Catalytic SuFEx Reactivity of Sulfonimidoyl Fluorides with Functionalized Amines with Automation Applicable Conditions

Sulfonimidamides have emerged as attractive chemical motifs in drug discovery and as sulfonamide bioisosteres that can offer improved pharmacokinetic and physiochemical properties. Here we report a mild SuFEx reaction of sulfonimidoyl fluorides using HOBt as a nucleophilic catalyst that is applicable to automated array technologies. A diverse set of sulfonimidamides was prepared with functionalized amines and sulfonimidoyl fluorides, with variation in carbon and nitrogen-substituents. Moreover, the discovery and utilization of SNAr reactivity of a fluoroaryl-sulfonimidoyl fluoride under modified conditions, occurring in the presence of the sulfonimidoyl fluoride functionality, allowed for the divergent generation of sulfonimidoyl fluoride reagents. Orthogonal SNAr or SuFEx processes are achieved highly chemoselectively, as well as sequentially in one-pot. A further 24-compound array was generated using an automated reaction set-up and purification.