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Issue 3, 2014
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Studies on the oxidative N-demethylation of atropine, thebaine and oxycodone using a FeIII-TAML catalyst

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Abstract

The reaction pathway and selectivity of the oxidative N-demethylation of the alkaloid atropine with H2O2 using a FeIII-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 FeIII-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 FeIII-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 FeIII-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.

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

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Article information


Submitted
20 Sep 2013
Accepted
26 Nov 2013
First published
27 Nov 2013

Green Chem., 2014,16, 1399-1409
Article type
Paper

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

D. D. Do Pham, G. F. Kelso, Y. Yang and M. T. W. Hearn, Green Chem., 2014, 16, 1399
DOI: 10.1039/C3GC41972J

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