Biocompatible SuFEx Click Chemistry: Thionyl Tetrafluoride (SOF 4 )‐Derived Connective Hubs for Bioconjugation to DNA and Proteins

We report here the development of a suite of biocompatible SuFEx transformations from the SOF 4 ‐derived iminosulfur oxydifluoride hub in aqueous buffer conditions. These biocompatible SuFEx reactions of iminosulfur oxydifluorides (R‐N=SOF 2 ) with primary amines give sulfamides (8 examples, up to 98 %), while the reaction with secondary amines furnish sulfuramidimidoyl fluoride products (8 examples, up to 97 %). Likewise, under mild buffered conditions, phenols react with the iminosulfur oxydifluorides (Ar‐N=SOF 2 ) to produce sulfurofluoridoimidates (13 examples, up to 99 %), which can themselves be further modified by nucleophiles. These transformations open the potential for asymmetric and trisubstituted linkages projecting from the sulfur(VI) center, including versatile S−N and S−O connectivity (9 examples, up to 94 %). Finally, the SuFEx bioconjugation of iminosulfur oxydifluorides to amine‐tagged single‐stranded DNA and to BSA protein demonstrate the potential of SOF 4 ‐derived SuFEx click chemistry in biological applications.