One-pot N-dealkylation and acid-catalyzed rearrangement of morphinans into aporphines

Article abstract of DOI:10.1016/j.tetlet.2009.12.103

The one-pot N-demethylation and acid-catalyzed rearrangement of morphinan-N-oxides offers a new, shorter and more efficient route to neuropharmacologically important N-substituted aporphines. An improved procedure is described for the preparation of the starting alkaloid N-oxides using Na₂WO₄ as catalyst. The transetherification during the rearrangement of codeinone into 2-O-alkyl-norapocodeines is documented.

Full text of DOI:10.1016/j.tetlet.2009.12.103

Tetrahedron Letters 51 (2010) 1196–1198
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot N-dealkylation and acid-catalyzed rearrangement of morphinans
into aporphines
a
a
b
a,c,*
Sándor Berényi , Zsuzsanna Gyulai , Antal Udvardy , Attila Sipos
a
Department of Organic Chemistry, University of Debrecen, H-4010, PO Box 20, Debrecen, Hungary
Department of Physical Chemistry, University of Debrecen, H-4010, PO Box 7, Debrecen, Hungary
Department of Pharmaceutical Chemistry, University of Debrecen, H-4010, PO Box 70, Debrecen, Hungary
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The one-pot N-demethylation and acid-catalyzed rearrangement of morphinan-N-oxides offers a new,
Received 24 November 2009
Revised 9 December 2009
Accepted 16 December 2009
Available online 24 December 2009
shorter and more efficient route to neuropharmacologically important N-substituted aporphines. An
improved procedure is described for the preparation of the starting alkaloid N-oxides using Na WO as
2 4
catalyst. The transetherification during the rearrangement of codeinone into 2-O-alkyl-norapocodeines
is documented.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Mihály Beck on the
occasion of his 80th birthday
Keywords:
Morphinans
Aporphines
Acid-catalyzed rearrangement
Dopaminergic
N-Dealkylation
The efficient synthesis of N-substituted aporphines is one of
the main research fields of dopamine- and/or serotonin-active
compounds. The need for high yielding synthetic routes to 2-
0 °C. Cold methansulfonic acid (99.5% purity, 84% of the total vol-
ume) was added dropwise to the suspension under an argon atmo-
sphere. The mixture was stirred at 0 °C for 15 min before being
heated at 90 °C for 30 min under argon. The resulting mixture
was poured into ice-water, the alcohol and some of the water were
removed under reduced pressure until extensive precipitation of
the mesylate salt occurred. The solution was cooled to 5 °C for
30 min after which the salt was filtered off. The extent of rear-
rangement during the heating period was checked by thin layer
1
substituted-noraporphines emerged when extended neurophar-
2
macological studies of the most active compounds were reported.
This raised the issue of the preparation of multi-gram batches
which in turn required large amounts of expensive starting mor-
phinans which are difficult to obtain.
Currently the main method for the preparation of 2-substi-
tuted-N-alkyl-noraporphines is via the three-step N-substitution
of the starting morphinans, acid-catalyzed rearrangement into
aporphines and further chemical modifications on this sensitive
7
3
6
X
X
backbone. Here we present a one-pot method for the N-dealkyla-
8
tion and rearrangement of previously oxidized morphinan into the
noraporphine derivative.
14
O
C
5
2 2 2 4
H O , Na WO
N
N
9
H
3
C
H
3
4
O
O
The N-oxides of morphinans are well known with the excep-
1
0
5
tion of oripavine N-oxide (8). Their syntheses were accomplished
2
3
in accordance with our recently developed method (Scheme 1).
1
OR
OR
Yield (%)
64
71
56
58
72
2
All the synthesized N-oxides were investigated in a new, one-
pot procedure for the N-deprotection and rearrangement. The mor-
phinan N-oxides (6–10, 1 equiv) and iron(II) sulfate monohydrate
7,8
1
morphine
Δ
Δ
, R=H, X= -OH
, R=CH , X=α-OH
α
6
7
8
9
10
7
,8
2 codeine
3
oripavine Δ ,7Δ
6
8,14
3
4
5
, R=H, X=OCH3
, R=CH , X=OCH
(
2.5 equiv) were suspended in anhydrous alcohol and cooled to
6
,7 8,14
thebaine Δ
Δ
3
3
7
,8
codeinone Δ , R=CH , X=O
3
*
Corresponding author. Tel.: +36 52 512 900/22478; fax: +36 52 453 836.
