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Electrochemically driven cross-electrophile coupling of alkyl halides

Nature volume 604, pages 292–297 (2022)Cite this article

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Abstract

Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp3 carbons—those bonded to four other atoms—in drug candidates and their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of carbon(sp3)–carbon(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross-coupling—commonly known as cross-electrophile coupling—provides a promising route towards this objective3,4,5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp3)–carbon(sp3) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon–carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.

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Fig. 1: Cross-coupling and XEC for C(sp3)–C(sp3) bond formation.
Fig. 2: Electroreductive coupling of α-halo Bpin with alkyl halides.
Fig. 3: Substrate scope and synthetic application.
Fig. 4: Anode passivation analysis and gram-scale synthesis.

Data availability

All data supporting the findings of this work are available within the paper and its Supplementary Information.

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Acknowledgements

Financial support was provided by NIGMS (R01GM134088; to S.L.), NSF Center for Synthetic Organic Electrochemistry (CHE-2002158; to K.A.S.), and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S.L. is grateful to the Research Corporation for Science Advancement for a Cottrell Scholar Award. This study made use of the NMR facility supported by the NSF (CHE-1531632). XPS data were collected at the Molecular Materials Research Center in the Beckman Institute of the California Institute of Technology. We thank C. Yang for providing propargylic chloride substrates.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

    Wen Zhang, Lingxiang Lu, Yi Wang, Jose Mondragon, Jonas Rein & Song Lin

  2. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA

    Wendy Zhang, Skyler D. Ware & Kimberly A. See

  3. Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA

    Neil Strotman & Dan Lehnherr

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Contributions

S.L. and K.A.S. supervised the project. N.S. and D.L. provided guidance on the project. Wen Zhang and S.L. conceived the work. Wen Zhang, L.L., N.S., D.L. and S.L. designed the experiments. Wen Zhang. and L.L. conducted the synthetic experiments and mechanism studies. Wendy Zhang, S.D.W. and K.A.S. conducted the analysis of electrode passivation. Y.W., J.M. and J.R. conducted the density functional theory calculations. Wen Zhang, L.L., Wendy Zhang, K.A.S. and S.L. wrote the manuscript. N.S., D.L. and S.D.W. edited the manuscript.

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Correspondence to Kimberly A. See or Song Lin.

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Zhang, W., Lu, L., Zhang, W. et al. Electrochemically driven cross-electrophile coupling of alkyl halides. Nature 604, 292–297 (2022). https://doi.org/10.1038/s41586-022-04540-4

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