Thebaine adducts with maleimides. Synthesis and transformations

Article abstract of DOI:10.1007/s11178-005-0306-8

Diels-Alder reaction of thebaine with maleimides is structurally specific and yields [7,8,3′,4′]-succinimido-endo-ethenotetrahydrothebaines containing N′-alkyl, cycloalkyl, aralkyl or aryl substituents. N′-[1(S)-hydroxymethyl-2-methylpropyl]-succinimido-6,14-endo- ethenotetrahydrothebaine formed in reaction of S-valinol with (7α,8α)-anhydrido-6,14-endo-ethenotetrahydrothebaine. The reduction of the adducts by LiAlH₄ afforded N′-substituted 7,8-pyrrolidino-endo-ethenotetrahydrothebaines. The reduction of fused succinimides by NaBH₄ resulted in the corresponding 2′α-hydroxylactam derivatives. O-Demethylation of the tetrahydrothebaine pyrrolidine derivatives effected by BBr₃ afforded compounds of the tetrahydrooripavine series. The O-demethylation of tetrahydrothebaine succinimide derivatives gave rise to the corresponding 6-demethyl-endo-ethenotetrahydrooripavines. Alkylation conditions were found for N′-(4-hydroxyphenethyl)-substituted tetrahydrothebaine succinimide derivatives. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11178-005-0306-8

Russian Journal of Organic Chemistry, Vol. 41, No. 8, 2005, pp. 1132−1144. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 8, 2005,
pp. 1155−1166.
Original Russian Text Copyright © 2005 by Shults, Shakirov, Tolstikov, Kalinin, Schmidhammer.
.
ThebaineAdducts with Maleimides. Synthesis and Transformations
E.E. Shults1, M.M. Shakirov1, G.A. Tolstikov1, V.N. Kalinin2, and G. Schmidhammer3
1Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
Novosibirsk, 630090 Russia
e-mail: schultz@nioch.nsc.ru
2Nesmeyanv Institute of Organoelemental Chemistry, Russian Academy of Sciences, Novosibirsk, Russia
3Institute of Pharmaceutical Chemistry at Innsbruck University, Austria
Received January 10, 2003
Abstract—Diels−Alder reaction of thebaine with maleimides is structurally specific and yields [7,8,3',4']-succinimido-
endo-ethenotetrahydrothebaines containing N'-alkyl, cycloalkyl, aralkyl or aryl substituents. N'-[1(S)-
hydroxymethyl-2-methylpropyl]-succinimido-6,14-endo-ethenotetrahydrothebaine formed in reaction of S-valinol
with (7α,8α)-anhydrido-6,14-endo-ethenotetrahydrothebaine. The reduction of the adducts by LiAlH4 afforded
N'-substituted 7,8-pyrrolidino-endo-ethenotetrahydrothebaines. The reduction of fused succinimides by NaBH4
resulted in the corresponding 2'α-hydroxylactam derivatives. O-Demethylation of the tetrahydrothebaine
pyrrolidine derivatives effected by ΒΒr3 afforded compounds of the tetrahydrooripavine series. The O-demethyla-
tion of tetrahydrothebaine succinimide derivatives gave rise to the corresponding 6-demethyl-endo-
ethenotetrahydrooripavines. Alkylation conditions were found for N'-(4-hydroxyphenethyl)-substituted
tetrahydrothebaine succinimide derivatives.
The nature of a substituent in positions 7,8 of
morphinane alkaloids in among the most important factors
affecting their biological activity [1]. For instance, the
opioid analgesic buprenorphine possesses a pharmaco-
logical profile interesting for development of antinarcotics
[2]. Aseries of studies treats the influence of a lipophilic
substituent at the C20 atom of the buprenorphine on the
pharmacological activity [3–6]. We previously reported
on thebaine cycloaddition to cyclic dienophiles providing
7α,8α-fused derivatives of 6,14-endo-ethenotetrahydro-
thebaine [7–10]. Among these thebaine derivatives
promising active analgesics were found [11]. Here we
report on thebaine (I) cycloaddition to various maleimides:
4-bromophenyl-substituted (IIa), 4- and 2-methoxy-
benzyl-substituted (IIb and IIc), arylethyl-substituted
(IId–IIg), cyclohexenylethyl- (IIh), and dimethylamino-
ethyl-substituted (IIi) maleimides. At short boiling of
reagents mixture in ethanol N'-substituted 7α,8α-succin-
imido-6,14-endo-ethenotetrahydrothebaines III–IX were
obtained as sole reaction products in a 82–96% yield
(Scheme 1).
atoms of thebaine was recently shown to afford a group
of selective μ-opioid agonists [13].
The other way to succinimide derivatives of endo-
ethenotetrahydrothebaine is a reaction of a thebaine
adduct with maleic anhydride XII [14, 15] and amines.
The heating of a mixture of compound XII with S-valinol
(XIII) in toluene in the presence of triethylamine and
molecular sieves (3A) afforded compound XIV. At the
use of excess amine XIII a considerable amount of
diamide XV was additionally isolated.
We investigated some transformations of the fused
thebaine derivatives synthesized. The additional lipophilic
groups were introduced into the molecule of 7,8-endo-
ethenotetrahydrothebaine (VII) by O-alkylation under the
conditions of a phase-transfer catalysis using 1,4-dibromo-
butane to obtain in 82% yield N'-bromobutoxyphenethyl
derivative XVI. The reaction of compound XVI with
aminoethanol in acetone in the presence of K2CO3
afforded a mixture of products of O- and N-alkylation
XVII and XVIII in 29 and 37% yield respectively
(Scheme 3).
It should be mentioned that in [12] thebaine adducts
were obtained with N-phenyl- and N-benzylmaleimides.
Annelation of N-arylsuccinimide fragments at the C7,8
The reduction of adducts III, VII, and XVI with excess
LiAlH4 in THF resulted in formation of the corresponding
7α,8α-pyrrolidino-6,14-endo-ethenotetrahydrothebaines
1070-4280/05/4108-1132©2005 Pleiades Publishing, Inc.

THEBAINE ADDUCTS WITH MALEIMIDES. SYNTHESIS AND TRANSFORMATIONS
1133
Scheme 1.
CH3O
2
3
4
1
11
14
CH3O
10
15
16
17
NCH3
O
12
5
O
13
19
18
O
NR
6
7 8
NCH3
5'
CH3O
1'
O
2'
O
N
CH3O
O
R
IIa_IIi
III_XI
I
R = C6H4Br (IIa, III), 4-MeOC6H4CH2 (IIb, IV), 2-MeOC6H4CH2 (IIc, V), C6H5(CH2)2 (IId, VI), 4-HOC6H4(CH2)2 (IIe, VII), 4-
FC6H4(CH2)2 (IIf, VIII), 2-FC6H4(CH2)2 (IIg, IX),
(CH2)2 (IIh, X), (CH2)2N(CH3)2 (IIi, XI).
Scheme 2.
CH3O
CH3O
CH3O
OH
O
O
H
NCH3
O
H2N
O
NCH3
XIII
NCH3
CH3O
H
CH3O
OH
N
O
H
O
O
H
CH3O
H
N
N
HO
O
HO
O
O
H
XII
XIV
XV
similar conditions is accompanied with 6-O-de-
methylation and results in diols XXVI and XXVII (yield
79–96%). As seen, here the O-demethylation of the aryl
methyl ether in position 3 involves also O-demethylation
of the alkyl methyl ether in position 6 of the morphinane
skeleton It is presumable that this reaction direction is
governed by the carbonyl group of the succinimide moiety.
