Alternative methods for the MnO2 oxidation of codeine methyl ether to thebaine utilizing ionic liquids

Article abstract of DOI:10.1016/S0040-4039(01)01383-1

The MnO₂ oxidation of codeine methyl ether, CME, to thebaine has been accomplished via the use of the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, bmimBF₄. The ionic liquid has been used to remove or extract excess MnO

Full text of DOI:10.1016/S0040-4039(01)01383-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6831–6833
Alternative methods for the MnO2 oxidation of codeine methyl
ether to thebaine utilizing ionic liquids
Robert D. Singera,* and Peter J. Scammellsb
aDepartment of Chemistry, Saint Mary’s University, Halifax, Nova Scotia, Canada B3H 3C3
bCentre for Chiral and Molecular Technologies, Deakin University, Geelong, Victoria 3217, Australia
Received 26 February 2001; revised 12 April 2001; accepted 27 July 2001
Abstract—The MnO2 oxidation of codeine methyl ether, CME, to thebaine has been accomplished via the use of the ionic liquid
1-butyl-3-methylimidazolium tetrafluoroborate, bmimBF4. The ionic liquid has been used to remove or extract excess MnO2 and
associated impurities from the reaction mixture to afford thebaine in 36 to >95% yield. © 2001 Elsevier Science Ltd. All rights
reserved.
Thebaine (Fig. 1) is a minor opium alkaloid found in
the poppy Papaver somniferum and has no known
direct medicinal applications. However, thebaine has
seen ample use as a synthetic precursor to many opiate
derivatives, such as buprenorphine, that are used in the
treatment of opiate and alcohol addiction as well as
opiate overdose.1 Although thebaine can now be iso-
lated in large quantities from the poppy plant there is
frequently a higher demand for thebaine to prepare
opiate derivatives than can be met from these sources.
Hence, we have sought to develop a synthetic method
with which thebaine can be prepared in an economical
fashion and in useful quantities.
of g-MnO2 and is conducted in tetrahydrofuran under a
nitrogen atmosphere. We have found it difficult to
reproduce such a high yield of thebaine via this
methodology (Table 1; entry 1). We believe that the-
baine is strongly adsorbing to the surface of the MnO2
particles and that use of such a large excess of oxidizing
agent in this methodology makes isolation of thebaine
extremely problematic.
Most recently, a new class of solvents known as ionic
liquids has been gaining popularity for use in a number
of synthetic applications. Ionic liquids have been uti-
lized in a wide range of reactions as a solvent3 and have
seen limited use as an extractant.4 It is this latter
application of ionic liquids that we wished to exploit.
Specifically, we have used ionic liquids to extract, or
remove, excess g-MnO2 and associated impurities from
the reaction mixture in which codeine methyl ether is
oxidized to thebaine. We have utilized the ionic liquid
1-butyl-3-methylimidazolium tetrafluroborate,5 bmim-
There are a number of procedures described in the
literature for the synthesis of thebaine.2 Most notable is
that by Barber and Rapoport in which it is reported
that codeine methyl ether (Fig. 1) can be oxidized with
g-MnO2 to afford an 80% yield of thebaine (67% over-
all from codeine).2b This method makes use of 25 equiv.
CH3O
O
CH3O
O
MnO2
Method 1 - 3
N
N
CH3
CH3
CH3O
CH3O
Codeine Methyl Ether
(CME)
Thebaine
Figure 1. Oxidation of codeine methyl (CME) ether to thebaine.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01383-1