E-mail address: asipos@puma.unideb.hu (A. Sipos).
Scheme 1. Formation of morphinan N-oxides 6–10.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.103

S. Berényi et al. / Tetrahedron Letters 51 (2010) 1196–1198
1197
OH
CH3SO2O
O
H
N
N
CH SO OH, CH OH
3
2
3
H C
H
H
3
O
FeSO4 H O
OH
OR
.
2
Ar atm.
OR
6
7
morphine N-oxide, R=H
codeine N-oxide, R=CH3
11 norapomorphine.HOSO CH , R=H
2 3
12 norapocodeine.HOSO CH , R=CH
2
3
3
Scheme 2. Transformation of morphine- and codeine-N-oxides 6 and 7.
OCH3
O
OQ
Yield (%)*
CH
CH SO OH, Q-OH
3 2
SO O
1
3 2-methoxynorapomorphine.HOSO
2
CH
3
, R=H, Q=CH
3
48
O
H
N
N
3
2
14 2-ethoxynorapomorphine.HOSO
2
CH
3
, R=H, Q=C
2
H
5
51
47
64
60
67
H C
H
H
3
FeSO4.H O
OH
OR
2
1
1
1
5 2-propoxynorapomorphine.HOSO CH , R=H, Q=C H
2
3
3
7
Ar atm.
6 2-methoxynorapocodeine.HOSO CH , R=CH , Q=CH
3
2
3
3
OR
7 2-ethoxynorapocodeine.HOSO CH , R=CH , Q=C H
2
3
3
2
5
8
9
oripavine N-oxide, R=H
thebaine N-oxide, R=CH3
18 2-propoxynorapocodeine.HOSO
CH
, R=CH
, Q=C H
3 7
2
3
3
*
reported yields are the average of 3 runs
Scheme 3. Versatile rearrangements of oripavine and thebaine N-oxides 8 and 9.
3
chromatography (dichloromethane–methanol-c. NH = 80:19:1)
O
O
OQ
and by using Dragendorff’s reagent which provided primary infor-
mation on the depth of colour of the visualized spots on interaction
with tertiary/quaternary amine functions. Morphinans appear as
brown spots, N-oxides are usually grey, while noraporphines are
black. During preliminary reactions, it was noted that in accor-
dance with previous observations,6 a reduction in the amount of
water had a crucial effect on the homogeneity of the product.
Therefore, absolute alcohols were used and commercially available
iron(II) sulfate heptahydrate was partially dehydrated to the
monohydrate at 120 °C under a nitrogen atmosphere for 5 h prior
3 2
CH SO O
O
H
N
N
CH SO OH, Q-OH
3 2
H C
H
H
3
FeSO4.H O
OH
2
Ar atm.
OCH3
-oxide
OCH3
10 codeinone
N
16, Q=CH3
1
1
7, Q=C H5
2
8, Q=C H7
3
7
to use.
Scheme 4. Novel rearrangements of codeinone N-oxide (10).
In the case of morphine- and codeine-N-oxides (6 and 7) abso-
lute methanol was used and the yields of products 11 and 12 were
4
7% and 59%, respectively (Scheme 2). This difference was com-
The N-propylation of noraporphines 11–18 was achieved in one
step. A mixture of 1 equiv of noraporphine salt, 1.5 equiv of n-pro-
monly noticed for apomorphine- and apocodeine-type products
which could be the result of the higher oxidative sensitivity of apo-
morphines. The physical and spectral data for the free base forms
of compounds 11 and 12 conformed with those of authentic
samples.
