Sustainable Amide Synthesis: A Green Pathway to the Ritter Reaction

Amides are vital chemical entities with numerous uses in materials science, biology, medicine, and synthesis. Among the on-hand methods for their preparation, the Ritter reaction—first reported by J.J. Ritter in 1948—stays a traditional path. However, conventional approaches frequently depend on severe conditions, including strong acids (e.g., triflic acid), toxic catalysts (e.g., CoCl₂), volatile solvents (e.g., DCE), reactive anhydrides, and elevated temperatures, raising safety and environmental issues. As part of our continued focus in developing safe and more sustainable technologies based on iron-based deep eutectic solvents (DESs), which serve the role of both solvents and catalysts, in this communication we report a sustainable Ritter-type amide synthesis using iron-based Lewis acidic DESs (LADESs). Secondary and tertiary alcohols react smoothly with a variety of aliphatic and aromatic nitriles in LADESs, under mild aerobic conditions (40 °C, 4 h), affording amides in up to 98% yield without chromatographic purification. The method enabled a multigram-scale synthesis of the actoprotector Chlodantane with CHEM21 metrics revealing its significantly reduced environmental impact, establishing this protocol as greener and more efficient alternate to traditional methods for the synthesis of amides.