N-acyloxy-N-alkoxybenzamides are mutagenic in TA100 without the need for metabolic activation with S9. Electronic effects of substituents on both the benzamide ring in N-acetoxy-N-butoxybenzamides or the benzyloxy ring in N-acetoxy-N-benzyloxybenzamides do not influence mutagenicity levels. For N-benzoyloxy-N-benzyloxybenzamides, mutagenicity levels are inversely related to the electron-withdrawing effect of substituents on the benzoyloxy leaving group. Since reactivities increase with increasing electron-withdrawing effects, mutagenicity correlates with stability rather than reactivity of these mutagens. Hydrophobicity is the dominant factor controlling mutagenicity levels and data for all mutagens correlate with computed logP values with a lower dependence (h=0.22) than that recorded for indirect mutagens (h=1.0), except where a sterically demanding p-tert-butyl substituent or a naphthyl group is present. N-acetoxy-N-butoxynaphthamide exhibits a much higher level of mutagenicity than predicted by its logP value and activity may be ascribed to an intercalative binding process with DNA rather than straightforward hydrophobic binding in the major or minor groove. Since these are direct-acting mutagens, structural factors influence binding and reactivity towards DNA.

N-Acyl-3,4-dihydro-1H-2,1-benzoxazines (3) undergo a thermal decomposition involving loss of formaldehyde in a retro-Diels-Alder reaction. The resultant N-acylazaxylylenes dagger (4) undergo a 6 pi electrocyclisation to give 2-substituted-4H-3, 1-benzoxazines (5) rather than a 4 pi electrocyclisation to give the N-acyl-1,2-dihydrobenzazetes (6). Compounds 5 have been fully characterised spectroscopically and their data is inconsistent with that reported previously by other workers for what are purported to be the same compounds. 2-Methyl-4H-3,1-benzoxazine (5b) and other 2-alkyl-substituted compounds undergo facile hydrolysis to o-aminobenzyl esters (9) which rearrange to the thermodynamically more stable o-hydroxymethylanilides (10). 2-Phenyl-4H-3,1-benzoxazine (5a) is relatively stable to hydrolysis but undergoes a novel photochemical ring opening (> 254 nm) to give the N-benzoylazaxylylene (12) which can be trapped with alcohols giving o'-alkoxymethylbenzanilides (11). In cyclohexanol at 160 degrees C, the intermediate in the thermal rearrangement of 3a to 5a, N-benzoylazaxylylene (12), was trapped as o'-cyclohexyloxymethylbenzanilide (11b). The rearrangements in mesitylene are unimolecular with activation energies of 35, 37 and 42 kcal mol(-1)double dagger for 3a; 3c and 3d,.respectively. The extrusion and electrocyclisation reaction pathways for N-acetyl-3,4-dihydro-2, 1-benzoxazine (3b) have been modelled using AM1 molecular orbital theory which predicts both a non-synchronous transition state for the retro-Diels-Alder reaction and the preferred mode of ring closure to be the 6 pi rather than the 4 pi electrocyclisation.

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N,N′-Diacyl-N,N′-dialkoxyhydrazines have been shown to decompose thermally to esters and nitrogen. An intramolecular crossover experiment has shown that the formation of esters is consistent with a three- centred rearrangement process which is characteristic of N-alkoxy N-amino amides. The four-centred mechanism previously proposed by earlier workers is less favourable energetically. AM1 molecular orbital calculations support these experimental findings.

Alkoxyiminyl radicals, generated by photolysis of N-bromo imidates, undergo exo-1,5 and exo-1,6 cyclization onto olefins on the O-alkyl side chains giving good yields of 4,5-dihydrooxazoles and 5,6-dihydro-4H-1,3-oxazines, respectively. exo-1,5 Cyclization onto an olefin on the iminyl side chain gives 2-alkoxy-Δ1-pyrrolines. 4,5-Dihydrooxazole formation is more favourable than cyclization to 2-alkoxy-Δ1-pyrrolines and both reactions are irreversible. These preferences are supported by MNDO molecular orbital calculations which predict that both processes are exothermic but cyclization onto the O- alkenyl side chain has a lower ΔH‡.

Deuterium labelling experiments and n.m.r.studies indicate that cyclisations of N-acyl-N-(2-phenylethyloxy) nitrenium ions occur via direct attack at the ortho position to give 34-dihydro-1 H-21-benzoxazines. In contrast N-acyl-N-(3-phenylpropyloxy)nitrenium ions cyclise to 1345-tetrahydro-21-benzoxazepines through ipso attack followed by 12-carbon migration. In both cases hydrogen circumambulation occurs in the sigma complex before aromatisation.

In aqueous acetonitrile, N-acetoxy-N-alkoxybenzamides undergo acid-catalysed solvolysis by the A(Al)1 mechanism to give acetic acid and nitrenium ions. This is indicated by an inverse dependence of the acid-independent rate constant, k(H), upon the activity of water, a solvent kinetic isotope effect of 0.44 and positive DELTA-S double-ended dagger values. In addition, relief of steric compression at the nitrogen enhances the rate of solvolysis. Hammett correlations with sigma+ substituent constants were found for the rates of solvolysis of para-substituted-N-acetoxy-N-butoxybenzamides and N-acetoxy-N-(para-substituted benzyloxy) benzamides. This fact and the low rho-values of -1.35 and -1.56, respectively, are indicative of a strong build-up of positive charge in the transition state which has both nitrenium ion and oxonium ion character and is in accordance with computed molecular-orbital properties of N-alkoxynitrenium ions. Greater levels of mutagenicity have been measured for those compounds which are more readily solvolysed to nitrenium ions.

N-chloro-O-alkylbenzohydroxamates react with silver acetate in ether giving N-acetoxy-N-alkoxybenzamides which, by analogy with N,O-diacyl-N-arylhydroxylamines, have been shown to be mutagenic in the Ames test.