Modular synthesis of CF<sub>2</sub>-containing compounds with PhSO<sub>2</sub>CF<sub>2</sub>H reagent through difluoromethylene radical anion synthon strategy.

Sun, Shuo; Jia, Rulong; Zhou, Xin; Wang, Zhongyi; Rong, Jian; Ni, Chuanfa; Hu, Jinbo · Nat Commun · 2025

basic_science · Level V

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Abstract

Difluoromethylene moiety has gained widespread applications in pharmaceuticals, agrochemicals, and materials owing to its augmented lipophilicity and being bioisosteric to ethereal oxygen. Possessing two orthogonal reactivity modes for bridging an electrophile and a radical acceptor to give gem-difluorides (R<sup>1</sup>-CF<sub>2</sub>-R<sup>2</sup>), the efficient difluoromethylene radical anion synthon (diFRAS) has been long sought after. In this work, we successfully utilize the readily available difluoromethyl phenyl sulfone (PhSO<sub>2</sub>CF<sub>2</sub>H) to couple with electrophiles and radical acceptors, thereby enabling PhSO<sub>2</sub>CF<sub>2</sub>H to serve as a novel diFRAS in organic synthesis. The generation of radicals (•CF<sub>2</sub>R) via visible light-promoted homolytic cleavage of C-S bonds in (phenylsulfonyl)difluoromethylated derivatives (PhSO<sub>2</sub>CF<sub>2</sub>R) is the linchpin in the diFRAS strategy to construct gem-difluorides (R<sup>1</sup>-CF<sub>2</sub>-R<sup>2</sup>) with structural complexity.