Work

Hydrocyclization/Defluorination of CF 3 ‐Substituted Acrylamides: Insights from Kinetics of Hydrogen Atom Transfer

Year: 2025

Type: article

Abstract: The introduction of F‐containing groups into organic molecules can significantly alter their physical and chemical properties. Particularly, gem ‐difluoroalkenes serve as versatile precursors for a broad variety of organofluorine compounds, commonly used in agrochemicals, pharmaceuticals, and materials science. Based on the kinetics of H• transfer to acrylamide ( k H = 2.28 × 10 −4 M −1 s −1 at 300 K in toluene), the study describes a nickel‐hydride‐(or Li[BEt 3 H]) initiated hydrocyclization/defluorination of CF 3 ‐substituted acrylamides, offering alternative access to 4‐fluorovinyl‐substituted 2‐pyrrolidones (Seletracetam derivatives that are antiepileptic drug candidates). This process proceeds with high yields and remarkable chemo‐ and regioselectivity. The hydrocyclization/defluorination can be initiated by either H• or H – transfer, followed by a 5‐exo‐trig cyclization and subsequent fluorine elimination. The strategy has been applied in the late‐stage functionalization of drug molecules, providing a valuable tool in the synthesis of pharmaceutical compounds.

Source: Advanced Science

DOI: 10.1002/advs.202501799

Authors: Yanjun Wan, Ronghui Shao, Jack R. Norton

Institutions: Zhejiang University of Technology, Nankai University, Columbia University

Language: English

Topic: Fluorine in Organic Chemistry

Subfield: Pharmaceutical Science

Field: Pharmacology, Toxicology and Pharmaceutics

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,730

Funder: U.S. Department of Energy