Catalytic electrophilic arene C-H chlorination by rethinking the century-old Willgerodt reagent.

An elusive variant of the Willgerodt reagent (III) with anticipated high electrophilicity has been successfully synthesized and unambiguously characterized by both nuclear magnetic resonance (NMR) and single-crystal X-ray crystallography. Compared to previous I-Cl type λ3-iodanes, this compound has an unusually short I-Cl bond length due to the weak trans-influencing endocyclic sulfonate moiety, and this feature endows III with significantly enhanced reactivity in arene electrophilic C-H chlorination reactions. Here we show that C-H chlorination of deactivated arenes is achieved catalytically via in situ formation of III from readily available 2-iodobenzenesulfonic acid. 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.