This assumption we confirmed by an example of reaction
of compound XIV containing a hydroxyethyl substituent
at the nitrogen of the succinimide fragment. Under the
standard reaction conditions a mixture was obtained of
6-demethyltetrahydrothebaine (XXVIII) and 6-demethyl-
oripavine (XXIX) in a ratio 1:2, i.e., the demethylation of
the alkyl methyl ether is twice faster than the demethyla-
tion of the aryl methyl ether. We succeeded in isolating
compound XXIX in 73% yield when the reaction mixture
was kept for a longer time at room temperature. When
tetrahydrothebaine XXIII containing a 2'-hydroxylactam
fragment was brought into reaction 6-demethyltetra-
XIX–XXI. The partial reduction of the cyclic imides with
various reagents [NaBH4, (i-Bu)2AlH,
NaAlH2(OCH2CH2OEt)2] was considered in detail in
review [16]. As a rule a problem of regio- and stereo-
selectivity arises for the unsymmetrically substituted
imides. We found that the reduction of compounds V and
VI with sodium borohydride in THF in the presence of
ethanol solution of HCl made it possible to isolate 2'α-
hydroxylactams of endo-ethenotetrahydrothebaine XXII
and XXIII in a 73–78% yield. The reaction is
characterized by the regio- and stereospecificity and is
apparently governed by the methoxy group attached to
C6 atom of the morphinane skeleton (Scheme 4).
An interesting result was obtained while investigating
the O-demethylation of adducts. Pyrrolidinooripavines
XXIV and XXV were cleanly formed at treating
compounds XIX and XX with excess ΒΒr3 in chloroform
[17]. 3-O-Demethylation of adducts III and IV under
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

SHULTS et al.
1134
Scheme 3.
CH3O
O
Br(CH2)4Br
NCH3
O
VII
CH3O
N
O
(CH2)2
O(CH2)4Br
XVI
CH3O
CH3O
O
NH2CH2CH2OH
NCH3
O
O
K2CO3
NCH3
O
CH3O
N
CH3O
O
(CH2)2
XVIII
O(CH2)4NH(CH2)2OH
N
O
O(CH2)4O(CH2)2NH2
(CH2)2
XVII
Scheme 4.
CH3O
CH3O
O
O
NCH3
NCH3
LiAlH4
NaBH4
H
III, VII, XVI
V, VI
CH3O
CH3O
O
2'
H
N
N
R
HO
R
XIX_XXI
XXII, XXIII
R = 4-BrC6H4 (XIX), 4-OHC6H4(CH2)2 (XX), (CH2)2C6H4O(CH2)4Br (XXI), 2-MeOC6H4CH2 (XXII), Ph(CH2)2 (XXIII).
hydrothebaine XXX was obtained in 69% yield. Thus the
substituent in the succinimide fragment significantly
affects the result of the O-demethylation reaction. This
influence is apparently due to the stabilization of the
reagent complex with the ether oxygen atom through
formation of a six-membered organoboron cyclic
intermediate with the oxygen-containing substituent of
the succinimide fragment. The selective demethylation
of the alkyl methyl ether in the presence of aryl methyl
ether was also observed in demethylation by LiAlH4–
THF in the presence of CCl4 of traces of thevinols
containing C20-hydroxy or C20-amino substituents [18]
(Scheme 5).
The structure of the synthesized endo-ethenotetra-
hydrothebaines and oripavines was established by analysis
of spectral data (Tables 1–3). In the IR spectra of adducts
III–XI and compounds XIV, XVI–XVIII, and XXVI–
XXIX appear characteristic bands of stretching vibrations
in the regions 1270–1251(C–N), 1696–1706, and 1762–
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

THEBAINE ADDUCTS WITH MALEIMIDES. SYNTHESIS AND TRANSFORMATIONS
1135
Scheme 5.
HO
HO
O
O
BBr3
NCH3
O
BBr3
NCH3
H
III, IV
XIX, XX
H
HO
CH3O
N
N
R
R
O
XXVI, XXVII
XXIV, XXV
R = 4-BrC6H4 (XXIV, XXVI), 4-OHC6H4(CH2)2 (XXV), Ph(CH2)2 (XXVII).
CH3O
HO
CH3O
O
O
O
NCH3
NCH3
BBr3
BBr3
NCH3
XXIII
XIV
HO
HO
O
H
O
H
HO
O
2'
N
N
H
N
O
HO
O
HO
HO
(CH2)2Ph
XXVIII
XXIX
XXX
considerable difference in the chemical shifts of H18 and
H19 protons, and also by existence of coupling between
the protons H5 and H19 (4J 1.2–1.5 Hz) (W-shaped
position of the bonds) (Table 1). The comparison of 1H
NMR spectra of adducts III–XI, and XIV reveals the
effect of the substituent on the nitrogen atom of the
succinimide fragment on some spectral parameters,
namely on the chemical shifts of the skeleton protons
H7,8,18,19. For instance, in the spectrum of N'-p-bromo-
phenyl-substituted adduct III these protons are shifted
downfield with respect to the corresponding protons in
the spectra of compounds with aralkyl (Δδ 0.11–0.24 for
H7,8 and 0.18–0.24 for H18,19) and alkyl (Δδ 0.07–0.13
for H7,8 and 0.09–0.11 for H18,19) substituents at the
nitrogen of the succinimide moiety. It should be
emphasized that protons H7,8,18,19 in the succinimide
thebaine derivatives are located downfield from the
corresponding protons in adduct XII. The reduction of
the succinimide fragment into a pyrrole one results in an
1775 (C=O) cm–1. In the IR spectrum of diamide XV the
absorption bands of amide groups are clearly seen at
1654 cm–1. The amide band in 2'-hydroxy-endo-etheno-
tetrahydrothebaines XXII, XXIII, and XXX is shifted to
lower frequencies. In pyrrolidino-endo-ethenotetra-
hydrothebaines and oripavines XIX–XXI, XXIV, and
XXV these absorption bands of amide groups disappear,
in the spectra of N-aryl-substituted derivatived XIX and
XXIV a strong band of stretching vibrations at 1595–
1605 cm–1 is observed (N–Ar). A special feature of the
IR spectra of the O-demethylation products XXVI,
XXVII, and XXIX is the presence of absorption bands
of hydroxy groups at 3240, 3380 or 3440 cm–1. The
difference in the absorption of hydroxy groups for
compounds XXVIII and XXIX is revealed in the spectrum
of 3-hydroxy derivative XXIX by appearance of an
additional absorption band at 3450 cm–1. The stretching
vibrations of hydroxy group in position 2' give rise in the
spectra of compounds XXII, XXIII, and XXX to narrow
bands in the region 3398–3415 cm–1.
upfield shift of the resonances from protons H7β,8β,9α
,
and also in increased difference between the chemical
The compounds were assigned to the endo-series
basing on the NMR spectra. In the 1H NMR spectra of
adducts III–XI and all derivatives thereof (Table 1) the
endo-orientation of the bridge was confirmed by the
shifts of protons H10,15,16 of the piperidine ring.
