Sulfenylcarbene-Mediated Carbon Atom Insertion for the Late-Stage Functionalization of N-Heterocycles

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. We harness the chemoselectivity of sulfenylcarbenes, which selectively react with alkenes even in the presence of more reactive functional groups such as alcohols, carboxylic acids, and amines. This reactivity allows sulfenylcarbenes to insert a single carbon atom bearing diverse functional groups, transforming pyrroles, indoles, and imidazoles into synthetically challenging pyridines, quinolines, and pyrimidines, respectively. Sulfenylcarbene precursors are easily synthesized in two steps from commercially available reagents. Our metal-free LSF approach employs benchtop-stable sulfenylcarbene precursors and enables late-stage modification of natural products, amino acids, pharmaceuticals, and C-glycosides. Mechanistic studies and density functional theory (DFT) calculations were conducted to investigate the regio- and chemoselectivity outcomes.