Pd-Catalyzed Difluoroalkylation of Alkenes Using Chlorodifluoroalkanes

Abstract

The gem-difluoromethylene unit (−CF₂−) plays a pivotal role in expanding chemical space due to its ability to induce unique molecular geometries and physicochemical properties, making it highly desirable in the development of pharmaceuticals, agrochemicals, and advanced materials. Despite their significance, efficient and versatile methods for incorporating −CF₂– groups into organic molecules remain challenging. We describe a palladium-catalyzed difluoroalkylation of alkenes via a formal Mizoroki–Heck reaction, providing a straightforward, cost-effective, and atom-economic route to synthesize a diverse array of RCF₂-alkenes from readily available alkenes and chlorodifluoroalkanes. This method facilitates the incorporation of gem-difluoromethylene groups into complex molecules under mild conditions and demonstrates remarkable functional group tolerance, enabling late-stage functionalization. Preliminary mechanistic studies support a hybrid palladium-catalyzed radical-polar crossover mechanism. This approach offers an efficient and selective means to incorporate difluoromethylene units, broadening opportunities for the design of bioactive molecules and advanced materials and advancing synthetic strategies for a variety of applications.