Cu-Electrocatalysis Enables Vicinal Bis(difluoromethylation) of Alkenes: Unraveling Dichotomous Role of Zn(CFH)(DMPU) as Both Radical and Anion Source.

The difluoromethyl group (CFH) serves as an essential bioisostere in drug discovery campaigns according to Lipinski's Rule of 5 due to its advantageous combination of lipophilicity and hydrogen bonding ability, thereby improving the ADME properties. However, despite the high prevalence and importance of vicinal hydrogen bond donors in pharmaceutical agents, a general synthetic method for doubly difluoromethylated compounds in the vicinal position is absent. Here we describe a copper-electrocatalyzed strategy that enables the vicinal bis(difluoromethylation) of alkenes. By leveraging electrochemistry to oxidize Zn(CFH)(DMPU)-a conventionally utilized anionic transmetalating source, we paved a way to utilize it as a CFH radical source to deliver the CFH group in the terminal position of alkenes. Mechanistic studies revealed that the interception of the resultant secondary radical by a copper catalyst and subsequent reductive elimination is facilitated by invoking the Cu(III) intermediate, enabling the second installation of the CFH group in the internal position. The utility of this electrocatalytic 1,2-bis(difluoromethylation) strategy has been highlighted through the late-stage bioisosteric replacement of pharmaceutical agents such as sotalol and dipivefrine.