Electrosynthesis of 1,1-Bis(difluoromethyl)alkenes via Twofold C-H Difluoromethylation as Bioisosteres of Elusive 1,1-Enediols.
basic_science · Level V
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- Record sourced from PubMed, PMID 42161973.
- Also identified by DOI 10.1038/s41467-026-73526-x.
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Abstract
Geminal bis(difluoromethyl)alkenes, featuring two CF<sub>2</sub>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 strategy that enables the direct conversion of 1,1-diarylalkenes into geminal bis(difluoromethyl)alkenes under mild oxidative conditions. This transformation relies on the use of Zn(CF<sub>2</sub>H)<sub>2</sub>(DMPU)<sub>2</sub> as a difluoromethyl radical precursor in combination with ZnCl<sub>2</sub>, allowing twofold C(sp²)-H difluoromethylation without transition-metal catalysis. The method exhibits broad functional-group tolerance and accommodates complex molecular scaffolds. Mechanistic studies indicate that the reaction proceeds through sequential CF<sub>2</sub>H radical additions followed by oxidation-induced carbocation formation and elimination. Voltammetric analysis further reveals that ZnCl<sub>2</sub> moderates electrode potentials and suppresses side reactions, facilitating sequential difluoromethylation. This electrosynthetic platform provides a general and practical entry to stable 1,1-bis(difluoromethyl)alkene architectures, expanding the toolbox of CF<sub>2</sub>H-based bioisosteres for medicinal chemistry.