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Reductive alkyl–alkyl coupling from isolable nickel–alkyl complexes

Nature volume 634, pages 585–591 (2024)Cite this article

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Abstract

The selective cross-coupling of two alkyl electrophiles to construct complex molecules remains a challenge in organic synthesis1,2. Known reactions are optimized for specific electrophiles and are not amenable to interchangeably varying electrophilic substrates that are sourced from common alkyl building blocks, such as amines, carboxylic acids and halides3,4,5. These limitations restrict the types of alkyl substrate that can be modified and, ultimately, the chemical space that can be explored6. Here we report a general solution to these limitations that enables a combinatorial approach to alkyl–alkyl cross-coupling reactions. This methodology relies on the discovery of unusually persistent Ni(alkyl) complexes that can be formed directly by oxidative addition of alkyl halides, redox-active esters or pyridinium salts. The resulting alkyl complexes can be isolated or directly telescoped to couple with a second alkyl electrophile, which represent cross-selective reactions that were previously unknown. The utility of this synthetic capability is showcased in the rapid diversification of amino acids, natural products, pharmaceuticals and drug-like building blocks by various combinations of dehalogenative, decarboxylative or deaminative coupling. In addition to a robust scope, this work provides insights into the organometallic chemistry of synthetically relevant Ni(alkyl) complexes through crystallographic analysis, stereochemical probes and spectroscopic studies.

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Fig. 1: Synthetic approach, synthesis and properties of Ni–alkyl complexes.
Fig. 2: Reactivity of organonickel complexes.
Fig. 3: Application to complex molecules.
Fig. 4: Mechanistic studies.

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Data availability

All experimental data, analytical procedures, cell designs, copies of spectra and CIF data are available in Supplementary Information.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH R35 GM138373) and a Camille and Henry Dreyfus Teacher Scholar Award to C.S.S. V.A. thanks the TÜBİTAK - BİDEB (2214-A International Research Fellowship Program for PhD Students) for a scholarship. We thank L. Lewis for assistance with EPR spectroscopic measurements.

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Author notes

  1. These authors contributed equally: Shivam Waske, Volkan Akyildiz

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA

    Samir Al Zubaydi, Shivam Waske, Volkan Akyildiz, Hunter F. Starbuck, Mayukh Majumder, Curtis E. Moore & Christo S. Sevov

  2. Department of Chemistry, Faculty of Science, Atatürk University, Erzurum, Turkey

    Volkan Akyildiz

  3. Discovery Chemistry, Merck & Co. Inc., Rahway, NJ, USA

    Dipannita Kalyani

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  1. Samir Al Zubaydi
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Contributions

S.A., D.K. and C.S.S. conceived the work and designed the experiments. S.W. and V.A. contributed equally. S.A., S.W., V.A., H.F.S. and M.M. performed all experiments and collected all data. S.A., S.W., V.A., H.F.S. and M.M. synthesized all substrates. H.F.S. performed parallel electrolysis reactions. C.E.M. performed collection and refinement of crystallographic data. M.M. performed computational studies. All authors analysed the data. S.A. and C.S.S. wrote the paper and all authors provided revisions.

Corresponding authors

Correspondence to Dipannita Kalyani or Christo S. Sevov.

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Al Zubaydi, S., Waske, S., Akyildiz, V. et al. Reductive alkyl–alkyl coupling from isolable nickel–alkyl complexes. Nature 634, 585–591 (2024). https://doi.org/10.1038/s41586-024-07987-9

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