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Ni-electrocatalytic Csp3–Csp3 doubly decarboxylative coupling

Nature volume 606, pages 313–318 (2022)Cite this article

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Abstract

Cross-coupling between two similar or identical functional groups to form a new C–C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling1,2. The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C–C bond3,4,5,6,7,8,9,10,11,12. As one of the oldest known Csp3–Csp3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates13. In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century5, thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%.

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Fig. 1: Kolbe heterocoupling simplifies synthesis.
Fig. 2: Reaction detail.
Fig. 3: Control studies and ligand analysis.

Data availability

The data that support the findings in this work are available within the paper and Supplementary Information.

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Acknowledgements

We are grateful to D.-H. Huang and L. Pasternack (Scripps Research) for nuclear magnetic resonance spectroscopic assistance. Financial support for this work was provided by National Science Foundation Center for Synthetic Organic Electrochemistry (CHE-2002158), and the National Institutes of Health (grant number GM-118176).

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Author notes

  1. These authors contributed equally: Benxiang Zhang, Yang Gao

Authors and Affiliations

  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Benxiang Zhang, Yang Gao, Yuta Hioki, Kevin X. Rodriguez, Hai-Jun Zhang, Yu Kawamata & Phil S. Baran

  2. Department of Discovery Synthesis, Bristol Myers Squibb, Research & Early Development, Princeton, NJ, USA

    Martins S. Oderinde

  3. Discovery Chemistry, Bristol Myers Squibb Company, Princeton, NJ, USA

    Jennifer X. Qiao

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Contributions

Conceptualization was done by B.Z., Y.K. and P.S.B. Experimental investigation was carried out by B.Z., Y.G., Y.H., M.S.O., J.X.Q., K.X.R., H.-J.Z. and Y.K. Data analysis was done by B.Z., Y.G., Y.H., M.S.O., J.X.Q., K.X.R., H.-J.Z., Y.K. and P.S.B. The manuscript was written by B.Z., Y.G., Y.K. and P.S.B. Finance was acquired by P.S.B. Project administration was done by Y.K. and P.S.B. Supervision was carried out by P.S.B.

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Correspondence to Phil S. Baran.

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Nature thanks Scott Bagley, Kevin Lam and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

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Supplementary Data

Source data for radical clock study.

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Zhang, B., Gao, Y., Hioki, Y. et al. Ni-electrocatalytic Csp3–Csp3 doubly decarboxylative coupling. Nature 606, 313–318 (2022). https://doi.org/10.1038/s41586-022-04691-4

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