Reductive alkyl-alkyl coupling from isolable nickel-alkyl complexes
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Nature ( 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 synthesis. 1,2 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 halides. 3–5 These limitations restrict the types of alkyl substrates that can be modified and, ultimately, the chemical space that can be explored. 6 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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Author notes
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These authors contributed equally: Shivam Waske, Volkan Akyildiz
Authors and Affiliations
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Department of Chemistry and Biochemistry, The Ohio State University, 151 W Woodruff Avenue, Columbus, OH, USA
Samir Al Zubaydi, Shivam Waske, Volkan Akyildiz, Hunter F. Starbuck, Mayukh Majumder, Curtis E. Moore & Christo S. Sevov
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Department of Chemistry, Faculty of Science, Atatürk University, Erzurum, Turkey
Volkan Akyildiz
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Discovery Chemistry, Merck & Co., Inc., Rahway, NJ, USA
Dipannita Kalyani
Authors
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Samir Al Zubaydi
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Shivam Waske
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Volkan Akyildiz
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Hunter F. Starbuck
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Mayukh Majumder
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Curtis E. Moore
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Dipannita Kalyani
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Christo S. Sevov
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Correspondence to Dipannita Kalyani or Christo S. Sevov .
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Zubaydi, S.A., Waske, S., Akyildiz, V. et al. Reductive alkyl-alkyl coupling from isolable nickel-alkyl complexes. Nature (2024). https://doi.org/10.1038/s41586-024-07987-9
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DOI : https://doi.org/10.1038/s41586-024-07987-9
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