Mechanochemistry-Amended Barbier Reaction as an Expedient Alternative to Grignard Synthesis

Abstract

Organomagnesium halides (Grignard reagents) are essential carbanionic building blocks widely used in carbon-carbon and carbon-heteroatom bond forming reactions with various electrophiles. In the Barbier variant of the Grignard synthesis, the generation of air- and moisture-sensitive Grignard reagents occurs concurrently with their reaction with an electrophile. Although operationally simpler, the classic Barbier approach suffers from low yields due to multiple side reactions, limiting its application scope. Here, we report a mechanochemical adaptation of the Mg-mediated Barbier reaction, which overcomes these limitations and makes it suitable for the coupling of versatile organic halides (allylic, vinylic, aromatic, aliphatic) with diverse range of electrophilic substrates (aldehydes, ketones, esters, amides, O-benzoyl hydroxylamine, chlorosilane, borate ester) to assemble C–C, C–N, C–Si, and C–B bonds. In contrast to the classic two-step Grignard synthesis, the mechanochemical approach offers the advantages of being essentially solvent-free, single step and operationally simple, immune to air, and surprisingly tolerant to water and other proton donors. Mechanistic studies clarify the role of mechanochemistry in the process, indicating that the reaction predominantly proceeds via generation of transient organometallics, which occurs rapidly due to improved mass transfer and activation of the surface of magnesium metal