Access to α,α-Difluoro-γ-amino Acids by Nickel-Catalyzed Reductive Aryldifluoroacetylation of N-Vinylacetamide
Qing-Wei Zhao
a
College of Chemistry, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, P. R. of China
,
Zhi-Fang Yang
b
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. of China eMail: xgzhang@mail.sioc.ac.cn
,
Xia-Ping Fu
b
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. of China eMail: xgzhang@mail.sioc.ac.cn
a
College of Chemistry, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, P. R. of China
b
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. of China eMail: xgzhang@mail.sioc.ac.cn
› InstitutsangabenThis work was financially supported by the National Natural Science Foundation of China (21931013, 21672238, 21991122, and 21421002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB20000000).
A nickel-catalyzed reductive aryldifluoroacetylation of N-vinylacetamide with ethyl chloro(difluoro)acetate and aryl iodides is described. This chelating amide carbonyl group-assisted strategy provides rapid access to a variety of protected α,α-difluoro-γ-amino acids that might have potential applications in peptide chemistry and protein engineering. An advantage of this method is its synthetic simplicity, with no preparation of organometallic reagents.
14Ethyl 4-Aryl-4-(acetylamino)-2,2-difluorobutanoates 4a–n; General Procedure
A 25 mL Schlenk tube was charged with N-vinylacetamide (1; 34.0 mg, 0.4 mmol, 1.0 equiv), the appropriate aryl iodide 2 (0.6 mmol, 1.5 equiv), NiCl2·DME (5 mol%), phen (5 mol%), and Zn (2.0 equiv) under an argon atmosphere. DMA (2 mL) was added and the mixture was stirred for 5 min at rt. ClCF2CO2Et (3b; 0.6 mmol, 1.5 equiv) and DMA (2 mL) were then added, the tube was screw-capped, and the mixture was stirred at rt for 12 h. The mixture was then diluted with EtOAc and washed with H2O. The organic phase was dried (Na2SO4), filtered, and concentrated, and the residue was purified by chromatography (silica gel).
