Chemical and microsomal oxidation of tertiary amides: regio- and stereoselective aspects

The conformationally restricted tertiary amides N-methyl-2-pyrrolidone 6, N -methyl-2-piperidone 7 and N-methyl-epsilon -caprolactam 8 were oxidised by 5,10,15,20-tetraphenylporphyrinatoiron(III) chloride/tert-butyl hydroperox ide (TPPFe/(BuOOH)-O-t) and by phenobarbital-induced rat liver microsomes. The products were the N-demethylated lactams together with the analogous N- methylimides and norimides. For the TPPFe/(BuOOH)-O-t reaction ring oxidati on is preferred to N-demethylation, paralleling the relative stabilities of the corresponding intermediate carbon-centred radicals as calculated by th e AM1 semi-empirical method. In contrast, the microsomal reaction of the N- methyllactams strongly favours N-demethylation, demonstrating that hydrogen atom abstraction from the alkyl group Z to the amide carbonyl oxygen atom i s preferred. The chiral tertiary amides N-methyl-N-(1-phenylethyl)benzamide 9 and N-methyl-5-phenyl-2-pyrrolidone 10 were also oxidised by TPPFe/(BuOO H)-O-t and by phenobarbital-induced rat liver microsomes. Using TPPFe/(BuOO H)-O-t, loss of the secondary alkyl group of 9 is preferred by a factor of ca. 6. Similarly, ring oxidation of 10 is favoured over demethylation by a factor of 9. For the microsomal reaction of (R)-9 dealkylation is preferred over demethylation by a factor of 1.7, whereas for (S)-9 demethylation is favoured by a factor of 1.25. For the microsomal reaction of (R)-10 and (S) -10 ring oxidation at the 5-position of the pyrrolidone ring is preferred o ver demethylation by factors of ca. 4 and 9 for the two isomers, respective ly, and the (S)-enantiomer undergoes ring oxidation 2-3 times more readily than the (R)-enantiomer. For both 9 and 10 there is negligible stereochemic al influence of the chiral centre upon the N-demethylation reaction. The re sults show that the stereochemical preference of the microsomal N-dealkylat ion reaction is modest.