We report herein the first catalytic strategy to harness amidyl radicals derived from N-chloroamides for C–C bond formation, allowing for the discovery of the first catalytic benzylic C–H difluoromethylation. Under copper-catalyzed conditions, a wide variety of N-chlorocarboxamides and N-chlorocarbamates direct selective benzylic C–H difluoromethylation with a nucleophilic difluoromethyl source at room temperature. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage difluoromethylation of bioactive molecules. This copper-catalyzed, chloroamide-directed strategy has also been extended to benzylic C–H pentafluoroethylation and trifluoromethylation. Mechanistic studies on the difluoromethylation reactions support that the reactions involve the formation of benzylic radicals via intramolecular C–H activation, followed by the copper-mediated transfer of difluoromethyl groups to the benzylic radicals.

No abstract

The difluoromethyl group (CF2H) is considered to be a lipophilic and metabolically stable bioisostere of an amino (NH2) group. Therefore, methods that can rapidly convert an NH2 group into a CF2H group would be of great value to medicinal chemistry. We report herein an efficient Cu‐catalyzed approach for the conversion of alkyl pyridinium salts, which can be readily synthesized from the corresponding alkyl amines, to their alkyl difluoromethane analogues. This method tolerates a broad range of functional groups and can be applied to the late‐stage modification of complex amino‐containing pharmaceuticals.

No abstract

The difluoromethyl group (CF2H) is considered to be a lipophilic and metabolically stable bioisostere of an amino (NH2) group. Therefore, methods that can rapidly convert an NH2 group into a CF2H group would be of great value to medicinal chemistry. We report herein an efficient Cu‐catalyzed approach for the conversion of alkyl pyridinium salts, which can be readily synthesized from the corresponding alkyl amines, to their alkyl difluoromethane analogues. This method tolerates a broad range of functional groups and can be applied to the late‐stage modification of complex amino‐containing pharmaceuticals.