboxylic Acids via Acyloxyphosphonium Ions: Direct Access to (fluoro)Ketones

Acyloxyphosphonium ions readily and conveniently prepared in-situ from parent a,a-difluorinated carboxylic acids and commodity chemicals are established as convenient acyl electrophiles that to be used in a copper-catalyzed cross-coupling protocol with organozinc reagents as carbon nucleophiles to smoothly afford a,a-difluoroketones. Several carboxylic acids can be employed efficiently using this copper-catalyzed protocol. In the case of CF2H- and CF3-ketones di- and trifluoroacetic acid can be employed under copper-free conditions. The transformations proceed under mild reaction conditions (0 oC-RT), produce the target compounds in short reaction times (45 min) and exhibit good chemoselectivity and functional group compatibility. Notably, this methodology was also demonstrated effective for the synthesis of non-fluorinated ketones (benzophenones) directly from benzoic acids.