5.05.2.1.6.4 Oxidative transformation of a tertiary carbon atom adjacent to a nitrogen atom The CYP3A4-catalyzed oxidation of the synthetic opioid alfentanil (126) follows two major pathways : N-dealkylation, to form noralfentanil (127), and cleavage of the spiro center, to generate N-phenylpropionamide (128) (Scheme 12). Moreover, 128 is found to come directly from alfentanil and not 127. The mechanism of how the C-N bond of the spiro center is cleaved is unknown.
The treatment of 1-phenylcyclobutylamine (129) with cytochrome P450 results in ring expansion and the production of 2-pheny-1-pyrroline (130). Presumably, the mechanism involves sequential formation of the aminium radical cation, homolytic ring opening, ring closure, then, finally, a second one-electron oxidation to form the pyrroline (Scheme 13).149
A relatively new aspect of cytochrome P450-catalyzed aromatic hydroxylation is the replacement of the substituent of a ^ara-substituted phenol with a hydroxy group; a phenomenon termed ipso substitution. In 1994, Ohe etal.150 reported that cytochrome P450 catalyzed the partial conversion of both ^-methoxyphenol (131) and ^-phenoxyphenol (132) to hydroquinone (133) (Scheme 14). In a subsequent paper, the scope of the reaction was investigated, and found to require the phenolic group.151 Nine ¿-substituted phenols (F, Cl, Br, NO2, CN, CH2OH, COCH3, COPh, CO2H) of diverse structure were incubated with rat liver microsomes, and the amount of 133 formed from each substrate was determined. All substrates gave measurable or significant levels of 133, except perhaps for^-tolylphenol (134). In the case of 134, the reaction stopped at the formation of the ipso adduct,^-toluquinol (135) (eqn ).
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