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Copper-catalysed difluorocarbene transfer enables modular synthesis

Nature Chemistry volume 15, pages 1064–1073 (2023)Cite this article

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Abstract

The use of metal catalysts to produce and control the reactivity of carbenes has long offered a powerful approach to organic synthesis; however, difluorocarbene transfer catalysed by metal is an outlier and remains a substantial challenge. In that context, copper difluorocarbene chemistry has been elusive so far. Here we report the design, synthesis, characterization and reactivity of isolable copper(I) difluorocarbene complexes, which enable the development of a copper-catalysed difluorocarbene transfer reaction. The method offers a strategy for the modular synthesis of organofluorine compounds from simple and readily available components. This strategy facilitates a modular difluoroalkylation by coupling difluorocarbene with two inexpensive feedstocks, silyl enol ethers and allyl/propargyl bromides, in a one-pot reaction via copper catalysis, providing a diversity of difluoromethylene-containing products without laborious multistep synthesis. The approach enables access to various fluorinated skeletons of medicinal interest. Mechanistic and computational studies consistently reveal a mechanism involving nucleophilic addition to an electrophilic copper(I) difluorocarbene.

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Fig. 1: Metal-catalysed difluorocarbene transfer.
Fig. 2: Characterization and reactivity investigation of the isolated copper(I) difluorocarbenes.
Fig. 3: Transformations of the resulting CF2-containing products.
Fig. 4: Mechanistic studies.
Fig. 5: Computed free-energy profile for the formation of 3 from D2.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2184819 (B1), 2184822 (D1), 2201058 (50) and 2184826 (58). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Experimental procedures, characterization of new compounds and all other data supporting the findings are available in the Supplementary Information.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (21931013 to X.Zhang, 22193072 to X.Zhang, 22122104 to X.-S.X. and 21933004 to X.-S.X.), the National Key R&D Program of China 2021YFF0701700 to X.-S.X. and Q.-Q.M., and the Science and Technology Committee of Shanghai Municipality (21XD1404400 to X.Zhang and 22JC1403500 to X.Zhang). We thank X. Leng and J. Sun at SIOC for the X-ray crystal structure analysis, K.N. Houk at the University of California, Los Angeles, D. O’Hagan at the University of St Andrews, and Y. Xu at the Tongji University for reviewing and editing the paper.

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Authors and Affiliations

  1. Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Xin Zeng, Yao Li, Qiao-Qiao Min, Xiao-Song Xue & Xingang Zhang

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  1. Xin Zeng
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Contributions

X.Zhang and X.Zeng conceived the research concept. X.Zhang directed the project. X.Zeng conducted the experiments. Q.-Q.M. conducted large-scale reactions. Y.L. and X.-S.X. conducted the DFT calculations. X.Zhang wrote the manuscript. All authors reviewed and edited the manuscript.

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Correspondence to Xiao-Song Xue or Xingang Zhang.

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Nature Chemistry thanks R. Baker and Wei Liu for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary text, Figs. 1–28, Tables 1–23, copies of NMR spectra and references.

Supplementary Data 1

Crystallographic data for complex B1; CCDC reference 2184819

Supplementary Data 2

Crystallographic data for complex D1; CCDC reference 2184822

Supplementary Data 3

Crystallographic data for compound 50; CCDC reference 2201058

Supplementary Data 4

Crystallographic data for compound 58; CCDC reference 2184826

Supplementary Data 5

Computational data for DFT calculations

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Zeng, X., Li, Y., Min, QQ. et al. Copper-catalysed difluorocarbene transfer enables modular synthesis. Nat. Chem. 15, 1064–1073 (2023). https://doi.org/10.1038/s41557-023-01236-8

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