康 · 学术｜Reaction of the Day No. 1441

转自：康龙化成

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

Prakash Kafle, Deacon Herndon, and Indrajeet Sharma*

Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019-5251, United States

—J. Am. Chem. Soc. 2025, org/10.1021/jacs.5c02012.

Recommended by Bingbing Chang_ MC5

KEY WORDS: skeletal editing, Late-stage functionalization (反应类型), pyrroles, indoles, imidazoles,sulfenylcarbene(原料), pyridines, quinolines, pyrimidines (产物)

ABSTRACT: 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. Indrajeet Sharma et alharness 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. Their 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- andchemoselectivity outcomes.

Reaction Development

FunctionalizedSulfenylcarbenes, Scope, and Regioselectivity of Pyrroles

Application to Indoles (selected examples)

Scope ofImidazoles

These benchtop-stable sulfenylcarbene precursorscan be synthesized on a large scale, highlighting their potential for commercial use. This metal-free non-diazo approach, mild reaction conditions, simple operational protocol, high chemoselectivity, and excellent functional group tolerancemake sulfenylcarbenes particularly advantageous. Their capability for late-stage functionalization to generate novel chemical entities presents promising opportunities for exploring uncharted chemical space in drug discovery.

（转自：康龙化成）