Microwave-promoted acid-catalyzed rearrangement of morphinans - A high-yield synthesis of R(-)-apomorphine

Article abstract of DOI:10.1080/00397910701845357

The microwave-promoted acid-catalyzed rearrangement of morphine (1), codeine (2), and thebaine (3) was investigated. In all cases, a significant improvement in the yields were achieved compared to the traditional techniques. R(-)-Apomorphine (4), which is a clinically important dopamine agonist, was synthesized from morphine (1) in 75% yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701845357

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Microwave‐Promoted Acid‐Catalyzed
Rearrangement of Morphinans—A High‐Yield
Synthesis of R(-)‐Apomorphine
C. Csutorás a , S. Berényi b & J. L. Neumeyer c
a Department of Chemistry , Eszterházy Károly College , Eger, Hungary
b Department of Organic Chemistry , University of Debrecen , Debrecen,
Hungary
c McLean Hospital, Harvard Medical School Alcohol and Drug Abuse Research
Center , Belmont, Massachusetts, USA
Published online: 22 Feb 2008.
To cite this article: C. Csutorás , S. Berényi & J. L. Neumeyer (2008) Microwave‐Promoted Acid‐Catalyzed
Rearrangement of Morphinans—A High‐Yield Synthesis of R(-)‐Apomorphine, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:6, 866-872, DOI:
10.1080/00397910701845357
To link to this article: http://dx.doi.org/10.1080/00397910701845357
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Synthetic Communicationsw, 38: 866–872, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845357
Microwave-Promoted Acid-Catalyzed
Rearrangement of Morphinans—A High-
Yield Synthesis of R(2)-Apomorphine
1
C. Csutoras, S. Berenyi, and J. L. Neumeyer
2
3
´
´
1
´
´
Department of Chemistry, Eszterhazy Karoly College, Eger, Hungary
2Department of Organic Chemistry, University of Debrecen, Debrecen,
Hungary
3McLean Hospital, Harvard Medical School Alcohol and Drug Abuse
Research Center, Belmont, Massachusetts, USA
Abstract: The microwave-promoted acid-catalyzed rearrangement of morphine (1),
codeine (2), and thebaine (3) was investigated. In all cases, a significant improvement
in the yields were achieved compared to the traditional techniques. R(-)-Apomorphine
(4), which is a clinically important dopamine agonist, was synthesized from morphine
(1) in 75% yield.
Keywords: acid-catalyzed rearrangement, apomorphine, aporphines, microwave
synthesis, morphinans, morphine
INTRODUCTION
A key step in the synthesis of many aporphines is the acid-catalyzed
rearrangement of the corresponding morphinan. It is well known that
morphine (1) and its congeners rearrange with concentrated acids to form
aporphines[1–4] (Scheme 1). However, the yields of the conversion of
morphine (1) to apomorphine (4)[1,2] and codeine (2) to apocodeine (5)[3]
are low, even using a variety of acids. Granchelli et al.[4] investigated the
acid-catalyzed rearrangement of thebaine (3) with methanesulfonic acid,
Received in Poland July 3, 2007
Address correspondence to Csaba Csutoras, Department of Chemistry, Eszterhazy
´ ´
Karoly College, H-3300 Leanyka Str. 6, Eger, Hungary. E-mail: csuti@ektf.hu
´
´
866

Synthesis of R(2)-Apomorphine
867
Scheme 1.
which resulted in the formation of 2,10-dimethoxy-11-hydroxyaporphine (6)
in 60% yield. The yield of this rearrangement can be improved[5] by
carrying out the rearrangement with methanesulfonic acid in the presence of
methanol. Recently we reported the investigation of the acid-catalyzed
rearrangement of a series of morphinans[6] using conventional thermal tech-
niques. The results of our study on the microwave-assisted acid-catalyzed
rearrangement of a series of morphinans are reported here.
Automated and focused microwave flash heating has recently proven to
be very effective in accelerating organic transformations and has been
widely applied in parallel syntheses and in drug discovery processes.
Numerous successful reactions with great efficiency and dramatically
enhanced reaction rates have been described.[7–9]
RESULTS AND DISCUSSION
The conditions of the microwave-promoted rearrangements with methanesul-
fonic acid and hydrochloric acid were optimized in the case of the morphine
(1) to apomorphine (4) rearrangement (Table 1).
The change in temperature and microwave power did not affect the yield
of the microwave assisted rearrangement. The optimal conditions were inves-
tigated in the case of the rearrangement reaction. Using methanesulfonic acid
at 908C, with 5 min stirring was found to be optimal for the rearrangement of
morphine (1). In the case of the rearrangement with hydrochloric acid the
optimal conditions for the microwave synthesis were the application of
1508C temperature, with 5 min stirring, under pressure. Methanesulfonic

