Studies on the oxidative N-demethylation of atropine, thebaine and oxycodone using a FeIII-TAML catalystElectronic supplementary information (ESI) available. See DOI: 10.1039/c3gc41972j

• Main Authors: Do Pham, Duy D, Kelso, Geoffrey F, Yang, Yuanzhong, Hearn, Milton T. W
• Format: Article
• Language: English
• ISSN: 1463-9262; 1463-9270
• DOI: 10.1039/c3gc41972j

The reaction pathway and selectivity of the oxidative N-demethylation of the alkaloid atropine with H 2 O 2 using a Fe III -TAML catalyst has been investigated. The conversion of atropine in ethanol with aqueous H 2 O 2 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 H 2 O 2 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 H 2 O 2 . 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 H 2 O 2 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. The reaction pathway and selectivity of the oxidative N-demethylation of several alkaloids with H 2 O 2 using a Fe III -TAML catalyst has been investigated.