The characteristic features of the 1H NMR spectrum
of diamide XV consist in the downfield shift of the protons
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

SHULTS et al.
1136
from the olefin double bond in the bridge and in the upfield
shift of the proton signal from H9α (Δδ 0.17 ppm) caused
by the substituent in the cis-position at the atom C8. The
value of the vicinal coupling constant for protons H7,8
(J 11.6 Hz) corresponds to the cisoid location of the
substituents [19].
hydrothebaines XX and XXI is a peak of m/z 393 (100%)
corresponding to the cleavage with formation of
N-methylenepyrrolidino[6,14,3',4']ethenotetrahydro-
thebainium ion. For compound XXV the most abundant
peak has m/z 379 (100%).
Thus the Diels−Alder reaction of thebaine with
N-substituted maleimides occurs stereoselectively
affording the products of the β-attack of the dienophile:
7α,8α-succinimido-6,14-endo-etheno-6,7,8,14-tetra-
hydrothebainesβ (6α,14α-ethenoisomorphinanes). The
reduction of adducts provided 7α,8α-fused pyrrolidino-
or 2'α-hydroxy-5'-oxopyrrolidinotetrahydrothebaines.
Depending on the nature of the substituent in the fused
fragment the O-demethylation effected by ΒΒr3 yielded
C6- (demethylation of alkyl methyl ether) and (or) C3-
(demethylation of aryl methyl ether) hydroxy derivatives
of isomorphinanes.
The position of the hydroxy group at the C2' atom and
its α-orientation in compounds XXII and XXIII was
proved by NOESYexperiment.At suppressing the signals
of the protons from the methoxy group attached to C6
atom the NOE-effect was observed for protons H5, H7
and H2'; suppression of the signal from the hydroxy group
results in the NOE-effect on the protons from the bridging
double bond H18,19. In the spectra of compounds XXII
and XXIII a downfield shift of the olefin protons H18,19
and proton signal from H8 should also be mentioned. Even
stronger downfield displacement of the mentioned signals
1
is characteristic of the H NMR spectrum of the 6-O-
EXPERIMENTAL
demethylation product hydroxylactam XXX (Table 1).
1H and 13C NMR spectra were registered on
spectrometers Bruker AC-200 [operating frequencies
200.13 (1H) and 50.32 (13C) ΜHz] and Bruker DRX-
500 [operating frequencies 500.13 (1H) and 125.76 (13C)
ΜHz] from 5% solutions in CDCl3, CD3OD, or CCl4.
The assignment of signals in the NMR spectra were done
with the use of various proton-proton and carbon-proton
procedures of correlation spectroscopy (COSY,
COLOC, CORRD), 1H 2D-NMR spectroscopy, spectra
with Overhauser effect NOESY, and also the data from
[7, 8]. 19F NMR spectra of 10% solutions of adducts
VIII and IX were registered on spectrometer Bruker
WP-200-SY, internal reference C6F6. IR spectra were
recorded on Vector-22 instrument from samples pelletized
with KBr. UV absorption spectra were taken on
spectrometer HP 8453 UV Vis in ethanol (C 10–4 M).
For recording mass spectra, molecular weight estimation,
and elemental analysis we used high resolution mass
spectrometer Finnigan MAT-8200 (ionizing electrons
energy 70 eV, vaporizer temperature 270–300°C).
Reaction progress was monitored by TLC on Silufol UV-
254 plates. The reaction products were isolated by column
chromatography on silica gel (eluent chloroform) or on
neutral or alkaline aluminum oxide (eluents chloroform,
chloroform–ethanol, 200:1–10:1).
In Table 2 are presented the 13C NMR spectra of
new endo-ethenotetrahydrothebaines III–XI and also
that of adduct XII for the sake of comparison. The
formation of the O- and N-alkylation products XVII and
XVIII is derived from the presence of the signals from
carbon atoms CH2O (δ 66.72, 64.14), CH2NH2 (δ 44.67)
for amine XVII and CH2NH (δ 51.92, 51.86), CH2OH
(δ 67.44 ppm) for alcohol XVIII.
We should call attention to the downfield shift of the
resonance from C5 atom in the products of complete
(XIX–XXI) and partial (XXII and XXIII) reduction of
the succinimide fragment (Table 3). Asimilar downfield
shift was observed for atom C5 in the spectrum of
oripavine XXV. Besides the spectra of 6-demethyl-
oripavines XXVI, XXVII, XXIX, and XXX are
characterized by a downfield shift of the signal from C2
atom and an upfield shift of the peaks from C3 and C6
(Table 3).
Mass spectra of adducts III–V, IX, XI, and XIV and
of their derivatives XVI, XVIII, XXII, and XXIII contain
molecular ion peaks (Table 1), and also a peak of a frag-
ment ion with m/z 310 (thebaine-1) (of abundance 100,
65.91, 65.88, 60.63, 60.92, 100, 100, 100, 87.12, 98.08%
respectively) corresponding to the ion generated by retro-
diene cleavage of the compounds. This fragment ion of
the retrodiene reaction (with m/z 282 and 296, abundance
100%) appears in the mass spectra of 6-demethyl-
oripavines XXVI, XXVII, and XXIX, and 6-demethyl-
tetrahydrothebaine XXVIII respectively. The main frag-
ment ion for the fused pyrrolidino-endo-ethenotetra-
The elemental analyses of compounds synthesized are
consistent with the calculated values.
S-Valinol (XIII), mp 31–32°C, bp. 75°C (6 mm Hg.),
20
[α] +17° (C 11, EtOH) was obtained by procedure
578
from [20].
