Mechanochemical Synthesis of Dipeptides Using Mg‐Al Hydrotalcite as Activating Agent under Solvent‐Free Reaction Conditions

Abstract

Given the high demand for green and sustainable synthetic methods for the formation of amides and peptidic bonds, herein we report the efficient, solvent‐free mechanochemical synthesis of dipeptides from N ‐protected amino acids and amino acid methyl ester hydrochlorides in the presence of 1‐hydroxybenzotriazole (HOBt) and N ‐ethyl‐ N′ ‐[3‐(dimethylamino)propyl]carbodiimide hydrochloride (EDC) as coupling reagents, and using Mg‐Al hydrotalcite‐like minerals as green activating agent. From commercial Mg‐Al hydrotalcite (HT‐S), we obtained its calcined (HT‐C) and reconstructed (HT‐R) modifications, which were evaluated as activating heterogeneous bases in amidation reactions, replacing commonly used toxic and/or corrosive bases (e.g., NEt 3 , i Pr 2 NEt and NaOH). As a practical application of this strategy, various α,α‐, α,β‐ and β,β‐dipeptides were prepared in good to excellent yields. Under optimized reaction conditions (vibrating mill at 25 Hz for 75 min) HT‐S and HT‐R showed higher activity (89 % yield of the desired peptide) compared with HT‐C (57 % yield). The present protocol offers several advantages, including the use of readily available reagents and inexpensive materials, easy workup, simple recovery and recyclability of the hydrotalcite activator, and short reaction times.