Copper Catalysis with Arynes: Unlocking Site-Selective Arylation of Pyrazoles

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.