A Condensation Reagent for Hindered Carboxylic Acids and Low-nucleophilic Amines

Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH, 1) is utilized as a condensation reagent for sterically congested carboxylic acids and amines. Treatment of 1 to, a carboxylic acid and an amine at room temperature along with N-methylimidazole as an activator affords the corresponding amide in good yields. The reaction proceeds with sterically hinderd amino acids such as valine and S-protected cysteines, as well as low nucleophilic aniline derivatives with little epimerization occuring. Due to these good synthetic properties, 1 is expected to have applications in synthesis scale-up for peptide synthesis, development of peptide drug candidates, and automated processees for peptide synthesis.