An SN2 Reaction at Amide Nitrogen Enables Hydrazide Synthesis

Abstract Nucleophilic substitutions are fundamentally important transformations in synthetic organic chemistry. Despite the substantial advances in bimolecular nucleophilic substitutions (S N 2) at saturated carbon centers, analogous S N 2 reaction at the amide nitrogen atom remains extremely limited. Here we report an S N 2 substitution method at the amide nitrogen atom with amine nucleophiles for nitrogen–nitrogen (N−N) bond formation that leads to a novel strategy toward biologically and medicinally important hydrazide derivatives. We found the use of sulfonate‐leaving groups at the amide nitrogen atom played a pivotal role in the reaction. This new N−N coupling reaction allows the use of O ‐tosyl hydroxamates as electrophiles and readily available amines, including acyclic aliphatic amines and saturated N ‐heterocycles as nucleophiles. The reaction features mild conditions, broad substrate scope (>80 examples), excellent functional group tolerability, and scalability. The method is applicable to late‐stage modification of various approved drug molecules, thus enabling complex hydrazide scaffold synthesis.