Modular synthesis of CF2-containing compounds with PhSO2CF2H reagent through difluoromethylene radical anion synthon strategy
Shuo Sun, Rulong Jia, Xin Zhou, Zhongyi Wang, Jian Rong, Chuanfa Ni, Jinbo Hu
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 (R1-CF2-R2), the efficient difluoromethylene radical anion synthon (diFRAS) has been long sought after. In this work, we successfully utilize the readily available difluoromethyl phenyl sulfone (PhSO2CF2H) to couple with electrophiles and radical acceptors, thereby enabling PhSO2CF2H to serve as a novel diFRAS in organic synthesis. The generation of radicals (•CF2R) via visible light-promoted homolytic cleavage of C−S bonds in (phenylsulfonyl)difluoromethylated derivatives (PhSO2CF2R) is the linchpin in the diFRAS strategy to construct gem-difluorides (R1-CF2-R2) with structural complexity. Difluoromethylene moiety is widely used in industry, though it is challenging to generate difluoromethylene radical anion synthons. Here the authors show a method to generate these radicals from difluoromethyl phenyl sulfone, triggered by the cleavages of C-S bonds.