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R. D. Singer, P. J. Scammells / Tetrahedron Letters 42 (2001) 6831–6833
Table 1. MnO2 oxidation of codeine methyl ether to thebaine7,8
Entry
Equiv. MnO2
Reaction conditionsa,b
Reaction time (h)
Yield (%) (% recovery)c
1
2
3
4
25
10
10
10
THF
24
120
168
144
25 (58)d
38 (80)
36 (100)
\95 (100)
BmimBF4, sonication
BmimBF4/Et2O (biphasic), sonication
THF, sonication
a In entries 2–4, MnO2 was extracted/immobilized in bmimBF4; opiates extracted into EtOAc layer.
b All reactions were monitored by TLC until no further change was discernible.
c Total recovery of opiates (Thebaine and unreacted CME)
d Best result obtained after repeated attempts.
BF4, in our initial studies and are currently investigat-
ing the use of other air and moisture stable ionic liquids
for this application (Fig. 2).
tions, CME underwent a 36% conversion to thebaine
after extended reaction time under sonication (ca. 168
h) as determined via H NMR analysis, and compari-
1
son to authentic samples, with a quantitative isolation
of combined opiate components. We believe that CME
did not partition very favorably between the etherial
upper layer and the lower ionic liquid layer that con-
tained the oxidant. This resulted in the low conversion
to thebaine. Once again, we envisage that use of a wider
range of ionic liquids, or perhaps even the addition of
a phase transfer reagent, may enable better conversion
of CME to thebaine in a biphasic, organic/ionic liquid
system.
We have demonstrated three methods employing ionic
liquids in the MnO2 oxidation of CME to thebaine
(Table 1; entries 2–4).6 First, the MnO2 oxidation of
CME was performed in the ionic liquid alone. In this
case, it was anticipated that use of the ionic liquid as a
reaction medium/solvent might enhance the rate of this
oxidation reaction in addition to facilitating the separa-
tion of products from excess MnO2, impurities and
unwanted by-products. After extended reaction times
under sonication (ca. 120 h), thebaine and unreacted
CME were easily extracted from the reaction mixture
using ethyl acetate. MnO2 and other impurities
remained in the bottom ionic liquid layer of this extrac-
tion process. CME underwent a 38% conversion to
thebaine under these conditions with approximately
80% of combined opiate components (i.e. thebaine and
CME) isolated as determined via 1H NMR analysis,
and comparison to authentic samples. Hence, the use of
ionic liquids as solvents for this oxidation reaction does
not appear to enhance the rate of reaction appreciably
under those conditions examined here. Further investi-
gation using a wider range of ionic liquids as solvents
(see Fig. 2) may allow the realization of this goal.
However, it has been demonstrated that this strategy
does allow easy isolation of opiate components from an
otherwise intractable mixture of reaction products.
Finally, the oxidation was performed in a conventional
covalent solvent (i.e diethyl ether or tetrahydrofuran) in
which the CME was initially dissolved followed by
addition of excess MnO2. The heterogeneous mixture
was then sonicated for an extended reaction time (ca.
144 h). The separation of MnO2 and other troublesome
impurities from the unreacted CME and the desired
product, thebaine, was then accomplished by adding an
appropriate amount of ionic liquid and extracting the
organic components from the inorganic components
(contained in the ionic liquid) using ethyl acetate and/
or diethyl ether.7 Under these conditions, CME under-
went a >95% conversion to thebaine after extended
reaction time under sonication (ca. 144 h) as deter-
mined via 1H NMR analysis, and comparison to
authentic samples, with a quantitative isolation of com-
bined opiate components. It is obvious that this method
is far superior to all others performed so far. In essence,
this method has combined the use of a good solvent for
this oxidation reaction (i.e. dry THF under inert atmo-
sphere) with use of an excellent selective extractant for
the unreacted MnO2 and other inorganic impurities.
The second method in which ionic liquids were used in
the MnO2 oxidation of CME to thebaine employed a
biphasic solvent system. The CME starting material
was dissolved in diethyl ether giving a clear solution
that formed an upper layer when combined with the
more dense ionic liquid containing the MnO2 oxidant.
Utilization of this method afforded comparable results
compared to those obtained using that employed previ-
ously (Table 1; entry 2). Under these biphasic condi-
It is possible that the ionic liquid dissolves MnO2 and
other inorganic impurities present in these reactions,
forms some kind of colloid with the MnO2 particles, or
CH3CH2CH2CH2
CH3
R
R'
X-
-
N
N
N
N
BF4
X-
N
R
+
1-Butyl-3-methylimidazolium tetrafluoroborate
[bmim]BF4
R, R' = alkyl
-
-
-
-
-
X- = PF6 , B(aryl)4 , NO3 , Al2Cl7 , SbF6
Figure 2. 1,3-Dialkylimidazolium and N-alkylpyridinium based ionic liquids.

