Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific SuFEx Reaction

Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, NBoc-sulfinamide salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemized by fluoride ions. Conditions are developed which trap fluoride, and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100% es) generating sulfonimidamides with up to 99% ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalization reactions, exemplified by coupling with a selection of complex amines in marketed drugs.