SO ₂ F ₂ ‐Mediated Cascade Skeletal Rearrangement via Concomitant N─O Bond Cleavage and C─N Bond Formation

Abstract A simple, mild, and practical method for the direct synthesis of N‐hydroxyureas from commercially available Boc‐protected hydroxylamine (BocNHOH) and amines has been developed. This one‐pot protocol utilizes sulfuryl fluoride (SO 2 F 2 ) and a base to efficiently promote the coupling reaction, which proceeds under remarkably mild conditions. The methodology demonstrates excellent functional group compatibility, accommodating a wide range of aliphatic and aromatic amines, including those bearing sensitive substituents, to afford the desired N‐hydroxyurea products in good to excellent yields. A plausible reaction mechanism was proposed, involving a SO 2 F 2 ‐promoted Lossen rearrangement of BocNHOH. This key step generates a highly reactive tert‐butoxy isocyanate intermediate in situ, which is subsequently trapped by the amine nucleophile to form the N‐hydroxyurea framework after workup. The practicality and scalability of this strategy were convincingly demonstrated through a one‐pot gram‐scale synthesis of N‐(2,5‐dimethylphenyl)‐N’‐hydroxyurea, a key precursor to important carbonic anhydrase inhibitors (CAIs). This operationally simple method provides a robust and versatile new strategy for the synthesis of N‐hydroxyureas, which are privileged scaffolds in medicinal chemistry and drug discovery.