Synthesis of N-Hydroxysuccinimide Esters, N-Acylsaccharins, and Activated Esters from Carboxylic Acids Using I₂/PPh₃

Abstract

A method for the syntheses of isolable, active esters is described in which carboxylic acids are treated with triphenylphosphine, iodine, and triethylamine. Active esters accessible in this way include N-hydroxysuccinimide esters, Nhydroxyphthalimide esters (N-(acyloxy)phthalimides), N-acylsaccharins, pentafluorophenol esters, pentachlorophenol esters, Nhydroxybenzotriazole esters, and hexafluoro-2-propanol esters. The approach can be similarly applied toward the formation of Nacylsaccharins and N-acylimidazoles. The method is suitable for the formation of isolable active esters of aromatic and aliphatic activated acids as well as α-amino acid derivatives. These products are widely used reagents in organic synthesis, peptide synthesis, medicinal chemistry, and chemical biology (e.g., for bioconjugations). The method has broad substrate scope, uses simple and inexpensive reagents, avoids the use of carbodiimides or other coupling agents, and occurs at room temperature. Additionally, the diastereomers of compound Boc-Ala−NHCHPh are demonstrated to be distinguishable by 1 H NMR (in DMSO-d 6 ), allowing for a straightforward NMR method to establish the degree of racemization of activated esters of Boc-Ala or amide bond formations using Boc-Ala.