Divergent Acyl and Decarbonylative Liebeskind-Srogl Cross- Coupling of Thioesters by Cu-Cofactor and Pd-NHC (NHC = N-Heterocyclic Carbene) Catalysis

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 function-alization 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 an acyl or a 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.

Automated summary

Transition-metal-catalyzed cross-coupling reactions of thioesters by selective acyl C(O)-S cleavage have been developed as a powerful strategy for the synthesis of complex molecules. In this study, a divergent Liebeskind-Srogl cross-coupling of thioesters was achieved using Pd-NHC catalysis, enabling the direct synthesis of functionalized ketones under mild conditions. The reaction also allowed for the functionalization of complex pharmaceuticals with sensitive functional groups, providing attractive products for medicinal chemistry programs. Furthermore, a decarbonylative Liebeskind-Srogl cross-coupling by C(acyl)-S/C(aryl)-C(O) cleavage was reported, which represents the mildest decarbonylative Suzuki cross-coupling discovered to date.