Electrosynthesis of 1,1-Bis(difluoromethyl)alkenes via Twofold C(sp2)-H Difluoromethylation: A Bioisosteric Gateway to an Elusive Functional Group

Geminal bis(difluoromethyl)alkenes, featuring two CF ₂ H groups as lipophilic hydrogen-bond donor surrogates, are highly coveted yet rarely accessible bioisosteres of 1,1-enediols that remain nearly theoretical due to their inherent instability. Here we report a catalyst-free electrosynthetic method that directly converts 1,1-diarylalkenes into these geminal bis(difluoromethyl) motifs in a single step under mild oxidative conditions. The key advance is the use of Zn(CF ₂ H) ₂ (DMPU) ₂ as a difluoromethyl radical precursor in combination with ZnCl ₂ as an additive to enable twofold C(sp²)–H difluoromethylation without the need for catalysts. This protocol exhibits broad substrate scope, tolerating diverse functional groups and complex molecular scaffolds, which highlights its generality and practicality. Mechanistic studies reveal that the transformation proceeds via two discrete additions of CF ₂ H radicals to the double bond, each followed by oxidation to a carbocation intermediate and an elimination step. Voltammetric analysis further shows that ZnCl ₂ buffers the electrode potentials and suppresses side reactions, facilitating the sequential difluoromethylation under mild conditions. This electrosynthesis platform thus provides the first general route to stable 1,1-bis(difluoromethyl)alkene architectures and offers a broadly applicable gateway to incorporate dual hydrogen-bond donor functionality in drug-like molecules, thereby expanding the repertoire of CF ₂ H-based functional-group surrogates in medicinal chemistry. Notably, preliminary biological evaluation revealed that one of the functionalized derivatives exhibits promising cytotoxicity against tumor cell lines, further highlighting the potential of this scaffold in therapeutic development.