A Toolbox of Reagents for Trifluoromethylthiolation: From Serendipitous Findings to Rational Design

Two types of electrophilic trifluoromethylthiolating reagents were developed in the past 10 years in our laboratory. The development of the first type of reagent, trifluoromethanesulfenate I, which is highly reactive toward a variety of nucleophiles, was based on an unexpected discovery in the initial design for the development of an electrophilic trifluoromethylthiolating reagent with a hypervalent iodine skeleton. A structure–activity study disclosed that α-cumyl trifluoromethanesulfenate (reagent II) without the iodo substituent is equally effective. Subsequent derivatization let us develop an α-cumyl bromodifluoromethanesulfenate III that could be used for the preparation of [18F]ArSCF3. To remediate the low reactivity of the type I electrophilic trifluoromethylthiolating reagent for Friedel–Crafts trifluoromethylthiolation of electron-rich (hetero)arenes, we designed and prepared N-trifluoromethylthiosaccharin IV, which exhibits broad reactivity toward various nucleophiles, including electron-rich arenes. A comparison of the structure of N-trifluoromethylthiosaccharin IV with that of N-trifluoromethylthiophthalimide showed that the replacement of one carbonyl group in N-trifluoromethylthiophthalimide with a sulfonyl group made N-trifluoromethylthiosaccharin IV much more electrophilic. Thus, the replacement of both carbonyls with two sulfonyl groups would further increase the electrophilicity. Such a rationale prompted us to design and develop the current most electrophilic trifluoromethylthiolating reagent, N-trifluoromethylthiodibenzenesulfonimide V, and its reactivity was much higher than that of N-trifluoromethylthiosaccharin IV. We further developed an optically pure electrophilic trifluoromethylthiolating reagent, (1S)-(−)-N-trifluoromethylthio-2,10-camphorsultam VI, for the preparation of optically active trifluoromethylthio-substituted carbon stereogenic centers. Reagents I–VI now constitute a powerful toolbox for the introduction of the trifluoromethylthio group into the target molecules.