´ ´
C. Csutoras, S. Berenyi, and J. L. Neumeyer
868
Table 1. Optimization of the microwave-assisted rearrangement reac-
tion of morphine (1)
Acid
Time (min)
T (8C)
Yield (%)a
99% CH3SO2OH
99% CH3SO2OH
99% CH3SO2OH
99% CH3SO2OH
37% HCl
5
10
5
60
60
50
52
75
64
70
60
90
2
150
150
150
5
10
37% HCl
aIsolated yield.
acid was shown to be an excellent solvent to mediate microwave energy, thus
lower microwave power was sufficient to achieve full conversion.
In the course of our study we found a significant improvement in the yields
in the acid-catalyzed rearrangements of morphinans using microwave heating,
compared to the conventional heating techniques (Table 2). Another advantage
of the use of microwave heating was the required shorter reaction time, thus the
obtained products did not need any further purification.
The morphine (1) to apomorphine (4) rearrangement (Scheme 1) was
carried out with methanesulfonic acid in 75% yield using microwave-
assisted heating at 908C for 5 min. This rearrangement was also attempted
Table 2. Microwave-assisted rearrangement of morphinans
Acid
Yield (%)[Ref.]
Conditions
Morphine (1) ! apomorphine (4)
37% HCl
34[1]
23[10]
45[6]
70
Thermal/1508C, 30 min, pressure
Thermal/908C, 30 min
Thermal/608C, 30 min
Microwave/1508C, 5 min, pressure
Microwave/908C, 5 min
99% CH3SO2OH
99% CH3SO2OH
37% HCl
99% CH3SO2OH
75
Codeine (2) ! apocodeine (5)
99% CH3SO2OH
99% CH3SO2OH
32[4]
65[6]
78
Thermal/908C, 30 min
Thermal/608C, 30 min
Microwave/908C, 5 min
99% CH3SO2OH
Thebaine (3) ! 2,10-dimethoxy-11-hydroxyaporphine (6)
99% CH3SO2OH
60[4]
(sideproduct: 7)
Thermal/908C, 30 min
99% CH3SO2OH
70
(sideproduct: 7)
95[5]
Microwave/908C, 5 min
CH3SO2OH/16% CH3OH
CH3SO2OH/16% CH3OH
Thermal/908C, 30 min
Microwave/908C, 5 min
95

Synthesis of R(2)-Apomorphine
869
in concentrated hydrochloric acid using microwave-assisted heating at 1508C
for 5 min under pressure. This reaction resulted in apomorphine (4) in 70%
yield, a considerable improvement compared to the classical method using tra-
ditional heating techniques.[1] In the case of codeine (2) and thebaine (3), the
optimized conditions were applied for the microwave-promoted rearrange-
ment with methanesulfonic acid. Heating of codeine (2) at 908C, for 5 min
in a microwave reactor with methanesulfonic acid resulted in the formation
of apocodeine (5) in 78% yield. 2,10-Dimethoxy-11-hydroxyaporphine (6)
was obtained from thebaine (3) with methanesulfonic acid in 70% yield
using similar conditions. Morphothebaine (7) was also isolated from the
reaction mixture, whose formation is the result of the water content of metha-
nesulfonic acid.[5,6] Yield of 95% was achieved by carrying out the
microwave-assisted rearrangement of thebaine (3) with methanesulfonic
acid in the presence of 16% methanol. Under these conditions morphothebaine
(7) was not formed.
CONCLUSION
In conclusion, the microwave-promoted synthesis was successfully applied for
the acid-catalyzed rearrangement of morphinans. R(2)-Apomorphine (4) was
synthesized from morphine (1) with methanesulfonic acid in 75% isolated
yield using microwave heating.
EXPERIMENTAL
Microwave irradiation was carried out with a CEM Discover microwave
instrument. Melting points were measured with a Thomas Hoover capillary
melting-point apparatus and are uncorrected. 1H NMR spectra were
obtained on Varian 300 spectrometer, chemical shifts are reported in parts
per million (d) from internal TMS, and coupling constants (J ) are measured
in hertz. Thin-layer chromatography (TLC) was performed on precoated
Merck 5554 silica-gel 40 F254 foils; the spots were visualized with Dragen-
dorff’s reagent.
General Procedure for the Microwave-Assisted Rearrangement of
Morphinans
The morphinan (0.3 mmol) was dissolved in the appropriate acid (1.5 mL) in a
10 mL glass tube, under nitrogen, with ice cooling. The vessel was sealed with
a septum and placed into the microwave cavity. The reaction mixture was
stirred for 5 min at 908C in a microwave reactor; after cooling to room temp-
erature, the reaction mixture was added to ice water (20 mL). The pH was