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

THEBAINE ADDUCTS WITH MALEIMIDES. SYNTHESIS AND TRANSFORMATIONS
1137
1
Table 1. Yields, melting points, data of mass, IR, and H NMR spectra of N'-substituted 7α,8α-succinimido-6α,14α-endo-etheno-
6,7,8,14-tetrahydrothebaines III, XIV, XVI–XVIII, 7α,8α-pyrrolidino-6α,14α-endo-etheno-6,7,8,14-tetrahydrothebaines XX–XXII,
corresponding oripavines XXV, XXVII, XXIX, and 6-demethyltetrahydrothebaines XXVIII, XXX a
Formula,
m/z calc/m/z exp
(Irel %)
Yield
mp, °C,
(solvent)
IR spectrum,
cm–1
,
1H NMR spectrum, δ, ppm (J, Hz)
%
III
91 245–246 C29H27N2O5Br,
710, 796, 810, 1.93 m (2H, H15), 2.41 s (3H, CH3N), 2.43 d.d (1H, H10,
(ethanol) 562.11037/562.10925, 886, 954, 1012, J 18.7, 6.6), 2.48 d.d.d (1H, H16, J 12.4, 4.0, 2.2), 2.55 d.d.d
562 (66), 389 (33),
346 (22), 311 (45),
310 (100), 355 (52), 1250, 1500,
229 (34), 216 (25),
188 (30)
1051, 1069,
1110, 1220,
(1H, H16, Jgem 12.6, Jvic 12.1 and 1.5), 3.15 d (1H, H7, J 8.1),
3.23 d (1H, H10β, Jgem 18.7), 3.68 s (3H, CH3OC6), 3.79 s (3H,
CH3OC3), 3.98 d (1H, H9α, J 6.6), 4.36 d (1H, H8, J 8.1),
4.66 d (1H, H5β, J 1.5), 5.42 d (1H, H19, J 8.7), 5.82 d.d (1H,
H18, J 8.7 and 1.4), 6.55 d (1H, H1, J 8.1), 6.63 d (1H, H2,
1598, 1628,
1706, 1775,
3068, 3454
J 8.1), 7.04 d (2H, H2',6'), 7.49 d (1H, H3',5'
)
XIV 72 266–267 C28H34N2O6,
718, 748, 771, 0.70 d (3H, CH3, J 7.0), 0.94 d (3H, CH3, J 7.0), 1.90 d.d.d
(ethyl 494.24167/494.24265, 818, 948, 984, (1H, H15, J 13.2, 5.4 and 1.4), 1.98 m (1H, H15, Jgem 13.2,
acetate) 494 (100), 479 (21), 1013, 1047,
J 12.2, 6.0), 2.26 m (1H, H-i-Pr), 2.46 s (3H, CH3N), 2.44 m
(2H, H10,16), 2.61 d.d.d (1H, H16, Jgem 12.6, Jvic 12.2 and 1.4),
3.15 d (1H, H7, J 8.3), 3.23 d (1H, H10β, Jgem 18.6), 3.62 m and
3.72 m (2H, CH2), 3.69 C (3H, CH3OC6), 3.79 s (3H,
CH3OC3), 3.94 d.d (1H, CH, J 7.0 and 5.6), 3.99 d (1H, H9α,
J 6.4), 4.23 d (1H, H8, J 8.3), 4.67 d (1H, H5β, J 1.4), 5.38 d
(1H, H19, J 8.7), 5.75 d.d (1H, H18, J 8.7 and 1.4), 6.54 d (1H,
H1, J 8.2), 6.62 d (1H, H2, J 8.2)
319 (64), 311 (27),
310 (71), 276 (68),
255 (34), 229 (31),
162 (28), 44 (33)
1083, 1145,
1228, 1252,
1268, 1500,
1599, 1630,
1694, 1764,
3060, 3445,
3489
XVI 82 180–182 C35H39N2O6Br,
(ethyl 662.15
747, 820, 922, 1.80 m (2H, CH2), 1.85 m (1H, H15), 1.90 m (2H, CH2 and
944, 999, 1017, 1H, H15), 2.47 s (3H, CH3N), 2.45 m (2H, H10,16), 2.57 d.d.d
acetate) 621 (17), 527 (39),
512 (25), 311 (34),
1051, 1110,
1159, 1213,
(1H, H16, J gem 12.4, Jvic 12.1 and 1.5), 2.67 d.t (2H, CH2), 3.01
d (1H, H7, J 8.0), 3.26 d (1H, H10, J 18.7), 3.43 m (2H,
CH2Br), 3.55 m (2H, CH2), 3.57 s (3H, CH3OC6), 3.78 s (3H,
H3OC3), 3.90 t (2H, CH2O), 3.93 d (1H, H9, J 6.7), 4.20 d
(1H, H8,
310 (100), 294 (23), 1250, 1501,
255 (39), 229 (28),
216 (21), 162 (34),
55(37), 28 (96)
1511, 1612,
1632, 1699,
1769, 3453
J 8.0), 4.62 d (1H, H5β, J 1.6), 5.23 d (1H, H19, J 8.7), 5.60 d.d
(1H, H18, J 8.7 and 1.6), 6.54 d (1H, H1, J 8.2), 6.61 d (1H,
H2, J 8.2), 6.74 d (2H, H2',6', J 8.7), 7.04 d (2H, H3',5', J 8.6)
XVII 29 162–164 C37H45N3O7,
722, 820, 921, 1.83 m (4H, 2CH2), 1.88 m (1H, H15), 1.95 m (1H, H15), 2.43
(ethanol) 643.32
944, 998, 1059, m (1H, H16), 2.43 s (3H, CH3N), 2.48 m (1H, H10), 2.54 d.d.d
1009, 1160,
1250, 1511,
1610, 1627,
1700, 1760,
3445
(1H, H16, Jgem 12.4, Jvic 12.1 and 1.8), 2.68 m (2H, CH2NH2),
3.01 d (1H, H7, J 7.9), 3.22 d (1H, H10, J 18.6), 3.58 m (2H,
CH2O), 3.64 m (2H, CH2), 3.67 s (3H, CH3OC6), 3.79 s (3H,
CH3OC3), 3.86 m (2H, CH2), 3.90 t (2H, CH2O), 3.95 d (1H,
H9, J 6.7), 4.16 d (1H, H8, J 7.9), 4.62 d (1H, H5β, J 1.6), 5.26
d (1H, H19, J 8.7), 5.48 m (2H, NH2), 5.60 d.d (1H, H18, J 8.7
and 1.6), 6.53 d (1H, H1, J 8.2), 6.61 d (1H, H2, J 8.2), 6.74 d,
6.75 d (2H, H2',6', J 8.7), 7.03 d, 7.08 d (2H, H3',5', J 8.6)
XVIII 37 142–144 C37H45N3O7,
(ethyl 643.32
750, 820, 944, 1.66 m (2H, CH2), 1.78 m (2H, CH2), 190 d.d.d (1H, H15,
998, 1052,
1017, 1051,
1110, 1159,
1213, 1250,
1501, 1511,
1612, 1632,
1699, 1769,
3453
J 13.4, 2.3, 1.8), 1.93 d.d.d (1H, H15, J 13.4, 12,1, 3.2), 2.27 m
and 2.62 m (2H, CH2N), 2.41 s (3H, CH3N), 2.45 m (2H,
H10,16), 2.54 d.d.d (1H, H16, Jgem 12.4, Jvic 12.1 and 1.8),
2.67 d.t (2H, CH2), 2.99 d (1H, H7, J 7.9), 3.22 d (1H, H10,
J 18.7), 2.48 m and 3.24 m (2H, CH2N), 3.56 m (2H, CH2),
3.66 s (3H, CH3OC6), 3.79 s (3H, CH3OC3), 3.82 and 3.88 m
(2H, CH2), 3.91 t (2H, CH2O), 3.95 d (1H, H9, J 6.7), 4.15 d
(1H, H8, J 7.9), 4.60 d (1H, H5β, J 1.6), 5.25 d (1H, H19, J 8.7),
5.61 d.d (1H, H18, J 8.7 and 1.6), 6.53 d (1H, H1, J 8.2), 6.61 d
(1H, H2, J 8.2), 6.748 d, 6.752 d (2H, H2',6', J 8.7), 7.05 d (2H,
H3',5', J 8.6)
acetate)
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

SHULTS et al.
1138
Table 1. (Contd.)
