A Brønsted acid–base approach for the net monoselective C–F substitution of (trifluoromethyl)alkanes

Abstract

We disclose a method for the net coupling of nucleophiles with a single fluorine of unactivated (trifluoromethyl)alkanes. The process occurs via an initial base-promoted dehydrofluorination/defluorinative nucleophilic addition cascade to generate vinylfluoride intermediates that undergo a rapid hydrofluorination second step to yield gem-difluorinated products. Thus, the aliphatic-CF₃ group of commercial building blocks and complex medicinal compounds can now be transformed into numerous classes of valuable α,α-difluoro(thio)ether substructures in an efficient and modular manner.