´ ´
C. Csutoras, S. Berenyi, and J. L. Neumeyer
870
adjusted to 9 by adding ammonia with ice cooling. The mixture was extracted
with ethyl acetate (3 ꢀ 10 mL); the organic layer was washed with brine
(20 mL), dried with sodium sulfate, filtered, and evaporated in vacuo to
afford the appropriate aporphines.
R(2)-Apomorphine Hydrochloride (4)
(a) Starting from morphine hydrate (1) using methanesulfonic acid, the
extraction was carried out with chloroform (5 ꢀ 10 mL), and after drying
with sodium sulfate, HCl ether was added to the filtered extract to afford
the hydrochloride salt. After evaporation, the solid, pure HCl salt was
filtered from anhydrous ether (68 mg, 75%), mp: 2108C . dec. [lit.
(Merck Index, 12th ed.) mp: 1958C (dec.)]. 1H NMR (CD3OD) d 2.75
(1H, t, C-H), 2.93–3.06 (1H, m, C-H), 3.09 (3H, s, NCH3), 3.32–3.55
(3H, m, C-H), 3.64–3.76 (1H, m, C-H), 4.18 (1H, m, C-H), 6.73 (2H,
dd, J ¼ 8 Hz, H-8, H-9), 7.15 (1H, d, J ¼ 8 Hz, H-3), 7.35 (1H, t, H-2),
8.42 (1H, d, J ¼ 8 Hz, H-1).
(b) Starting from morphine hydrate (1), using concentrated hydrochloric
acid, the rearrangement was carried out in microwave reactor for 5 min, at
1508C, under pressure in a sealed vial. The workup was identical to the pre-
viously mentioned method. Yield: 63 mg (70%), mp: 2108C . dec. [lit.
1
(Merck Index, 12th ed.) mp: 1958C (dec.)]. The H NMR spectrum was
identical to the previous spectrum.
R(2)-Apocodeine Hydrochloride (5)
Starting from codeine (3) using methanesulfonic acid, the product was
converted to the hydrochloride salt with HCl ether to yield a white solid
1
(75 mg, 78%), mp: 269–2708C (dec.) [lit.[2] mp: 260–2638C (dec.)]. H
NMR (CD3OD) d 2.8 (1H, t, C-H), 2.96–3.18 (1H, m, C-H), 3.2 (3H, s,
NCH3), 3.33–3.6 (3H, m, C-H), 3.77–3.86 (1H, m, C-H), 3.91 (3H, s,
OCH3), 4.33 (1H, m, C-H), 6.89 (2H, dd, J ¼ 8.5 Hz, H-8, H-9), 7.19 (1H,
d, J ¼ 8 Hz, H-3), 7.38 (1H, t, H-2), 8.44 (1H, d, J ¼ 8 Hz, H-1).
2,10-Dimethoxy-11-hydroxyaporphine Hydrochloride (6)
(a) Starting from thebaine (3) and using methanesulfonic acid, the two-
component product was separated by column chromatography (silica gel 60,
chloroform–methanol 19:1).
The first eluted compound was converted into the hydrochloride with HCl
ether to give white solid crystals of 6 (73 mg, 70%), mp: 87–908C (lit.[6] mp:
87–908C). 1H NMR (CD3OD) d 2.5 (1H, m, C-H), 2.8 (1H, t, C-H), 3.1 (1H,

Synthesis of R(2)-Apomorphine
871
m, C-H), 3.2 (3H, s, NCH3), 3.3–3.6 (2H, m, C-H), 3.8 (1H, m, C-H), 3.81
(3H, s, OCH3), 3.86 (3H, s, OCH3), 4.23 (1H, m, C-H), 6.76 (1H, d,
J ¼ 1.5 Hz, H-3), 6.88 (2H, dd, J ¼ 8 Hz, H-8, H-9), 8.1 (1H, d,
J ¼ 1.5 Hz, H-1).
The second eluted compound was converted into the hydrochloride with
HCl ether to give white solid crystals of 7 (15 mg, 15%), mp: 258–2608C [lit.
(Merck Index, 12th ed.) mp: 256–2608C]. 1H NMR (DMSO) d 2.9–3.6 (5H,
m, C-H), 3.46 (3H, s, NCH3), 4.09 (1H, m, C-H), 4.27 (3H, s, OCH3), 4.62
(1H, m, C-H), 6.98 (1H, s, H-3), 7.22 (1H, d, J ¼ 8 Hz, H-8), 7.35 (1H, d,
J ¼ 8 Hz, H-9), 8.24 (1H, s, H-1).
(b) Starting from thebaine (3) using methanesulfonic acid in the
presence of 16% methanol, the pure oily product was converted into the
hydrochloride with HCl ether to give white solid crystals of 6 (99 mg,
95%), mp: 87–908C (lit.[6] mp: 87–908C). The 1H NMR spectrum was
identical with the previously mentioned data.
ACKNOWLEDGMENT
The authors thank the Hungarian National Science Foundation (OTKA
F061607) and the Branfman Family Foundation for financial support of this
work. The authors also thank CEM Corporation for the microwave
equipment provided for evaluation. The alkaloids were generously supplied
by Mallinckrodt Inc.
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