Formula,
m/z calc/m/z exp
(Irel %)
Yield, mp, °C,
(solvent)
IR spectrum,
1H NMR spectrum, , ppm (J, Hz)
%
cm–1
XX
92 162–164 C31H36N2O4,
(ethanol) 500.26749/
500.26812,
774, 829, 880,
932, 948, 981,
1.77 d.d.d (1H, H15, J 13.2, 4.0, 1.5), 1.96 m (1H, H3', J 9.2),
2.10 t.d (1H, H15, J 13.2, 12.5, 5.6), 2.15 d.d (1H, H2', J 9.8,
1018, 1053, 1109, 9.2), 2.33 s (3H, CH3N), 2.32 m (1H, H10), 2.40 m (1H, H16),
500 (1.6), 394
1144, 1252, 1276, 2.48 d.d.d (1H, H16, Jgem 12.6, Jvic 12.5 and 1.5), 2.59 m (2H,
(28), 393 (100), 1345, 1500, 1515, CH2), 2.65 m (2H, CH2), 2.73 m (1H, H7, J 9.2, 7.3, 8.1), 3.09
152 (37)
1598, 1615, 1631, d (1H, H9, J 6.4), 3.12 t.d (1H, H3', J 8.1, 8.1), 3.16 t.d (1H,
2799, 2934, 3036, H2', J 9.8 and 7.3 ), 3.20 d (1H, H10β, Jgem 19.4), 3.49 C (3H,
3431
H3OC6), 3.66 d.d.d (1H, H8, J 9.2), 3.79 s (3H, CH3OC3),
4.58 d (1H, H5β, J 1.3), 5.31 d (1H, H19, J 8.8, 1.2), 5.75 d.d
(1H, H18, J 8.8, 1.5 and 1.3), 6.50 d (1H, H1, J 8.1), 6.60 d (1H,
H2, J 8.1), 6.64 d (2H, H2',6', J 8.4), 6.94 d (2H, H3',5', J 8.5)
0.93 t (2H, CH2), 1.44 m (2H, CH2), 1.71 m (2H, CH2),
XXI
85 188–190 C35H43N2O4Br, 723, 773, 833,
(ethanol) 634.82,
394 (29), 393
980, 1013, 1034, 1.80 d.d.d (1H, H15, J 13.6, 5.2, 1.8), 2.10 d.t (1H, H15, J 13.6,
1054, 1105, 1247, 12.0, 5.6), 2.30 s (3H, CH3N), 2.35 m (1H, H10, Jgem 18.7),
(100), 152 (36), 1512, 1596, 1615, 2.49 m (1H, H16), 2.50 d.d.d (1H, H16, Jgem 12.2, Jvic 12.0 and
107 (12), 42 (14), 1630, 2936, 3010, 1.8), 3.03 m (1H, H7), 3.06 d (1H, H9, J 5.6), 3.07 m (4H,
31 (11)
3425
2CH2), 3.20 d (1H, H10β, Jgem 18.7), 3.49 s (3H, CH3OC6),
3.35 m (2H, CH2), 3.79 s (3H, CH3OC3), 3.88 t (2H, CH2,
J 7.2), 4.00 m (1H, H8, J 9.5, 6.8, 2.2), 4.59 d (1H, H5β, J 1.4),
5.41 d (1H, H19, J 8.7), 5.85 d.d (1H, H18, J 8.7 and 1.4), 6.52 d
(1H, H1, J 8.2), 6.61 d (1H, H2, J 8.2), 6.79 d (2H, H2',6', J 8.5),
7.08 d (2H, H3',5', J 8.6)
XXII 73 249–250 C31H34N2O6,
795, 880, 905,
1.85 d.d.d (1H, H15, J 13.2, 5.9 and 1.7), 1.96 d.d.d (1H, H15,
(ethanol) 530.24167/530.24935, 961, 1026, J 13.2, 12.3, 3.8), 2.44 s (3H, CH3N), 2.43 m (1H, H10),
180,
530 (38), 311
1050, 1086, 1108, 2.46 d.d.d (1H, H16, J 12.6, 5.9, 3.8), 2.55 d.d.d (1H, H16,
1600, 1628, 1685, Jgem 12.6, Jvic 12.3 and 1.7), 2.70 m (1H, H7, J 9.6, 7.3, 1.1),
(45), 310 (87), 3024, 3082, 3416 3.21 d (1H, H10β, Jgem 18.7, J 1.0), 3.66 s (3H, CH3OC6),
174 (41),
121(100), 91 (35)
3.79 s, 3.80 s (6H, CH3OC3,2'), 4.01 d (1H, H8, J 9.6), 4.18 d
(1H, H9α, J 6.6), 4.28 d, 4.61 d (2H, CH2, J 15.2), 4.51 d (1H,
H5β, J 1.5), 4.86 d (1H, OH, J 2.5), 5.25 d.d (1H, H2', J 7.3,
2.5), 5.48 d.d (1H, H19, J 8.9, 1.2), 5.96 d.d (1H, H18, J 8.9, 1.3
and 1.5), 6.55 d (1H, H1, J 8.2), 6.63 d (1H, H2, J 8.2), 6.81 dd
(1H, H3', J 7.2, 1.4), 6.85 d.t (1H, H5', J 7.2, 7.0 and 1.4), 7.16
d.d (1H, H6', J 7.2, 1.5), 7.19 d.t (1H, H4', J 7.2, 7.0 and 1.5)
1.85 d.d.d. (1H, H15, J 12.9, 6.2, 2.8), 2.04 m (1H, H15), 2.14 m
(2H, CH2), 2.42 m (2H, H10,16), 2.35 s (3H, CH3N), 2.54 d.d.d
(1H, H16, Jgem 12.8, Jvic 12.2 and 2.8), 2.81 d.t (2H, CH2, J 7.1
XXV 92 228–230 C30H34N2O4,
701, 727, 771,
800, 833, 883,
937, 945, 980,
(ethanol) 486.25184/
486.25117,
486 (1.4), 380
1031, 1050, 1102, and 2.1), 3.06 d (1H, H7, J 5.1), 3.12 m (2H, H3',2'), 3.28 d (1H,
(29), 379 (100), 1125, 1217, 1233, H10β, Jgem 18.2), 3.35 d (1H, H9α, J 6.8), 3.46 m (2H, H2',3'),
152 (58), 104
(17)
1250, 1321, 1613, 3.48 s (3H, OCH3), 3.70 d.d.d (1H, H8, J 6.8, 3.4, 2.6), 4.61 d
1636, 3032, 3230, (1H, H5β, J 1.4), 5.30 d (1H, H19, J 7.2), 5.71 d.d (1H, H18,
3428
J 7.2 and 1.4), 6.47 d (1H, H1, J 6.8), 6.64 d (1H, H2, J 6.8),
6.70 d (2H, H2'',6'', J 7.4), 6.99 d (2H, H3'`'5''
)
XXVII 92 161–164 C29H28N2O5,
(ethyl 484.19981/
750, 794, 819,
1.91 d.d.d (1H, H15, J 13.6, 5.4, 1.8), 2.04 d.d.d (1H, H15
,
934, 973, 1037, J 13.6, 12.6, 5.4), 2.46 m (1H, H10), 2.51 m (1H, H16), 2.52 s
1075, 1105, 1153, (3H, CH3N), 2.63 d.d.d (1H, H16, Jgem 12.7, Jvic 12.6 and 1.8),
1228, 1250, 1501, 2.81 t.d (2H, CH2, J 7.7 and 3.2), 2.86 d (1H, H7, J 8.1), 3.28 d
acetate) 484.19795,
484 (36), 308
(30), 283 (40), 1610, 1632, 1650, (1H, H10β, Jgem 18.8), 3.70 d.t (2H, CH2, J 7.8 and 0.9), 3.95 d
282 (100), 227 1693, 1766, 3050, (1H, H9α, J 6.7), 4.26 d (1H, H8, J 8.1), 4.49 d (1H, H5β, J 1.5),
(30), 44 (26)
3080, 3439
5.21 d (1H, H19, J 8.8), 5.59 d.d (1H, H18, J 8.8 and 1.5),
6.53 d (1H, H1, J 8.1), 6.68 d (1H, H2, J 8.1), 7.20 m (3H, Ph),
7.27 m (2H, Ph)
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

THEBAINE ADDUCTS WITH MALEIMIDES. SYNTHESIS AND TRANSFORMATIONS
Formula,
1139
Table 1. (Contd.)
