Revitalizing reformatsky reagent for catalyst-free direct alkylation with unactivated alkyl halides

Lingpu Meng, Zimeng Li, Tian Zhang, Yi Xu, Yangxiao Li, Botao Wu () and Qilong Shen ()
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Lingpu Meng: Chinese Academy of Sciences
Zimeng Li: Chinese Academy of Sciences
Tian Zhang: Chinese Academy of Sciences
Yi Xu: Chinese Academy of Sciences
Yangxiao Li: Chinese Academy of Sciences
Botao Wu: Chinese Academy of Sciences
Qilong Shen: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Reformatsky reagents are commonly employed with activated electrophiles, such as aldehydes, ketones, or activated alkyl halides. However, their limited nucleophilicity remains a considerable challenge for direct reactions with unactivated alkyl halides, typically necessitating transition metal catalysis. Here, we present a transition-metal-catalyst-free approach that facilitates direct nucleophilic substitution between Reformatsky reagents and diverse unactivated alkyl halides, which enables formal reductive cross-electrophile coupling via a one-pot process. Mechanistic studies reveal the pivotal role of highly polar solvents and the formation of zincate enolate intermediates containing hindered alkyl groups, which streamlines the SN2 reaction with unactivated alkyl halides via open-frame transition states. The modular nature of the current protocol eliminates the need for strong bases and transition metal catalysts, allowing easy access to esters, amides, and ketones bearing all-carbon quaternary centers with a wide range of functional groups, thereby providing a simple and expedient synthetic avenue to build complex molecules.

Date: 2025
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DOI: 10.1038/s41467-025-62833-4

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