Nickel‐Catalyzed Umpolung Difluoroalkylation of Imines Enables General Access to β‐Difluoroalkylated Amines
Abstract
Abstract Fluoroalkylated amines play a pivotal role in medicinal chemistry, yet the general and efficient synthesis of β‐difluoroalkylated amines remains elusive. Here, we 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 amphetamine, using the current approach shows the promising potential of this protocol in advancing drug discovery and development.
Article Details
Authors (6)
Fei‐Fei Tong
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
Xiao‐Tian Feng
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
Yuan‐Zhan Han
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
Ming‐Chen Huang
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
Hai‐Yang Zhao
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
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