Reductive alkyl–alkyl coupling from isolable nickel–alkyl complexes

Samir Al Zubaydi, Shivam Waske, Volkan Akyildiz, Hunter F. Starbuck, Mayukh Majumder, Curtis E. Moore, Dipannita Kalyani () and Christo S. Sevov ()
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Samir Al Zubaydi: The Ohio State University
Shivam Waske: The Ohio State University
Volkan Akyildiz: The Ohio State University
Hunter F. Starbuck: The Ohio State University
Mayukh Majumder: The Ohio State University
Curtis E. Moore: The Ohio State University
Dipannita Kalyani: Merck & Co. Inc.
Christo S. Sevov: The Ohio State University

Nature, 2024, vol. 634, issue 8034, 585-591

Abstract: 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 halides3–5. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07987-9

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