Yield, mp, °C,
%
IR spectrum,
cm–1
m/z calc/m/z exp
(Irel %)
1H NMR spectrum, ? , ppm (J, Hz)
(solvent)
XXVIII 28 181–183 C27H32N2O6,
(ethyl 480.22602/
acetate) 480.23060,
480 (33), 395
708, 727, 750,
775, 797, 818,
0.71 d (3H, CH3, J 7.0), 0.95 d (3H, CH3, J 7.0), 1.91 d.d.d
(1H, H15, J 13.4, 4.1 and 1.4), 1.98 d.d (1H, H15, J 13.4,
983, 1011, 1015, 11.8, 2.4), 2.26 m (1H, H-i-Pr), 2.44 s (3H, CH3N), 2.45 m
1048, 1079,
1109, 1143,
1499, 1596,
(2H, H10,16), 2.57 d.d.d (1H, H16, Jgem 12.5, Jvic 11.8 and 1.4),
2.86 d (1H, H7, J 8.2), 3.24 d (1H, H10β, Jgem 18.6), 3.62 d.d
and 3.94 d.d (2H, CH2, J 10.6, 6.8, 4.5), 3.72 d.d (1H, CH,
J 6.8 and 4.5), 3.79 s (3H, CH3OC3), 3.89 d (1H, H9α, J 6.4),
(10), 297 (26),
296 (100), 241
(29), 162 (18), 42 1621, 1690,
(40)
1761, 3240, 3331 4.24 d (1H, H8, J 8.2), 4.43 d (1H, H5β, J 1.4), 5.34 d (1H,
H19, J 8.7), 5.77 d.d (1H, H18, J 8.7 and 1.4), 6.53 d (1H, H1,
J 8.2), 6.62 d (1H, H2, J 8.2)
XXIX 56 (73) 228–230 C26H30N2O6,
(ethanol) 466.21037/
466.21500,
724, 751, 788,
820, 857, 933,
0.69 d (3H, CH3, J 7.0), 0.91 d (3H, CH3, J 7.0), 1.84 d.d.d
(1H, H15, J 13.3, 3.6 and 1.6), 1.99 m (1H, H15, J 13.3, 12.6,
952, 1016, 1031, 2.1), 2.21 m (1H, H-i-Pr), 2.38 m (1H, H10), 2.41 s (3H,
466 (28), 381
(18), 283 (42),
282 (100), 227
(31), 148 (41), 44 1764, 3441
(79)
1077, 1105,
1503, 1622,
1635, 1690,
CH3N), 2.42 m (1H, H16), 2.53 d.d.d (1H, H16, Jgem 12.7,
J
J
vic 12.6 and 1.6), 2.98 d (1H, H7, J 8.2), 3.19 d (1H, H10β
,
gem 18.4), 3.74 d.d and 3.99 d.d (2H, CH2), 3.72 m (1H, CH,
J 7.0 and 5.6), 3.89 d (1H, H9α, J 6.6), 4.22 d (1H, H8, J 8.2),
4.46 d (1H, H5β, J 1.4), 5.29 d (1H, H19, J 8.7), 5.70 d.d (1H,
H18, J 8.7 and 1.4), 6.45 d (1H, H1, J 8.2), 6.58 d (1H, H2,
J 8.2)
XXX
69 238–241 C30H32N2O5,
(ethanol) 500.12
722, 751, 802,
815, 891, 930,
1.90 d.d.d (1H, H15, J 13.5, 4.0, 1.6), 2.08 m (1H, H15, J
13.5, 12.0, 5.0), 2.46 s (3H, CH3N), 2.48 m (1H, H10), 2.49
960, 1000, 1030, m (1H, H16), 2.63 d.d.d (1H, H16, Jgem 12.5, Jvic 12.0 and
1050, 1085,
1106, 1160,
1304, 1330,
1500, 1596,
1610, 1667,
1678, 1767,
1.6), 2.86 m (2H, CH2), 2.90 d.d.t (1H, H7, J 9.0, 6.0, 1.4),
3.19 d (1H, H10β, Jgem 18.7), 3.40 m, 3.60 m (2H, CH2), 3.84
s (3H, CH3OC3), 4.10 d (1H, H8, J 9.0), 4.20 d (1H, H9α, J
6.5), 4.50 d (1H, H5β, J 1.5), 5.06 m (1H, OH), 4.87 d (1H,
H2', J 6.0), 5.57 d (1H, H19, J 8.9), 6.05 d.d (1H, H18, J 8.9
1.5 and 1.4), 6.52 d (1H, H1, J 8.2), 6.62 d (1H, H2, J 8.2),
3048, 3300, 3422 7.23 m (3H, Ph), 7.30 m (2H, Ph)
a
Compound IV, yield 92%, mp 188–190 (from ethyl acetate); compound V, yield 80%, mp 210–212 (from ethanol); compound VI, yield 96%,
mp 239–241 (from ethanol); compound VII, yield 92%, mp 278–280 (from ethanol); compound VIII, yield 82%, mp 212–214 (from ethyl
acetate); compound IX, yield 87%, mp 219–220 (from ethyl acetate); compound X, yield 85%, mp 192–195 (from ethyl acetate); compound
XI, yield 85%, mp 188–190 (from ethanol); compound XIX, yield 72%, mp 248–250 (from ethyl acetate); compound XXIII, yield 78%,
mp 185–186 (from mixture ethyl acetate–ether); compound XXIV, yield 79%, mp 221–222 (from ethanol); compound XXVI, yield 96%,
mp 219–220 (from ethyl acetate).
Maleimides IIb–IIi. To a solution of 0.02 mol of
maleic anhydride in 80 ml of acetic acid was added
0.02 mol of amine. The reaction mixture was boiled for
2–10 h (TLC monitoring). The solvent was removed in
a vacuum, water was eliminated from the residue by
an azeotropic distillation with benzene, then the residue
was dissolved in a minimum amount of chloroform, and
the solution was passed through a bed of silica gel. The
chloroform was evaporated in a vacuum, the residue was
ground with ether to isolate the corresponding maleimide
as a solid substance that was recrystallized from an
The thebaine adduct with maleic anhydride was
prepared as in [15]. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.89 d.d.d (1H, H15, J 13.3, 4.1 and 1.4), 1.91
d.d.d (1H, H15, J 13.3, 11.2 and 3.1), 2.44 s [3H, (CH3N)],
2.48 m (1H, H16, J 12.3, 10.3 and 1.4), 2.45 d.d (1H, H10,
J 18.6, 1.2), 2.58 d.d.d (1H, H16, Jgem 12.3, Jvic 4.2 and 1.5),
3.35 d (1H, H10β, Jgem 18.6), 3.30 d (1H, H8, J 8.6), 3.67
C (3H, CH3OC6), 3.80 s (3H, CH3OC3), 3.89 d (1H,
H9α, J 6.4), 4.55 d (1H, H7, J 8.6), 4.59 d (1H, H5β, J
1.3), 5.48 d (1H, H19, J 8.7), 5.88 d.d (1H, H18, J 8.7 and
1.3), 6.57 d (1H, H1, J 8.2), 6.64 d (1H, H2, J 8.2).
