BF <sub>3</sub> -Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling
E. Ali McKnight, Ramon Arora, Ekadashi Pradhan, Yuriko H. Fujisato, Ayonitemi J. Ajayi, Mark Lautens, Tao Zeng, Christine M. Le
Abstract
A BF 3 -catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides is reported. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C–F bonds through a halide recycling mechanism. The developed method provides access to 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivatives of known protein kinase inhibitors. Experimental and computational studies support a stepwise mechanism for the fluorocarbamoylation reaction involving a turnover-limiting cyclization step, followed by internal fluoride transfer from a BF 3 -coordinated carbamoyl adduct. For methylene oxindoles, a thermodynamically driven Z–E isomerization is facilitated by a transition state with aromatic character. In contrast, this aromatic stabilization is not relevant for γ-lactams, which results in a higher barrier for isomerization and the exclusive formation of the Z -isomer.