In Situ Formed N -Sulfonyl Guanidinium for Efficient Amide Coupling

Amides are ubiquitous in the world; therefore, it is highly desired to develop an effective and practical method for the synthesis of amides. In this paper, in situ formed N-sulfonyl guanidinium by inexpensive 2-(tert-butyl)-1,1,3,3-tetramethylguanidine and trifluoromethanesulfonic anhydride was used as the efficient and robust coupling reagent of carboxylic acids and amines. In this protocol, reactions of N-sulfonyl guanidinium with carboxylic acids provided carboxylic acid-sulfonic acid mixed anhydrides, and treatments of the mixed anhydrides with 2-(tert-butyl)-1,1,3,3-tetramethylguanidine afforded N-acyl guanidiniums. Subsequent nucleophilic attacks of amines to highly active mixed anhydrides or N-acyl guanidiniums in the presence of 2-(tert-butyl)-1,1,3,3-tetramethylguanidine at room temperature gave corresponding amides or dipeptides (almost without epimerization) in excellent yields. Therefore, the present method provides a novel and useful strategy for the synthesis of amides and peptides.