Copper difluorocarbene-involved catalytic gem-difluoropropargylation

Abstract

Abstract The use of metal for catalytic difluorocarbene transfer reactions has long been hindered by the lack of understanding of metal difluorocarbene chemistry, despite the potential implications for medicinal chemistry and advanced materials science. Here, we report a copper-catalyzed difluorocarbene transfer reaction via 1,1-migration of copper difluorocarbene, in contrast to the previous nucleophilic addition of copper difluorocarbene pathway. This reaction enables the development of a modular catalytic gem-difluoropropargylation reaction using a variety of simple and widely available potassium propiolates, terminal alkynes, and allyl/propargyl electrophiles to couple difluorocarbene, opening an avenue to the precise synthesis of organofluorine compounds without tedious synthetic procedures. The impact of this protocol is demonstrated by the efficient synthesis of complex fluorinated skeletons and the rapid synthesis of key intermediates for pheromone derivatives and PGF2 agonists. Mechanistic studies reveal that the migratory insertion of difluorocarbene into the C-Cu bond of the alkynylcopper species is a key step in the reaction.