Abstract
The importance of constructing Csp2–Csp3 bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here we show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl–aryl couplings, including those that were previously unknown. These reactions rely on the discovery of unusually persistent organonickel complexes that serve as stoichiometric platforms for C(sp2)–C(sp3) coupling. Aryl, heteroaryl or vinyl complexes of Ni can be inexpensively prepared on a multigram scale by mild electroreduction from the corresponding C(sp2) electrophile. Organonickel complexes can be isolated and stored or telescoped directly to reliably diversify drug-like molecules. Finally, the procedure was miniaturized to micromole scales by integrating soluble battery chemistries as redox initiators, enabling a high-throughput exploration of substrate diversity.
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Data availability
All experimental data, copies of spectra and crystallographic data are available in the Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition no. CCDC 2290873 (complex 1). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
We thank the National Institutes of Health (NIH R35 GM138373) and the Alfred P. Sloan Research Fellowship for supporting this work.
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L.P.D., T.B.H. and C.S.S. conceived the work and designed the experiments. L.P.D., H.F.S., T.B.H., M.J.L. and D.K. performed all experiments and collected all data. L.P.D. and H.F.S. performed all high-throughput reactions. L.P.D. and C.Q.H. performed parameterization studies. All authors analysed the data. C.S.S. wrote the paper, and all authors provided revisions.
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L.P.D., T.B.H., H.F.S. and C.S.S. have filed patent applications directed to the technology described here. The other authors declare no competing interests.
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Supplementary Information
Supplementary Figs. 1–24, X-ray crystal structure, all synthetic procedures and NMR spectra.
Supplementary Data 1
Crystallographic data for complex 1; CCDC reference 2290873.
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Dinh, L.P., Starbuck, H.F., Hamby, T.B. et al. Persistent organonickel complexes as general platforms for Csp2–Csp3 coupling reactions. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01528-7
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DOI: https://doi.org/10.1038/s41557-024-01528-7
