Using mixed anhydrides from amino acids and isobutyl chloroformate in N-acylations: a case study on the elucidation of mechanism of urethane formation and starting amino acid liberation using carbon dioxide as the probe

A case study on the elucidation of mechanism of urethane by-product formation and starting amino acid liberation during the conventional two-step isobutyl chloroformate mediated N-acylation is described using carbon dioxide offgas as the probe. The main reason for the urethane formation and starting amino acid liberation was found to be the formation of the symmetrical anhydride of the amino acid during the preparation of the mixed carboxylic-carbonic anhydride intermediate, as determined by quantifying the evolved carbon dioxide. New conditions were developed to minimize this side reaction.