Studies on the oxidative N-demethylation of atropine, thebaine and oxycodone using a FeIII-TAML catalyst

Abstract

The reaction pathway and selectivity of the oxidative N-demethylation of the alkaloid atropine with H₂O₂ using a Fe^III-TAML catalyst has been investigated. The conversion of atropine in ethanol with aqueous H₂O₂ produces noratropine as the main product and N-formyl-noratropine and other atropine derivatives involving carbon-hydroxylated tropane species as minor by-products. Comparative reactivity studies with noratropine, N-formyl-noratropine and atropine N-oxide demonstrated that the Fe^III-TAML catalyses the N-demethylation of atropine by a biomimetic oxidation pathway involving the formation and then decomposition of a N-hydroxymethylnoratropine intermediate. The reaction selectivity for atropine N-demethylation versus N-methyl oxidation to N-formyl-noratropine was found to be sensitive to the structure of the alcohol co-solvent, the rate of H₂O₂ addition and the concentration of water, whereas temperature mainly affected the atropine conversion efficiency. The use of tert-butyl or cumene hydroperoxide as oxidants shifted the reaction selectivity toward N-methyl oxidation compared to aqueous H₂O₂. Various inorganic oxidants were found to be ineffective. The Fe^III-TAML also catalysed the N-demethylation of the opiate alkaloids thebaine and oxycodone with aqueous H₂O₂ in higher conversion efficiencies compared to atropine but with lower selectivity. These investigations thus document key mechanistic features of the Fe^III-TAML-catalysed N-demethylation of these alkaloids and provide insight into how this benign catalytic system could find broader utilisation for N-demethylation in general.