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<p>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.</p>

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Electrosynthesis of 1,1-Bis(difluoromethyl)alkenes via Twofold C−H Difluoromethylation as Bioisosteres of Elusive 1,1-Enediols

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Seonyoung Kim,
  • Eunji Kwon,
  • Sung Bum Park,
  • Areum Park,
  • Hyuk Lee,
  • Hyunwoo Kim

摘要

Geminal bis(difluoromethyl)alkenes, featuring two CF2H 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(CF2H)2(DMPU)2 as a difluoromethyl radical precursor in combination with ZnCl2, 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 CF2H radical additions followed by oxidation-induced carbocation formation and elimination. Voltammetric analysis further reveals that ZnCl2 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 CF2H-based bioisosteres for medicinal chemistry.