Discovery of a Distinctive Reagent for Divergent AreneTrifluoromethylsulfinylation

Simple and direct arene trifluoromethylsulfinylation is highly desirable in drug design but remains a major challenge. Herein, we report a modular, mild, innate C–H trifluoromethylsulfinylation of a wide variety of arenes via a distinctive trifluoromethylsulfinylating reagent <i>N</i>-hydroxyphthalimide-<i>O</i>-trifluoromethanesulfinate following divergent efficient pathways. This trifluoromethylsulfinylation can be conducted in a redox-neutral manner at room temperature with light-, metal-, and photocatalyst-free mild conditions. Mechanistic studies and density functional theory (DFT) calculations revealed that the success of this approach hinges upon the design of an activated trifluoromethanesulfite ester that proceeds via homolytic cleavage with a very low bond dissociation energy to generate a dummy aminoxyl radical (PINO) and active CF₃S(O) radical, which could accidentally be transformed into a trifluoromethanesulfonic anhydride, CF₃S(O)OS(O)CF₃, for the transfer of the S(O)CF₃ group into an exemplary set of strong EDG-substituted arenes. DFT computation corroborates that this novel reagent can be activated by TfOH via heterolytic cleavage to produce highly active CF₃S(O)OTf, which is responsible for electrophilic trifluoromethylsulfinylation of the challenging weak EDG-substituted arene substrates through an electrophilic addition–elimination mechanism. Such C–H functionalization using <i>N</i>-hydroxyphthalimide-<i>O</i>-trifluoromethanesulfinate affords an innovative strategy and marked improvement over functionalization with previously developed reagents. Notably, simple and mild conditions, broad reactivities, good functional group compatibility, divergent reaction modes (homolysis and heterolysis), as well as late-stage trifluoromethylsulfinylation (LST) of complex biologically active molecules in these reactions underline the great potential of <i>N</i>-hydroxyphthalimide-<i>O</i>-trifluoromethanesulfinate for the preparation of functionalized drug-like molecules.