Enol esters for sustainable amide-bond formation under aqueous conditions

Amide bonds are among the most ubiquitous and essential linkages in chemistry, pharmaceuticals, materials, and biological systems. Here, we report a sustainable and efficient protocol for amide-bond formation under aqueous conditions using bench-stable enol esters as preactivated coupling reagents derived from carboxylic acids and 1,3-diones. In contrast to conventional activation strategies, the reaction proceeds smoothly under redox-neutral, additive-free, and physiologically relevant conditions without external coupling reagents or catalysts. The method shows a broad scope across amines, amino acids, peptides, and proteins and is operationally simple and scalable. Importantly, the 1,3-dione precursor is regenerated as a by-product and can be recovered from the buffer solution and reused to prepare the corresponding enol esters. These features establish enol esters as a practical platform for sustainable amide-bond formation in water.