Direct and Waste-Free Amidations and Cycloadditions by Organocatalytic Activation of Carboxylic Acids at Room Temperature

摘要

The amide bond is ubiquitous in nature.It links amino acids to form peptides and proteins and is an important component of many natural products.Furthermore,it has been estimated that as many as 25% of all synthetic pharmaceutical drugs contain an amide unit.Consequently,the development of efficient amidation methods continues to be an important scientific pursuit.Despite the favorable thermodynamic stability of the resulting amide bond,the simple thermal dehydration reaction between a carboxylic acid and an amine is plagued by a large activation energy.The initial formation of a stable ammonium carboxylate salt deters the dehydration step,and the intermediate salt collapses to provide the amide product only at very high temperatures (over 160 °C) that are incompatible with most functionalized molecules (Scheme l).