Zirconium-Catalyzed Reductive Sulfonamidation of Amides and Its Application to Site-Selective <i>N</i>-Alkylation of Pharmaceuticals

The direct catalytic reductive amination of amides remains a challenging transformation, particularly when using weakly nucleophilic amines. However, this strategy offers several synthetic advantages, particularly due to the wide availability of amides, as well as <i>N</i>-sulfonyl and <i>N</i>-sulfinyl amines. We present a mild catalytic approach for the monoalkylation of sulfonamides, sulfamates, sulfamides, and sulfinamides using amides. This protocol exploits the oxophilic character of zirconium, an early, earth-abundant metal, to drive dual reductive cycles and enable the critical amination step. This chemistry is carried out at room temperature using just 10 mol % of Cp₂ZrCl₂ in combination with hydrosilane reductant, yielding products in up to 94% isolated yield with excellent selectivity. This chemistry enables site-selective monoalkylation of sulfonamides, including examples of late-stage <i>N</i>-alkylation in pharmaceutical applications.