Inverting Conventional Chemoselectivity of Metal Carbenes with Sulfenylcarbenes for Late-Stage Functionalizations

Late-stage functionalization (LSF) is a crucial strategy in drug discovery, allowing the modification of complex molecules, including pharmaceuticals, to enhance chemical diversity in drug libraries. In this study, we leverage the unique reactivity of sulfenylcarbenes, which exhibit inverse chemoselectivity compared to metal carbenes. Notably, they selectively react with alkenes in the presence of more reactive functionalities like alcohols, carboxylic acids, and amines. This reactivity allows sulfenylcarbenes to insert a single carbon atom bearing diverse functional groups, transforming pyrrole, indole, and imidazole scaffolds into synthetically challenging pyridines, quinolines, and pyrimidines, respectively. Our metal-free LSF approach employs benchtop-stable sulfenylcarbene precursors compatible with various functional groups and enables late-stage modification of natural products, amino acids, and pharmaceuticals. Mechanistic studies and DFT calculations were conducted to investigate the regioselectivity outcomes.