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

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 S_N2 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.