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Nickel-electrocatalysed C(sp3)–C(sp3) cross-coupling of unactivated alkyl halides

Nature Catalysis volume 7, pages 412–421 (2024)Cite this article

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Abstract

The C(sp3)–C(sp3) linkages are undoubtedly important in natural products, pharmaceuticals and organic compounds. Electrochemical cross-electrophile coupling with a broad range of available alkyl halides is an attractive and useful strategy for the construction of C(sp3)–C(sp3) bonds, although success could only be seen on activated alkyl halides in previous reports, due to the great challenge of reactivity and selectivity control of unactivated alkyl halides. Here we report a general strategy for electrochemical cross-electrophile coupling of unactivated alkyl halides under nickel catalysis. The highly selective electrochemical cross-electrophile coupling process was carried out in an operationally simple manner with high selectivity, setting the stage for the challenging C(sp3)–C(sp3) bonds construction with versatile unactivated alkyl halides, including the cross-coupling of primary–primary halides, primary–secondary halides, primary–tertiary halides and secondary–secondary halides with high selectivity and excellent functional group compatibility. The diverse products, as well as the various late-stage modifications of bio-relevant compounds, demonstrated its potential use in organic synthesis and pharmaceutical chemistry.

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Fig. 1: Cross-coupling for the construction of C(sp3)–C(sp3) bonds.
Fig. 2: Substrate scope for the nickel-catalysed eXEC system.
Fig. 3: Application for the nickel-catalysed eXEC system.
Fig. 4: Mechanistic studies.
Fig. 5: Radical-trapping experiments and proposed mechanism.

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Data availability

The data that support the findings in this work are available within the paper and Supplementary Information or from the authors upon reasonable request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 2285024. These data can be obtained free of charge via www.ccdc.cam.ac.uk/structures/.

Code availability

The Python code used for kinetic simulations is made available in Supplementary Information, or in the GitHub repository (https://github.com/TMSCN/Computational_Chemistry_Utils/tree/main/Kinetic_Simulation), or is available from the corresponding author upon reasonable request.

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Acknowledgements

Financial support from National Key R&D Program of China (2022YFA1503200 to Y.A.Q.), National Natural Science Foundation of China (grant no. 22371149, 22188101 to Y.A.Q.), the Fundamental Research Funds for the Central Universities (no. 63223015 to Y.A.Q.) and Frontiers Science Center for New Organic Matter, Nankai University (grant no. 63181206 to Y.A.Q.). State Key Laboratory of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, and College of Chemistry in Nankai University are gratefully acknowledged. We are sincerely grateful to Q.-L. Zhou for his generous and key support. We thank group members for checking the data and repeating the results of this work.

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Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, China

    Pengfei Li, Zile Zhu, Chengcheng Guo, Guangsheng Kou, Siyi Wang, Pengfei Xie, Dengke Ma, Tian Feng, Yanwei Wang & Youai Qiu

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Contributions

Y.Q. supervised the project, and provided guidance on the project. Y.Q. and P.L. conceived and designed the study. P.L., C.G., G.K. and P.X. performed the experiments. P.L., S.W. and Y.W. performed mechanistic studies. Z.Z. conducted the DFT calculations. P.L., Y.Q., D.M. and T.F. wrote and revised the paper. All authors contributed to the analysis and interpretation of the data.

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Correspondence to Youai Qiu.

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Nature Catalysis thanks Chen Zhu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Figs. 1–20, Methods, References and Tables 1–15.

Supplementary Data 1

Cartesian coordinate.

Supplementary Data 2

Code of kinetic simulation.

Supplementary Data 3

Crystallographic data.

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Li, P., Zhu, Z., Guo, C. et al. Nickel-electrocatalysed C(sp3)–C(sp3) cross-coupling of unactivated alkyl halides. Nat Catal 7, 412–421 (2024). https://doi.org/10.1038/s41929-024-01118-3

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