Synthesis and kinetic investigation of the selective acydolysis of para-substituted N-phenylacetyl-N-benzyl- and N-phenylacetyl-N-phenyl-alpha,alpha-dialkylglycine cyclohexylamides

Abstract

Several derivatives of N-phenylacetyl-N-benzyl-alpha,alpha-dimethylglycine cyclohexylamide and their alpha,alpha-dibenzylglycine analogues were synthesised by a Ugi-Passerini reaction. In addition, a few analogues of the former but having an N-phenyl instead of a benzyl group at the nitrogen atom were synthesised. The compounds in each of these three sets differed from each other at the position 4 of the N-benzyl (and N-phenyl) group. These adducts were submitted to acidolysis with TFA to obtain the corresponding free acids, the reactions being monitored by HPLC and data collected for kinetic purposes. The kinetic data were submitted to Hammett uni- and biparametric relationships and the results analysed in terms of structure-reactivity in connection to the sensitivity of the reaction rates to the electronic contributions of the various substituents in position 4 of the aromatic rings. The results allowed comparison with information obtained in previous investigations and rationalise the contribution of the substituent at the nitrogen atom to the lability of the C-terminal amide bond.