Ligand-enabled hydrohydrazidation of alkynes catalyzed by unsymmetrical gold(i)–thiazol-2-ylidenes

Abstract

Acyl hydrazines represent a privileged class of amide derivatives in organic synthesis and drug discovery; however, methods for effecting site-selective hydrohydrazidation remain underdeveloped. Herein, we report highly selective Au(I)–NHC-catalyzed (NHC = N-heterocyclic carbene) addition of acyl hydrazines to alkynes made feasible by the development of gold(I) complexes of “half-umbrella” shaped thiazole-derived N-heterocyclic carbenes. This method exhibits a broad substrate scope and functional group tolerance for the synthesis of acyl hydrazones, including highly challenging late-stage hydrohydrazidation of pharmaceuticals. Structural and extensive DFT studies demonstrate the beneficial effect of thiazol-2-ylidenes in systematic lowering of activation barriers for rate-determining nucleophilic addition and proton transfer steps. The study provides an efficient approach to synthesize privileged hydrazide motifs and establishes thiazolium-derived carbenes as highly effective catalysts in gold-catalyzed π-activation chemistry.