The unique diene structure of the C ring of oripavine and thebaine
N-oxides (8 and 9) offers possibilities of extended transformation in
comparison to other morphinans.8 In addition, the C6-ether func-
tion gives the opportunity for in situ transetherification during
rearrangement into aporphine.6b Combination of this strategy with
the simultaneous iron-mediated N-deprotection led to a variety of
noraporphines in 47–67% yields (Scheme 3). In the case of norapo-
morphines13–15, theproductswereobtainedafter recrystallization
from methanol. The physical and spectral data for the free base
forms of compounds 13–18 were in accord with those obtained via
different synthetic routes.2
Codeinone (5) is known to produce 2-methoxyapocodeine on
acid-catalyzed rearrangement.11 However, a systematic investiga-
tion of the acid-catalyzed rearrangement of 5 has not yet been car-
ried out. Here we present the first examples of the rearrangement
in the presence of anhydrous alcohols and an iron(II) salt
pyl iodide and 3.5 equiv of NaHCO , was allowed to reflux for 24 h
3
in the presence of a catalytic amount of KI in CH CN. The mixture
3
was cooled then filtered and the filtrate was evaporated to dryness.
The crude product was purified on a silica gel column using ether
as the solvent to afford N-propyl-noraporphines in 65–87% yield.
To demonstrate the effectiveness of this methodology, N-propylno-
rapomorphine was obtained in 27% overall yield from morphine
(1), which is at least fivefold higher in comparison to the best re-
ported method.
The development of efficient synthetic routes to highly active
and selective dopaminergic aporphines is important for discover-
ing efficacious alternatives for the management of diseases related
to the malfunction of the dopaminergic system (e.g., Parkinson’s
disease). One of our main intentions is to develop efficient solu-
tions for the preparation of pharmacologically promising deriva-
tives. The present one-pot method reduces the number of steps
towards 2-substituted-N-alkylnoraporphines and significantly
raises the overall yield.
,9
1
0
,3a
Acknowledgement
(Scheme 4). The electronic structure of the C ring and the C6-oxo
function also offer the opportunity for transetherification. As a
proof of concept, products 16, 17 and 18 were obtained in 67%,
The authors are grateful for the financial support of the National
Science Foundation (Grant OTKA reg. K 79126, NI61336 and NKTH-
OTKA K 68482).
7
1% and 63% yields, respectively.

1
198
S. Berényi et al. / Tetrahedron Letters 51 (2010) 1196–1198
6
7
8
9
.
.
.
.
(a) Berényi, S.; Hosztafi, S.; Makleit, S. J. Chem. Soc., Perkin Trans. 1 1992, 2693;
b) Berényi, S.; Czirják, M.; Makleit, S. J. Chem. Soc., Perkin Trans. 1 1993, 2137.
McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J. J. Org. Chem. 2003, 68,
847.
For a review on the chemistry of morphinandienes, see: Berényi, S.; Csutorás,
C.; Sipos, A. Curr. Med. Chem. 2009, 16, 3215.
Berényi, S.; Csutorás, C.; Sipos, A.; Gyulai, Z. Lett. Org. Chem. 2007, 4, 32; Sipos,
A.; Csutorás, C.; Berényi, S.; Uustare, A.; Rinken, A. Bioorg. Med. Chem. 2008, 16,
4
References and notes
(
1
.
Zhang, A.; Zhang, Y.; Branfman, A. R.; Baldessarini, R. J.; Neumeyer, J. L. J. Med.
Chem. 2007, 50, 171; Herm, L.; Berényi, S.; Vonk, A.; Rinken, A.; Sipos, A. Bioorg.
Med. Chem. 2009, 17, 4756; Giorgioni, G.; Piergentili, A.; Ruggieri, S.; Quaglia,
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R. J. Chem. Rev. 2007, 107, 274. and references cited therein.
9
2
3
.
.
Sipos, A.; Berényi, S. Synlett 2008, 1703.
563.
0. 2-Methoxy-norapocodeine mesylate (16) was prepared from thebaine N-oxide
4) or codeinone N-oxide (10) in 64% or 67% yields, respectively. Off-white,
(a) Gao, Y.; Ram, V. J.; Campbell, A.; Kula, N. S.; Baldessarini, J. R.; Neumeyer, J.