R. D. Singer, P. J. Scammells / Tetrahedron Letters 42 (2001) 6831–6833
6833
simply adsorbs to the surface of the MnO2 particles
preferentially to CME or thebaine. Regardless of the
interaction between the ionic liquid and MnO2, the
inorganic components of these reactions preferentially
partition into the ionic liquid layer versus the upper
organic layer into which the opiate components prefer-
entially partition. This allows the facile isolation of all
opiates in high yields; hence, the major drawbacks of
previous methods for the MnO2 oxidation of CME to
thebaine have been overcome. Our method requires the
use of less than half the amount of g-MnO2 as reported
elsewhere2b and has proven to be easily reproducible.
The use of sonication has also resulted in decreased
reaction times required for the reaction to go to com-
pletion as compared with unsonicated reactions. Hence,
our method offers significant advantages from an
industrial point of view, especially in the context of
disposal of unreacted MnO2. Depending on the method
used, CME can be converted into thebaine in varying
degrees. It has been reproducibly demonstrated that
using the ionic liquid strictly as an extractant for inor-
ganic impurities and by-products in those reactions in
which CME is converted to thebaine in a covalent,
molecular solvent affords high yields of thebaine. The
actual nature of the interaction between the ionic liquid
and MnO2 is a topic of current investigations. Also
noteworthy is the fact that these reactions represent one
of the first examples of an oxidation reaction conducted
in an ionic liquid.3c,8
Coop, A.; Rice, K. C. Heterocycles 1998, 49, 43; (d) Dung,
J.-S.; Mudryk, B.; Sapino, C.; Sebastian, A. European
Patent Application EP 0 889 045 A1, 1998.
3. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Holbrey, J.
D.; Seddon, K. R. Clean Prod. Process. 1999, 1, 233–236;
(c) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed.
2000, 39, 3772–3789.
4. Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.;
Rogers, R. D. Chem. Commun. 1998, 1765–1766.
5. The moisture stable 1-butyl-3-methylimidazolium was pre-
pared via
a modified version to those preparations
reported in the literature using NaBF4 in acetone; see: (a)
Wilkes, J. S.; Zaworotko, M. J. J. Chem. Soc., Chem.
Commun. 1990, 965; (b) Fuller, J.; Carlin, R. T.; Ostery-
oung, R. A. Electrochem. Soc. 1997, 144, 3881.
6. Scammells, P. J.; Ripper, J. A.; Singer, R. D. Australian
Provisional Patent, PQ9683, 2000.
7. Typical procedure: g-MnO2 Oxidation of CME to the-
baine: CME (0.50 g, 1.6 mmol) was dissolved in 10 mL of
freshly dried and distilled THF followed by addition of
g-MnO2 (0.70 g, 8.0 mmol). The heterogeneous mixture
was then sonicated at ambient temperature for 48 h, under
N2, after which time TLC analysis showed incomplete
reaction. An additional 5 equiv. of g-MnO2 (0.70 g, 8.0
mmol) was then added and the mixture sonicated for a
total of 144 h. 10 mL of 1-butyl-3-methyl-imidazolium
tetrafluoroborate, bmimBF4, were then added to the reac-
tion mixture to extract the MnO2, impurities and
unwanted by-products into a bottom ionic liquid layer.
The reaction mixture was then extracted, first with diethyl-
ether (3×30 mL), and then with ethyl acetate (3×30 mL)
that had formed an upper organic layer above the ionic
liquid layer. The combined organic extracts were then
washed with distilled water to remove residual ionic liquid,
dried with anhydrous MgSO4, filtered, and concentrated in
vacuo to afford 0.5 g of yellow solid. 1H NMR analysis
and comparison to authentic samples then showed >95%
conversion of CME to thebaine with essentially 100%
recovery of opiate from the reaction mixture. Less than 5%
of CME was the only other component present in the
reaction product mixtures determined by 1H NMR. The
yellow color of the products can be attributed to this
unreacted CME. The yellow color of the crude product
could be easily removed via recrystalization from ethanol
with a 93% recovery from crude to give pure thebaine with
a white color.
Acknowledgements
This work was supported by an operating grant from
the Natural Sciences and Engineering Research Council
of Canada and the Centre for Chiral and Molecular
Technologies, Deakin University, Australia. The dona-
tion of codeine methyl ether by Glaxo SmithKline
Australia is greatly appreciated.
References
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E. J. Chem. Soc. 1967, 89, 1942; (b) Barber, R. B.;
Rapoport, H. J. Med. Chem. 1975, 18, 1074–1077; (c)
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