Water Solvent Method for Esterification and Amide Formation between Acid Chlorides and Alcohols Promoted by Combined Catalytic Amines: Synergy between N ‐Methylimidazole and N,N,N′,N′ ‐Tetramethylethylenediamine (TMEDA)

An efficient method for esterification between acid chlorides and alcohols in water as solvent has been developed by combining the catalytic amines, N ‐methylimidazole and N,N,N′,N′ ‐tetramethylethylenediamine (TMEDA). The present Schotten–Baumann‐type reaction was performed by maintaining the pH at around 11.5 using a pH controller to prevent the decomposition of acid chlorides and/or esters and to facilitate the condensation. The choice of catalysts (0.1 equiv.) was crucial: the combined use of N ‐methylimidazole and TMEDA exhibited a dramatic synergistic effect. The catalytic amines have two different roles: (i) N ‐methylimidazole forms highly reactive ammonium intermediates with acid chlorides and (ii) TMEDA acts as an effective HCl binder. The production of these intermediates was rationally supported by a careful 1 H NMR monitoring study. Related amide formation was also achieved between acid chlorides and primary or secondary amines, including less nucleophilic or water‐soluble amines such as 2‐(or 4‐)chloroaniline, the Weinreb N ‐methoxyamine, and 2,2‐dimethoxyethanamine.