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

Iley, Jim; Tolando, Roberto and Constantino, Luis (2001). Chemical and microsomal oxidation of tertiary amides: regio-and stereoselective aspects. Journal of the Chemical Society: Perkin Transactions 2 pp. 1299–1305.

DOI: https://doi.org/10.1039/b102731j

Abstract

The conformationally restricted tertiary amides N-methyl-2-pyrrolidone 6, N-methyl-2-piperidone 7 and N-methyl-ε-caprolactam 8 were oxidised by 5,10,15,20-tetraphenylporphyrinatoiron() chloride/tert-butyl
hydroperoxide (TPPFe/ButOOH) 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/ButOOH reaction ring oxidation is preferred to N-demethylation, paralleling the relative stabilities of the corresponding intermediate carbon-centred radicals as calculated by the 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 is 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/ButOOH and by phenobarbital-induced rat liver microsomes. Using TPPFe/ButOOH, 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 over demethylation by factors of ca. 4 and 9 for the two isomers, respectively, and the (S)-enantiomer undergoes ring oxidation 2–3 times more readily than the (R)-enantiomer. For both 9 and 10 there is negligible stereochemical influence of the chiral centre upon the N-demethylation reaction. The results show that the stereochemical preference of the microsomal N-dealkylation reaction is modest.

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