Transition-metal-catalyzed cross-coupling reactions of thioesters by selective acyl C(O)-S cleavage have emerged as a powerful platform for the preparation of complex molecules. Herein, we report divergent Liebeskind-Srogl cross-coupling of thioesters by Pd-NHC (NHC = N-heterocyclic carbene) catalysis. The reaction provides straightforward access to functionalized ketones by highly selective C(acyl)-S cleavage under mild conditions. Most crucially, the conditions enable direct functionalization of a range of complex pharmaceuticals decorated with a palette of sensitive functional groups, providing attractive products for medicinal chemistry programs. Furthermore, decarbonylative Liebeskind-Srogl cross-coupling by C(acyl)-S/C(aryl)-C(O) cleavage is reported. Cu metal cofactor directs the reaction pathway to acyl or decarbonylative pathway. This reactivity is applicable to complex pharmaceuticals. The reaction represents the mildest decarbonylative Suzuki cross-coupling discovered to date. The Cu-directed divergent acyl and decarbonylative cross-coupling of thioesters opens up chemical space in complex molecule synthesis.
Keywords: C–S activation; Liebeskind-Srogl; N-heterocyclic carbenes; Pd–NHCs; acyl coupling; biaryls; cross-coupling.