Reductive alkyl–alkyl coupling from isolable nickel–alkyl complexes

• Published in: Nature (London) 2024-10, Vol.634 (8034), p.585-591
• Main Authors: Al Zubaydi, Samir, Waske, Shivam, Akyildiz, Volkan, Starbuck, Hunter F., Majumder, Mayukh, Moore, Curtis E., Kalyani, Dipannita, Sevov, Christo S.
• Format: Article
• Language: English
• Subjects: 140/131; 639/638/403/933; 639/638/549/975; 639/638/77/888; Alkylation; Amines; Amino acids; Amino Acids - chemical synthesis; Amino Acids - chemistry; Biological Products - chemical synthesis; Biological Products - chemistry; Carbon; Carboxylic acids; Chemical reactions; Chemistry Techniques, Synthetic - methods; Combinatorial analysis; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coupling (molecular); Cross coupling; Crystallography; Deamination; Decarboxylation; Diversification; Esters; Esters - chemical synthesis; Esters - chemistry; Halides; Halogens - chemistry; Humanities and Social Sciences; multidisciplinary; Natural products; Nickel - chemistry; Organometallic compounds; Oxidation-Reduction; Pharmaceutical Preparations - chemical synthesis; Pharmaceutical Preparations - chemistry; Pyridinium; Pyridinium Compounds - chemistry; Science; Science (multidisciplinary); Spectrum Analysis; Stereoisomerism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07987-9

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 substrate 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. Alkyl–alkyl cross-coupling reactions are achieved by forming nickel–alkyl complexes directly by oxidative addition of alkyl halides, redox-active esters or pyridinium salts, and then combining them with a second alkyl electrophile.