Condensation of carboxylic acids with amines using the Boc2O/DMAP system under solvent-free conditions

Abstract

The present study describes the use of the di-tert-butyl dicarbonate (Boc₂O)/4-(N,N-dimethylamino)pyridine (DMAP) system for the amidation of carboxylic acids under neat conditions without heating. A set of carboxylic acids was explored, such as non-steroidal anti-inflammatory drugs (NSAIDs), fatty acids and protected prolines in the presence of aromatic, benzylic and aliphatic amines as nucleophilic partners. The scope of this easy approach was extended to the preparation of thirty-two diverse carboxylic amides, which were recovered with isolated yields varying from moderate to excellent. To increase the value of this protocol, a scalable chemoselective amidation of oleic acid with ethanolamine was successfully established. The corresponding fatty carboxylic amide, N-oleoylethanolamide (OEA), was recovered with 73% yield. This study highlights the potency of the use of mixed anhydrides formed in situ and the pursuit of the reaction profile reveals sequential steps rather than a one-pot process.