Sustainable amide bond formation through the combination of deep eutectic solvents and next-generation carbodiimides

Amide bond formation is one of the most widely employed transformations in pharmaceutical and peptide synthesis, yet conventional carbodiimide-mediated coupling protocols still rely on hazardous reagents and large volumes of volatile organic solvents, resulting in significant waste generation. Herein, we demonstrate that the combination of next-generation carbodiimide coupling reagents with appropriately selected deep eutectic solvents (DES) provides an efficient and sustainable platform for amide bond formation. Comparative screening identified the TBDCTsOH/reline combination as the optimal system, enabling efficient carboxylic acid activation and rapid amidation under mild conditions. The optimized protocol afforded rapid amidation of aliphatic and aromatic carboxylic acids, primary amines, as well as protected amino acids. The methodology was successfully extended to peptide bond formation, showing excellent compatibility with Fmoc-, Boc-, and Cbz-protected amino acids, with no detectable epimerization by 1H NMR under the optimized conditions. Notably, the high solubility of the urea-derived byproduct in the DES significantly simplified product isolation and eliminated the need for chromatographic purification. Green metrics analysis revealed that the DES-based methodology maintains high synthetic efficiency while reducing the environmental footprint, achieving nearly 91% reductions in both process mass intensity (PMI) and E-factor compared with conventional carbodiimide-mediated protocols. Overall, the results demonstrate that the synergistic combination of carbodiimide reagent and DES, rather than either component alone, is responsible for the superior performance of the developed methodology, providing a practical strategy for more sustainable amide and peptide bond formation relevant to pharmaceutical synthesis.