The oxidative dealkylation of tertiary amides: mechanistic aspects

N-(But-3-enyl)-N-methylbenzamide 14a undergoes microsomal oxidation by rat liver microsomes to yield both N-methyl- and N-(but-3-enyl)benzamides 18a a nd 19, the products of N-dealkylation. Cyclic products, that could be deriv ed from a carbon-centred radical formed by hydrogen atom abstraction from t he N-methyl group, were not observed. When generated independently, this ca rbon-centred radical underwent cyclisation, the 5-exo-trig mode being prefe rred to 6-endo-trig by a factor of 5. In contrast, N-(but-3-ynyl)-N-methylb enzamide 15 undergoes microsomal oxidation to yield the products of dealkyl ation 18a and 23 and also N-benzoylpiperidone 24. Dealkylation is preferred by factor of 3 and the piperidone accounts for ca. 45% of the reaction at the N-methyl group. Piperidone formation is consistent with the generation of a carbon-centred radical alpha- to the amide nitrogen atom during dealky lation and implies that cyclisation proceeds preferentially via the 6-endo- dig mode. Generated independently the radical undergoes cyclisation by both 5-exo-dig and 6-endo-dig modes, the former being favoured by a factor of 1 0. Similarly, N,N-dimethylacrylamide 26 and N-methyl-N-(3-pyridyl)acrylamid e 27 undergo microsomal oxidation to form, via the 5-endo-trig cyclisation mode, 3-hydroxy-N-methyl-2-pyrrolidone 33 and 3-hydroxycotinine dagger 34, respectively, confirming the intermediacy of a carbon-centred radical in th e dealkylation process. Attempts to trap N-acyliminium ions during microsomal dealkylation failed. Thus, although N,N-dimethylaniline 35 reacts in the presence of NaCN to for m N-cyanomethyl-N-methylaniline 37 (Nu=CN), N,N-dimethylbenzamide undergoes dealkylation without forming N-cyanomethyl-N-methylbenzamide. Similarly, m icrosomal reaction of N,N-dimethylaniline in the presence of NaBD4 gives ri se to multiple incorporation of deuterium atoms into the methyl groups of t he starting material, whereas N,N-dimethylbenzamide undergoes dealkylation but with no such deuterium incorporation into the starting material. Furthe r, microsomal oxidation of N,N-dimethylsalicylamide 38 yields N-methylsalic ylamide 40 with no evidence for the formation of N-methyl-2,3-dihydro-4H-1, 3-benzoxazin-4-one 39, the potential product of intramolecular cyclisation of the phenolic oxygen atom onto the putative N-aroylmethylene iminium ion.