A Multifunctional Sulfur(VI) Fluoride for SuFEx Reactions: <i>N</i> ‐CF ₂ H Sulfamoyl Fluorides

ABSTRACT Sulfur(VI) fluorides based on sulfur(VI) fluoride exchange (SuFEx) chemistry have demonstrated their unique versatility and high efficiency in the field of medicinal chemistry. Acting as both covalent and hydrogen bond donors, the novel N ‐CF 2 H sulfamoyl fluoride will enhance the binding strength between drugs and receptors in organism, thereby injecting new vitality into the research of targeted drugs. Herein, we report the two‐step synthesis of N ‐CF 2 H sulfamoyl fluorides from primary amines via successive fluorosulfonylation and insertion of difluorocarbene. This method shows broad scope, provides a platform for rapidly generating N ‐CF 2 H sulfamoyl fluorides by virtue of the diversity and availability of amines. The stability of N ‐CF 2 H sulfamoyl fluorides was tested in aqueous environment at different pH, showing that most compounds remained &gt;95% intact for 72 h. As a novel SuFEx building block, N ‐CF 2 H sulfamoyl fluoride shows chemoselectivity toward phenol and does not react with amines and alcohols. Besides, N ‐CF 2 H sulfamoyl fluorides were subjected to debenzylation and amide‐bond‐formation reactions to generate peptides, Sitagliptin derivative and bioactive alkylamine. Finally, N ‐CF 2 H sulfamoyl fluoride underwent successful F‐18 labeling. With the reported syntheses, we believe that N ‐CF 2 H sulfamoyl fluoride will soon be practically applied in drugs, covalent targeted radioligand, F‐18 PET tracers, electrolyte in general.