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

SHULTS et al.
1140
Table 2. 13C NMR spectra of N'-substituted 7α,8α-succinimido-6α,14α-endo-ethenotetrahydrothebaines III, IV, VI–XI, XIV,
XVI–XVIII, δ, ppma
Atom no.
III
IV
VI
VII
VIII
IX
X
XI
XII
XIV
XVI
XVII XVIII
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
119.85 119.81 119.49 119.77 119.81 119.68 119.74 119.78 120.13 119.84 119.80 119.72 119.80
113.43 113.39 113.17 113.48 113.42 113.34 113.31 113.49 114.17 113.58 114.43 113.53 113.42
141.93 142.04 141.61 141.95 142.00 141.85 141.94 142.02 142.17 142.11 142.05 141.92 141.96
147.68 147.75 147.38 147.66 147.69 147.59 147.67 147.80 147.71 147.77 147.63 147.66 147.67
90.48 90.48 90.37 90.78 90.81 90.68 90.81 90.68 90.55 90.39 90.99 90.79 90.75
80.59 80.53 80.16 80.44 80.48 80.34 80.45 80.54 79.93 80.52 80.52 80.43 80.49
41.31 41.18 40.88 41.25 41.27 41.13 41.19 41.28 42.71 40.95 39.69 39.85 41.23
42.20 42.12 41.76 42.03 42.12 41.98 42.07 42.24 43.43 43.15 41.23 41.24 42.06
58.16 56.96 56.53 56.86 56.89 56.71 56.85 56.93 56.59 56.33 56.95 56.82 56.87
22.26 22.36 21.93 22.25 22.28 22.15 22.61 22.31 22.50 22.46 22.36 22.22 22.26
127.38 128.98 127.18 127.40 127.44 127.40 127.46 127.56 127.19 129.21 127.53 127.44 127.48
132.25 132.50 132.26 132.46 132.49 132.46 132.56 132.64 131.99 133.26 131.65 132.50 132.51
47.78 47.68 47.36 47.68 47.78 47.61 47.72 47.78 47.95 47.68 47.75 47.66 47.73
45.13 44.89 44.53 44.83 44.89 44.73 44.80 44.92 44.97 44.84 45.03 44.83 44.88
33.43 33.32 33.99 33.35 33.48 33.31 33.42 33.48 33.50 33.03 33.47 33.37 33.41
44.91 45.05 44.67 44.95 44.99 44.87 44.95 45.06 44.87 45.08 44.94 44.92 44.98
17-NCH3 43.09 43.13 42.87 43.10 43.19 43.05 43.13 43.21 43.12 41.66 43.15 43.08 43.17
18
19
133.59 133.09 132.78 133.06 133.16 133.07 133.04 133.21 134.28 133.26 133.15 133.08 133.15
128.77 127.94 128.10 128.65 128.75 128.61 128.79 128.88 129.26 129.56 128.68 128.61 128.71
OCH3C3 56.78 56.27 55.95 56.28 56.30 56.19 56.23 56.35 56.45 56.99 56.45 56.28 56.33
OCH3C6 51.52 51.47 51.19 51.56 51.62 51.46 51.54 51.50 51.95 51.41 51.63 51.52 51.57
CH2N
CH2R
C2'
C2'
–
–
41.67 39.25 39.84 39.65 38.16 37.16 36.19
32.99 32.38 32.53 26.88 35.72 55.85
–
–
–
39.79 39.85 39.94
–
61.47 32.38 32.47 32.54
172.56 173.73 173.46 173.88 173.84 173.61 173.81 174.05 167.46 175.06 173.88 173.74 173.84
175.93 176.96 176.77 177.20 177.15 176.92 177.21 177.34 170.91 178.65 176.82 177.09 177.19
a
Signals of other carbon atoms, δ, ppm: III, 122.10 s, 127.69 d, 131.92 d, 132.25 s (Ar); IV, 56.95 q, 113.63 d, 113.91 d, 128.98 s, 129.95 d,
158.97 s (Ar); VI, 126.14 d, 128.01 d, 128.36 d, 137.27 s (Ar); VII, 115.16 d, 129.80 d, 129.50 s, 154.26 s (Ar); VIII, 115.07 d, 115.23 d,
130.12 d, 130.18 d, 133.25 s, 162.54 s (Ar); IX, 115.16 d, 123.77 d, 124.53 s, 128.23 d, 130.90 d, 160.13 s (Ar); X, 22.04 t, 22.61 t,
25.14 t, 27.46 t, 123.73 d, 133.78 s; XI, 45.10 q, 45.03 q (CH3); XIV, 19.81 q, 19.93 q (CH3), 26.06 d (CH), 60.53 d (CH); XVI, 27.64 t,
29.22 t, 33.12 t, 66.57 t (CH2), 114.22 d (C3',5'), 129.56 s (C1'), 29.62 d (C2',6'), 157.34 c (C4'); XVII, 25.84 t, 29.56 t, 44.67 t, 64.14 t, 66.72 t,
67.30 t (CH2), 114.34 d (C3',5'), 129.65 d (C2',6'), 131.54 s (C1'), 155.54 s (C4'); XVIII, 25.81 t, 26.71 t, 51.92 t, 51.86 t , 61.65 t,
67.44 t (CH2), 114.31 d (C3',5'), 129.54 d (C2',6'), 131.13 s (C1'), 157.56 s (C4').
289 (3.02). 1H NMR spectrum (CDCl3), δ, ppm: 2.84 d,
appropriate solvent. N-(4-Methoxybenzyl)maleimide
(IIb). Yield 56%, mp 101–103°C (from ether) (publ.: mp
101.5–103°C [21]). 1H NMR spectrum (CDCl3), δ, ppm:
2.70 m, 2.84 m (2H, CH2), 3.73 s (3H, CH3O), 6.56 s
(2H, H3,4), 6.79 m (2H, H2',6'), 7.22 m (2H, H3',5').
2.89 d (2H, CH2, J 7.8 Hz), 3.68 d, 3.75 d (2H, CH2,
J 7.8 Hz), 6.59 s (2H, H3,4), 7.19 m (5H, Ph). 13C NMR
spectrum (CDCl3), δ, ppm: 34.27 t (CH2Ar), 38.87 t
(CH2N), 126.46 d (C4'), 128.34 d, 128.61 d (C3',5,2',6'),
137.67 s (C1'), 133.81 d (C3,4), 170.38 d (C2,5).
N-(2-Methoxybenzyl)maleimide (IIc). Yield 68%,
mp 108–110°C (from ethyl acetate). 1H NMR spectrum
(CD3OD), δ, ppm (J, Hz): 3.68 d, 3.75 d (2H, CH2,
J 7.6), 3.87 s (3H, CH3O), 6.60 s (2H, H3,4), 6.96 m (2H,
H3',5'), 7.12 m (2H, H4',6').
