Full-Spectrum Fluoromethyl Sulfonation via Modularized Multicomponent Coupling

Abstract

Modular free-assembly construction of mono-, di-, and tri-fluoromethyl sulfones was comprehensively achieved by a combination of halides, a sulfur dioxide surrogate, and halofluorocarbons. The industrial raw material thiourea dioxide served as the sulfur dioxide source, combined with readily available fluorocarbon sources such as 2-bromo-2- fluoroacetate and chlorodifluoromethane (ClCF2H, Freon) employed as fluoromethyl reagents. Notably, four methyl sulfone-containing pharmaceuticals were modified into three types of fluoromethyl sulfones, displaying their great potential for drug discovery via the current strategy. Mechanistic studies further demonstrated that C-F H-N interactions between thiourea dioxide and halofluorocarbons play a key role in stabilizing monofluoromethyl electrophiles and difluorocarbene species.