The oxidative dealkylation of tertiary amides: mechanistic aspects

Abstract

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 and 19, the products of N-dealkylation. Cyclic products, that could be derived from a carbon-centred radical formed by hydrogen atom abstraction from the N-methyl group, were not observed. When generated independently, this carbon-centred radical underwent cyclisation, the 5-exo-trig mode being preferred to 6-endo-trig by a factor of 5. In contrast, N-(but-3-ynyl)-N-methylbenzamide 15 undergoes microsomal oxidation to yield the products of dealkylation 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 α- to the amide nitrogen atom during dealkylation 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 10. Similarly, N,N-dimethylacrylamide 26 and N-methyl-N-(3-pyridyl)acrylamide 27 undergo microsomal oxidation to form, via the 5-endo-trig cyclisation mode, 3-hydroxy-N-methyl-2-pyrrolidone 33 and 3-hydroxycotinine34, respectively, confirming the intermediacy of a carbon-centred radical in the 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 form N-cyanomethyl-N-methylaniline 37 (NuCN), N,N-dimethylbenzamide undergoes dealkylation without forming N-cyanomethyl-N-methylbenzamide. Similarly, microsomal reaction of N,N-dimethylaniline in the presence of NaBD₄ gives rise to multiple incorporation of deuterium atoms into the methyl groups of the starting material, whereas N,N-dimethylbenzamide undergoes dealkylation but with no such deuterium incorporation into the starting material. Further, microsomal oxidation of N,N-dimethylsalicylamide 38 yields N-methylsalicylamide 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.

p