Mechanochemical Bodroux Reaction: Sustainable Ball Milling Approach for Direct Amidation of Esters

ABSTRACT The mechanochemical synthesis of amides via direct ester amidation through ball milling represents a significant advancement in sustainable organic synthesis. This methodology exploits the in situ generation of isopropylmagnesium bromide within the mechanochemical environment to activate ester substrates toward nucleophilic attack by amines, effectively implementing the historically underutilized Bodroux reaction under mild, solvent‐minimized conditions. Mechanochemical activation overcomes traditional limitations of organomagnesium chemistry by eliminating moisture sensitivity concerns and enabling efficient mixing of heterogeneous reaction components. The method demonstrates remarkable versatility, accommodating a diverse range of substrates, including heteroaromatic, heterocyclic, and aliphatic components. Notably, substrates bearing sensitive functional groups perform exceptionally well under these mechanochemical conditions. Successful gram‐scale synthesis of pharmaceutical and agrochemical targets validates the practical utility and scalability of this approach, positioning mechanochemical amidation as a viable alternative to traditional coupling reagent‐based methodologies.