Solid-state reactions using mechanochemical activation have emerged as solvent-free atom-efficient strategies for sustainable chemistry. Herein we report a new mechanochemical approach for the amide coupling of carboxylic acids and amines, mediated by combination of (1-сyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU) or N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and K₂HPO₄. The method delivers a range of amides in high 70–96% yields and fast reaction rates. The reaction protocol is mild, maintains the integrity of the adjacent to carbonyl stereocenters, and streamlines isolation procedure for solid amide products. Minimal waste is generated due to the absence of bulk solvent. We show that K₂HPO₄ plays a dual role, acting as a base and a precursor of reactive acyl phosphate species. Amide bonds from hindered carboxylic acids and low-nucleophilic amines can be assembled within 90 min by using TCFH in combination with K₂HPO₄ or N-methylimidazole. The developed mechanochemical liquid-assisted amidation protocols were successfully applied to the challenging couplings of all six carboxylate functions of biotin[6]uril macrocycle with phenylalanine methyl ester, resulting in an 80% yield of highly pure hexa-amide-biotin[6]uril. In addition, fast and high-yielding synthesis of peptides and versatile amide compounds can be performed in a safe and environmentally benign manner, as verified by green metrics.

使用机械化学活化的固态反应已经成为可持续化学的无溶剂原子高效策略。本文中，我们报告了一种新的机械化学方法，用于通过（1-сyano-2-ethoxy-2-oxoethylidenaminooxy）甲基氨基吗啉代碳六氟磷酸（COMU）或N，N，N '，N'-的组合介导的羧酸和胺的酰胺偶联六氟磷酸四甲基氯甲ami（TCFH）和K ₂ HPO ₄。该方法以高70-96％的产率和快速的反应速度提供了一系列酰胺。该反应方案温和，保持与羰基立体中心相邻的完整性，并简化了固体酰胺产物的分离程序。由于没有大量溶剂，因此产生的废物最少。我们表明，K ₂ HPO ₄ 发挥双重作用，充当活性酰基磷酸酯物质的碱和前体。通过将TCFH与K ₂ HPO ₄ 或N结合使用，可以在90分钟内组装受阻羧酸和低亲核胺的酰胺键-甲基咪唑。所开发的机械化学液体辅助酰胺化方案已成功地应用于生物素[6] uril大环化合物的全部六个羧酸盐功能与苯丙氨酸甲酯的挑战性偶联，从而获得了80％的高纯度六酰胺-生物素[6] uril收率。 。此外，可以通过安全，环保的方式快速，高产地合成肽和多种酰胺化合物，这已通过绿色指标验证。