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• 2556-73-2 1-methyl-2-azepanone 

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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-ε-caprolactam 8 were oxidised by 5,10,15,20-tetraphenylporphyrinatoiron(III) 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.

Ruthenium Tetroxide Oxidation of N-Alkyllactams

Ruthenium tetroxide (RuO4) oxidation of N-alkyllactams proceeded regioselectively depending on the size of lactam ring, except for the seven-membered ring.Four- and eight-membered N-methyl- and N-ethyllactams were oxidized at the exocyclic α-carbon adjacent to nitrogen to produce the N-acyllactams and NH-lactams, while five- and six-membered lactams underwent endocyclic oxidation to yield the cyclic imides.Oxidation of seven-membered lactams yielded a mixture of products arising from both exocyclic and endocyclic oxidations.These regioselectivities were confirmed in the oxidation of substrates having a tertiary carbon at the oxidation position.Keywords---oxidation; ruthenium tetroxide oxidation; regioselective oxidation; hydroxylation; imide synthesis; N-alkyllactam; N-acyllactams; imide; ruthenium tetroxide; two-phase method