Copper-catalyzed carbo-difluoromethylation of alkenes via radical relay

Organic molecules that contain alkyl-difluoromethyl moieties have received increased attention in medicinal chemistry, but their synthesis in a modular and late-stage fashion remains challenging. We report herein an efficient copper-catalyzed radical relay approach for the carbo-difluoromethylation of alkenes. This approach simultaneously introduces CF2H groups along with complex alkyl or aryl groups into alkenes with regioselectivity opposite to traditional CF2H radical addition. We demonstrate a broad substrate scope and a wide functional group compatibility. This scalable protocol is applied to the late-stage functionalization of complex molecules and the synthesis of CF2H analogues of bioactive molecules. Mechanistic studies and density functional theory calculations suggest a unique ligand effect on the reactivity of the Cu-CF2H species. Compounds that contain alkyl-difluoromethyl moieties are of interest for medicinal chemistry, but their synthesis is challenging. Here, the authors report a copper-catalyzed radical relay approach for the carbodifluoromethylation of alkenes that simultaneously introduces CF2H groups and complex alkyl or aryl groups into alkenes.