Mechanochemical Extrusion for Sustainable Synthesis of Amides and Amines via the Leuckart Reaction

An extrusion-based, solvent-free method was developed for the synthesis of amides and amines via the Leuckart reaction, representing the first adaptation of this classical transformation into a continuous mechanochemical platform. The production of amides was demonstrated through the model reaction between ammonium formate and vanillin, leading to vanillyl formamide, while the synthesis of tertiary amines was investigated using ammonium formate, vanillin, and morpholine as reactants. A thorough parametric analysis revealed that the mechanochemical-based strategy allowed extremely fast processes: at 100-150 °C, reactions were quantitative in 5-15 min with product selectivity >99% for vanillin formamide and up to 83% for the corresponding tertiary amine. An investigation of the substrate scope (four examples) confirmed the robustness of the protocol for both reaction types. Benzyl-type amides and tertiary amines were synthesized with high conversion and selectivity, exceeding 95%, across different aldehydes. Moreover, morpholine could be successfully replaced by other secondary amines (diethanolamine and N-methyl-p-anisidine), thereby further demonstrating the versatility of the reactive extrusion for the preparation of amines. Overall, this work underscores the novelty and impact of solvent-free continuous extrusion, establishing it as a scalable and sustainable alternative to liquid-phase synthesis, and marking a significant step forward in green chemistry practices.