Palladium difluorocarbene involved catalytic coupling with terminal alkynes

Abstract

Difluoromethylated alkynes are a versatile synthon for the diversity-oriented synthesis of difluoromethyl compounds that are of great interest in life and materials sciences. However, the catalytic cross-coupling for the synthesis of difluoromethylated alkynes remains challenging, despite impressive achievements made in the cross-coupling reactions for alkynes, including the Sonogashira reaction. Here, we report a palladium difluorocarbene involvement in catalytic coupling with terminal alkynes, representing a new mode of conjugation reaction, which circumvents the radical pathway usually encountered during the coupling of alkynes with fluoroalkyl electrophiles. The reaction uses inexpensive and abundant industrial raw material chlorodifluoromethane (ClCF2H) as the difluorocarbene precursor, and features cost-effectiveness, excellent functional group tolerance, and broad substrate scope, including synthesis of drug-like complex molecules. Our mechanistic studies showed a unique catalytic pathway of this process, in which additive hydroquinone plays a pivotal role in promoting the reaction.