A comparison of the reactivity and mutagenic N-(benzoyloxy)-N-(benzyloxy)benzamides

A new series of N-(acyloxy)-N-alkoxybenzamides, N-(benzoyloxy) -N-(benzylox y)benzamides 7 have been synthesized and have been found to be direct actin g mutagens in Salmonella TA100. They undergo A(Al)1 solvolysis to give N-be nzoyl-N-(benzyloxy)nitrenium ions 3 under conditions of acid catalysis as w ell as unusual B(Al)2 reactions at nitrogen with hydroxide. The latter proc ess affords as intermediates the anomeric hydroxamic esters 4 which rearran ge intramolecularly to esters in a HERON reaction. Rates of acid-catalyzed solvolysis and reaction with hydroxide ions correlate with Hammett a values with low sensitivity (rho = +0.32 and +0.55, respectively) in accordance w ith the A(Al)1 and B(Al)2 mechanisms. Mutagenicity for the series also appe ars to correlate with Hammett sigma values but with low, negative sensitivi ty (rho = -0.57), and their biological activity may be attributable to thei r stability under conditions of the Ames assay and hydrophobic binding to D NA, rather than their chemical reactivity.