ABSTRACT Amide bonds are fundamental linkages in biomolecules and pharmaceuticals, yet their construction often relies on stoichiometric coupling reagents and high‐energy input. Here, we report a mechanistically distinctive ester‐to‐amide conversion that integrates solvent‐minimized ball milling with either metal‐free conditions or lanthanide promotion, achieving efficient amidation under mild and scalable conditions. The method employs methyl and 2‐picolyl (Pic) esters as acyl donors and proceeds rapidly with both primary and secondary amines without solvent pre‐drying or inert handling. The 2‐picolyl group facilitates acyl activation through La 3 + coordination with the carbonyl oxygen and pyridyl nitrogen, while the stability of 2‐picolyl alcohol drives amide formation. Electronic substituents at the α‐position modulate the preference between metal‐promoted and nonmetallic pathways. Incorporation of electron‐withdrawing groups such as fluorine or cyano further expands reactivity. The reaction operates efficiently under both ball‐milling and aqueous conditions, with gram‐scale amidations confirming practicality. Representative examples include pharmaceutically relevant compounds, glycan derivatives, amino acids, and fluorescent probes, as well as biomacromolecular functionalization. This work establishes a novel and mechanistically defined platform for sustainable amide bond formation, bridging mechanochemistry and solution‐phase reactivity.
Li et al. (Sun,) studied this question.