amines. Additionally, procedures utilizing photochemis-
try,7 electrochemistry,8 and microorganisms9 have been
investigated.
Efficien t N-Dem eth yla tion of Op ia te
Alk a loid s Usin g a Mod ified Non cla ssica l
P olon ovsk i Rea ction
The Polonovski reaction has also proven to be effective
for the demethylation of tertiary N-methylamines.10,11
This approach initially involves conversion of the amine
to the corresponding N-oxide using an appropriate per-
oxide or peracid. The amine N-oxide is then reacted with
an “activating agent” which induces an elimination and
ultimately affords an iminium ion intermediate that
reacts further to yield the N-demethylated product and
formaldehyde.11 There are three main categories of
activating agents, namely, acylating agents (acid anhy-
drides and chlorides), iron salts, and sulfur dioxide. To
date, the Polonovski reaction has been unsuccessful in
the N-demethylation of opiate alkaloids.12,13 Morphine
N-oxide has been reported to react with acetic anhydride
to give predominantly 3,6-diacetylmorphine (heroin), with
only trace amounts 3,6,17-triacetylnormorphine de-
tected.12 In contrast, treatment with acetyl chloride gave
a 50-70% yield of ∆16,17-dehydroheronium acetate.13
Because iron salts were successfully used to N-demeth-
ylate galanthamine-N-oxide,14 the application of this
nonclassical variant of the Polonovski reaction for the
N-demethylation of opiate alkaloids was explored. The
mechanism of this process is believed to involve two
successive one-electron steps involving Fe(II)/Fe(III) re-
dox reactions (Scheme 1).11 In this mechanism, the iron-
(II) coordinates to the protonated N-oxide which subse-
quently undergoes a one-electron reduction resulting in
cleavage of the N-O bond and formation of an aminium
radical cation. The radical cation loses an R-proton and
undergoes an electron reorganization to form a carbon-
centered radical which is oxidized by iron(III) to form an
iminium ion. Hydrolysis of this iminium ion affords the
secondary amine. The major byproduct from such reac-
tions is generally the parent tertiary N-methylamine
which results from iron(II) reduction of the intermediate
aminium radical cation.
Kristy McCamley,† J ustin A. Ripper,‡
Robert D. Singer,§ and Peter J . Scammells*,†
Department of Medicinal Chemistry, Victorian College of
Pharmacy, Monash University, 381 Royal Parade,
Parkville, Victoria 3052, Australia, School of Biological and
Chemical Sciences, Deakin University, Geelong,
Victoria 3217, Australia, and Department of Chemistry,
Saint Mary’s University, Halifax,
Nova Scotia, B3H 3C3, Canada
peter.scammells@vcp.monash.edu.au
Received August 25, 2003
Abstr a ct: A modified Polonovski reaction has been em-
ployed to N-demethylate several opiate alkaloids in moder-
ate to high yield. This method provides an alternative to
traditional N-demethylation procedures which utilize toxic
reagents such as cyanogen bromide or expensive reagents
such as vinyl chloroformate. The current synthesis involves
N-oxide formation, isolation of the corresponding N-oxide
hydrochloride, and an FeSO4‚7H2O mediated Polonovski
reaction to afford the desired secondary amine.
The opium poppy, Papaver somniferum, is the primary
source of the analgesic opiate alkaloids morphine and
codeine. A number of synthetic opiate derivatives have
also been approved for therapeutic use. In many of these
synthetic, pharmaceutically useful opiates, the naturally
occurring N-methyl group has been replaced by other
alkyl groups to give, for example, the antagonists nalor-
phine (1) and naltrexone (2) and the mixed agonist-
antagonist buprenorphine (3) (Chart 1).1 The N-demeth-
ylation of naturally occurring opiates has been achieved
in numerous ways. Certain chloroformates2 are effective
reagents for N-demethylation; however, usage on a large
scale is limited by their expense. The von Braun reaction3
is another alternative, though large scale application is
restricted because of poor yields and the toxicity of
cyanogen bromide. Other reagents such as azocarboxylic
esters,4 nitrous acid,5 and thiolates6 have also been
employed in the demethylation of tertiary N-methyl-
Our initial studies were performed on codeine (4),
codeine methyl ether (CME) (5), thebaine (6), the 14-
hydroxy opiates 7-9, and thevinone (10) (Chart 2).
Oxidation by m-CPBA or H2O2 produced the corre-
sponding N-oxides of 4-7 in quantitative yields, whereas
the oxidation of 8-10 was less efficient (Table 1).
Although the oxidation of thebaine (6) under acidic
(7) Ripper, J . A.; Tiekink, E. R. T.; Scammells, P. J . Bioorg. Med.
Chem. Lett. 2001, 11, 443.
(8) (a) Smith, P. J .; Mann, C. K. J . Org. Chem. 1969, 34, 1821. (b)
Barry, J . E.; Finkelstein, M.; Mayeda, E. A.; Ross, S. D. J . Org. Chem.
1974, 39, 2695. (c) Portis, L. C.; Klug, J . T.; Mann, C. K. J . Org. Chem.
1974, 39, 3488.
(9) (a) Madyastha, K. M. Proc. Indian Acad. Sci. 1994, 106, 1203.
(b) Vijay Bhasker Reddy, G.; Madyastha, K. M. J . Chem. Soc., Perkin
Trans. 1 1994, 911.
† Monash University.
‡ Deakin University.
§ Saint Mary’s University.
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J . Org. Chem. 1975, 40, 1850. (c) Rice, K. C.; May, E. L. J . Heterocycl.
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(3) Von Braun, J . Chem. Ber. 1909, 42, 2035.
(4) Merz, H.; Pook, K. H. Tetrahedron 1970, 26, 1727.
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1980, 103, 371.
(6) (a) Manoharan, T. S.; Madyastha, K. M. Synthesis 1983, 809.
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(11) Grierson, D. Org. React. 1990, 39, 85-295.
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(13) Allen, A. C.; Moore, J . M.; Cooper, A. C. J . Org. Chem. 1983,
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10.1021/jo035243z CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/12/2003
J . Org. Chem. 2003, 68, 9847-9850
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