Abstract
Arynes are among the most reactive species in organic chemistry-six-membered rings so strained that their energy rivals that of a hand grenade. (1) Since their discovery in 1902, chemists have used arynes to achieve innovative transformations and access diverse natural products, however, their application for catalytic cross-coupling remains unrealized. (2) A major challenge in late-stage functionalization is the selective N -arylation of unsymmetric pyrazoles to create a core found in blockbuster medicines worth over nineteen billion dollars annually. (3) Traditional cross-coupling methods usually favor one type of regioisomer and thus, limit late-stage access to alternatives that could speed up drug discovery. (4,5) Here, we show that copper catalysis harnesses arynes to achieve switchable arylation of pyrazoles. By tuning metallotautomers via ligand choice, we direct N -arylation to either nitrogen site in a pyrazole, unlocking site-selective control. (6,7) Mechanistic studies reveal how steric and electronic forces guide regioselectivity and turn an unpredictable process into a precise synthetic tool.