摘要：Fei-Fei Tong, Xiao-Tian Feng, Yuan-Zhan Han, Ming-Chen Huang, Hai-Yang Zhao, and Xingang Zhang*

转自：康龙化成

Nickel-Catalyzed Umpolung Difluoroalkylation of Imines Enables General Access to β-Difluoroalkylated Amines

Fei-Fei Tong, Xiao-Tian Feng, Yuan-Zhan Han, Ming-Chen Huang, Hai-Yang Zhao, and Xingang Zhang*

State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

—Angew. Chem. Int. Ed., 2025, 10.1002/anie.202500990.

Recommended by Shi Li_MOC

KEYWORDS:Ni catalysisUmpolung reaction, difluoroalkylation(反应类型), imine, difluoroalkyl bromides, difluoroalkyl iodides (原料), β-difluoroalkylated amines (产物), C(sp3)–C(sp3) (成键类型)

ABSTRACT: Fluoroalkylated amines play a pivotal role in medicinal chemistry, yet the general and efficient synthesis of β-difluoroalkylated amines remains elusive. Here, X-G. Zhang group developed a nickel-catalyzed umpolung strategy that enables the difluoroalkylation of 2-azaallyl anions generated from aliphatic and aromatic imines, effectively overcoming the previous limitations. By inverting the polarity of imines, this strategy allows for the coupling of a variety of readily accessible difluoroalkyl bromides and iodides. This approach is characterized by its high efficiency, broad substrate scope, high functional group tolerance, and ease of synthesis. The rapid modification of bioactive molecules by the efficient synthesis of difluorinated analogs of key amine moieties present in bioactive molecules, including amphet amine, using the current approach shows the promising potential of this protocol in advancing drug discovery and development.

Background

Synthetic scope

Proposed mechanism

Prof. X-G. Zhang et al developed a nickel-catalyzed umpolung difluoroalkylation of imines, providing a general and efficient route to a diverse range of β-difluoroalkylated amines.This reaction leverages the cross-coupling between readily available difluoroalkyl halides and in situ-generated 2-azaallyl lithiums from imines, featuring high efficiency, broad substrate scope, high functional group tolerance, and synthetic convenience. The capability of precise introduction of the CF₂ group into the amine not only expands the synthetic toolbox for the preparation of β-difluoro alkylated amines but also addresses the challenges that have historically hindered the efficient synthesis of these valuable compounds. The significance of this approach is further highlighted by its ability to rapidly access difluorinated analogs of amine frameworks in bioactive molecules, such as difluorinated amphetamine, a valuable building block for pharmaceutical applications, showing the prospect of medicinal chemistry.

来源：新浪财经