Mechanochemically‐Assisted Passerini Reactions: A Practical and Convenient Method for the Synthesis of Novel α‐Acyloxycarboxamide Derivatives

A carboxylic acid, an aldehyde, and an isonitrile were combined in a single step (Passerini reaction) under mechanochemical activation to produce several α‐acyloxycarboxamide derivatives in high to excellent yields within 15 min of milling. Mechanochemistry, when combined with the diversity provided by multicomponent reactions, enables the efficient synthesis of the target compounds, with great atom economy, shorter reaction times, and experimental simplicity. The method allows for the rapid production of a vast library of complex compounds from a limited number of substrates. The formation of novel α‐acyloxycarboxamides from a carboxylic acid/phenol, an aldehyde/ketone and substituted isocyanide was investigated under mechanochemical conditions in the absence of organic solvents or in the presence of a catalytic amount of H2SO4−SiO2 (solid‐assisted grinding, SAG) to create libraries of structurally complicated molecules for consideration as lead compounds in drug discovery and development. The advantage of this one‐pot multicomponent reaction protocol includes the utilization of ambient conditions, fast reaction kinetics, significant reduction or elimination of solvent consumption, and, frequently, no lengthy workup step.