L. J. Med. Chem. 1990, 33, 39; (b) Søndergaard, K.; Kristensen, J. L.; Gillings, N.;
Begtrup, M. Eur. J. Org. Chem. 2005, 4428.
1
(
25
powder; mp 212–214 °C (ether); ½
aꢀ
ꢁ123 (c 0.1, DMSO); R
f
for the base
D
4
.
.
Casy, A. F.; Parfitt, R. T. Opioid Analgesics; Plenum Press: New York and London,
+
(
3
CHCl
3
–MeOH = 8:2) 0.18; HRMS (ESI) m/z (%) calcd for
20.1263 (M+Na ), Found: 320.1267 (M+Na , 100); d
C
18
H
19NO
3
Na :
1
986.
+
+
H
(360 MHz DMSO-d
6
5
Oripavine N-oxide (8) was prepared from oripavine (3) according to the
2
for the base) 9.59–9.10 (2H, br s, C11–OH, @N–H), 7.23 (1H, d, C1–H, J1–3 1.2),
6.98 (1H, d, C3–H, J1–3 1.2), 6.75 (1H, d, C8–H, J8–9 8.3), 6.73 (1H, d, C9–H, J8–9
method described in Ref. in 56% yield. White, plate-shape crystals; mp 198–
2
5
2
00 °C (ether); ½
a
ꢀ
ꢁ198 (c 0.5, MeOH); R
f
(CHCl
Na : 336.1212 (M+Na ), Found: 336.1230
(360 MHz DMSO-d ) 9.76 (1H, br s, C3–OH), 6.62 (1H, d, C1–
3
–MeOH = 8:2) 0.45; HRMS
D
+
+
8.3), 4.32 (1H, td, C6a–H, J6a–7a 9.1, J6a–7b 2.5), 3.93 (3H, s, C2–OCH
s, C10–OCH ), 3.35–2.84 (6H, m, C4–Ha, C4–Hb, C5–Ha, C5–Hb, C7–Ha, C7–
Hb); d (90 MHz DMSO-d ) 159.31 (C2), 147.73 (C10), 144.31 (C11), 133.94,
32.20, 129.98, 124.62, 124.12, 123.49, 119.91, 117.34, 111.78 (9C, aromatic),
7.62, 57.56, 56.83 (C6a, C2–OCH , C10–OCH ), 44.23 (C5), 37.94 (C7), 27.89
3
), 3.86 (3H,
(
(
ESI) m/z (%) calcd for C18H19NO
4
+
3
M+Na , 100); d
H
6
C
6
H, J1–2 8.0), 6.59 (1H, d, C2–H, J1–2 8.0), 5.68 (1H, d, C8–H, J7–8 5.5), 4.93 (1H, d,
C7–H, J7–8 5.6), 4.70 (1H, s, C5–H), 4.54 (1H, dd, C9–H, J 12.9, J 5.7), 3.59 (3H, s,
1
5
3
3
C6–OCH
NCH ), 2.03–1.94 (2H, m, C15–Ha, C15–Hb); d
47.61 (C4), 139.43 (C3), 132.19, 130.09, 128.64, 128.01, 122.99, 118.66 (6C, 4
aromatic, C8, C14), 95.01 (C7), 91.78 (C5), 77.49 (C9), 64.56 (C14), 56.68, 56.12
C6–OCH , N–CH ), 47.57 (C13), 36.39 (C10), 34.81 (C15).
3
), 3.34–2.94 (4H, m, C10–Ha, C10–Hb, C16–Ha, C16–Hb), 2.91 (3H, s,
(
C4).
3
C
(90 MHz DMSO-d ) 154.45 (C6),
6
11. Knorr, L. Ber. Dtsch. Chem. Ges. 1903, 36, 3074; Granchelli, F. E.; Filer, C. N.;
1
Soloway, A. H.; Neumeyer, J. L. J. Org. Chem. 1980, 45, 2275.
(
3
3