BF3‑Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling

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Date

2023-05-12

Authors

McKnight, E. Ali
Arora, Ramon
Pradhan, Ekadashi
Fujisato, Yuriko H.
Ajayi, Ayonitemi, J.
Lautens, Mark
Zeng, Tao
Le, Christine M.

Journal Title

Journal ISSN

Volume Title

Publisher

American Chemical Society

Abstract

A BF3-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 BF3-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.

Description

Keywords

fluorocarbamoylation, Lewis acid, halide recycling

Citation

J. Am. Chem. Soc. 2023, 145, 20, 11012–11018