Catalytic Electrophilic Arene C–H Chlorination by Rethinking of the Century-old Willgerodt Reagent

A highly anticipated yet elusive variant of the Willgerodt reagent, III , has been successfully synthesized and characterized unambiguously by both nuclear magnetic resonance (NMR) and single-crystal X-ray crystallography. Compared to previous I–Cl type λ ³ -iodanes, this compound has an unusually short I–Cl bond length due to the trans-influence of the endocyclic sulfonate moiety, and this feature endows III with significantly enhanced reactivity in arene electrophilic C–H chlorination reactions. A catalytic C–H chlorination of deactivated arenes via in situ formation of III is achieved with catalytical amount of readily available 2-iodobenzenesulfonic acid as the precursor of III . The relative mildness of this protocol has been showcased by the late-stage chlorinations of various highly functionalized drugs and natural products. Mechanistic studies as well as density functional theory (DFT) calculations are carried out to shed light on the origin of the enhanced reactivity in electrophilic arene C–H chlorination.