N-(4-Hydroxyphenethyl)maleimide (IIe). Yield
62%, mp 174–176°C (from ethanol) (publ.: mp 175–
1
178°C [23]). H NMR spectrum (CDCl3), δ, ppm:
2.88 m (2H, CH2), 3.28 m (2H, CH2), 6.60 s (2H, H3,4),
6.88 d (2H, H2',6', J 8.5 Hz), 7.08 d (2H, H3'5', J 8.5 Hz).
N-(Phenethyl)maleimide (IId). Yield 82%, mp 108–
110°C (from ethanol) (publ.: mp 112°C [22]). IR spectrum,
Cm–1: 743, 824, 842, 954, 1085, 1138, 1583, 1606, 1705,
1755. UV spectrum, λmax, nm (lg å): 208 (4.48), 248 (3.28),
N-(4-Fluorophenethyl)maleimide (IIf). Yield 68%,
mp 148–150°C (from ethyl acetate). 1H NMR spectrum
(CDCl3), δ, ppm: 2.84 d, 2.89 d (2H, CH2, J 7.6 Hz),
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

THEBAINE ADDUCTS WITH MALEIMIDES. SYNTHESIS AND TRANSFORMATIONS
1141
Table 3. 13C NMR spectra of N'-substituted 7α,8α-pyrrolidino- (XIX–XXI), 7α,8α-(2'-hydroxy-5-oxo)pyrrolidino- (XXII, XXIII) -
endo-ethenotetrahydrothebaines and 6-demethyltetrahydrothebaines XXVIII, XXX and the corresponding oripavines XXIV–
XXVII, XXIX, δ, ppma
Atom no. XIX
XX
XXI
XXII
XXIII XXIV XXV
XXVI
XVII XXVIII XXIX
XXX
1
2
3
119.21 119.10 119.53 119.72 119.79 119.80 120.82 120.42 120.36 119.80 120.40 120.02
113.28 112.94 113.52 113.34 113.63 116.57 117.85 117.53 117.22 113.93 117.41 116.22
141.93 141.84 142.04 141.75 141.79 137.79 139.93 138.01 137.91 142.07 138.03 141.18
146.90 147.75 147.54 147.58 147.63 148.41 148.14 146.46 146.32 147.88 146.43 147.28
4
5
6
7
8
93.81
81.28
40.22
43.57
59.08
22.14
92.98
81.63
41.93
40.69
58.71
22.02
91.89 93.34
81.05 81.75
40.72 44.36
39.34 38.85
58.58 56.48
22.10 22.15
93.40
81.88
41.31
38.81
56.56
22.21
93.24 93.98 94.94
81.50 82.79 76.08
42.58 43.67 45.30
40.33 41.27 41.61
59.12 60.10 56.92
22.42 23.15 22.59
95.33
75.80
44.99
41.26
56.92
22.58
95.31
75.69
44.84
40.89
56.68
22.36
95.13
76.04
45.03
41.24
56.88
22.50
97.22
79.12
45.05*
44.52*
58.06
22.27
9
10
11
12
13
14
15
16
127.71 127.69 127.12 128.18 128.17 127.15 127.77 126.42 127.29 127.32 126.54 126.82
133.90 134.19 133.22 133.03 133.08 133.79 131.01 132.28 132.36 132.61 132.53 132.03
47.98
45.30
32.96
48.30
44.46
32.62
48.35 48.06
44.76 45.08* 45.10* 45.42 46.10 44.99
32.37 33.42 33.48 32.80 33.72 32.31
44.88 45.01* 45.08* 45.42 46.58 43.10
43.48 43.16 44.32 43.50 43.63 45.30
48.09
48.26 48.36 47.66
47.79
45.02
33.21
45.49
43.14
47.54
44.88
32.68
45.47
43.11
47.79
45.07
32.36
45.50
43.18
48.22
47.25
33.38
46.66
43.10
49.86* 45.17
43.54
17-NCH3 42.22
18
19
134.49 135.34 134.96 133.10 133.19 134.61 134.99 133.73 133.37 133.62 133.90 133.80
129.18 130.04 130.21 127.75 127.30 129.03 131.43 130.22 130.43 131.41 130.52 128.88
OCH3C3 56.42
OCH3C6 51.99
56.30
51.48
56.41 56.36
51.83 52.92
56.46
53.05
38.81
33.66
83.12
–
–
–
–
–
–
–
–
56.45
–
–
–
56.19
55.05
37.41
32.12
51.60 52.33
–
–
50.98
51.53
CH2N
CH2R
C2'
C5'
–
–
56.10* 55.96* 37.99
33.94 31.12
39.86
33.71
–
39.74
32.51
–
–
61.31
60.51
49.94* 56.38* 55.82* 82.23
51.00 58.11
175.84* 177.01* 178.42* 178.48* 86.12
175.92* 177.28* 178.51* 178.40* 177.12
56.22 172.36 172.34
–
a
The starred signals should probably be interchanged within the same column. The signals of the other carbon atoms , δ, ppm: XIX,
108.15 s (C1'), 114.27 d, 112.79 d (C3',5'), 128.87 d, 131.47 d (C2',6'), 148.12 s (C4'); XX, 115.32 d, 129.95 d, 129.38 s, 155.02 s (Ar); XXI,
27.86 t, 29.26 t, 33.34 t, 67.35 t (CH2), 114.86 d (C3',5'), 129.77 s (C1'), 130.22 d (C2',6'), 156.84 s (C4'); XXII, 55.36 q (CH3), 110.19 d ,
120.24 d, 124.30 s, 128.33 d, 129.64 d, 157.27 s (Ar); (XXIII) – 126.12 d, 128.17 d, 128.28 d, 128.32 d, 128.62 d, 139.02 s (Ph); XXIV,
126.49 d, 128.01 d, 128.96 d, 137.48 s (Ar); XXV, 115.46 d, 129.18 d, 129.56 s, 155.18 s (Ar); XXVI, 137.29 s (C1'), 126.35 d, 128.68 d
(C2',3',5',6'), 128.29 s (C4'); XXVII, 127.35 d, 128.51 d, 128.88 d, 136.43 s (Ar); XXVIII, 19.64 q, 19.85 q (CH3), 26.00 d (CH), 60.64 d (CH);
XXIX, 19.88 q, 20.03 q (CH3), 26.34 d (CH), 60.70 d (CH); XXX, 126.24 d, 126.32 d, 128.45 d, 128.70 d, 138.46 s (Ph).
spectrum (CDCl3), δ, ppm: 1.62 m (4H, H4',5'), 1.99 m
(4H, H3',6'), 2.14 m (2H, CH2), 2.29 m (2H, CH2), 5.33 m
(1H, H2'), 6.64 s (2H, H3,4).
3.71 d, 3.73 d (2H, CH2, J 7.8 Hz), 6.62 s (2H, H3,4),
6.93 m (2H, H2',6'), 7.12 m (2H, H3',5'). 13C NMR
spectrum (CDCl3), δ, ppm: 33.50 t (CH2Ar), 38.92 t
(CH2N), 115.15 d, 115.36 d (C3',5'), 130.10 d, 130.18 d
(C2',6'), 133.35 s (C1'), 133.91 d (C3,4), 160.42 s (C4'),
170.38 d (C2,5).
N-[2-(N,N-Dimethylamino)ethyl]maleimide (IIi).
1
Yield 58%, mp 175–178°C (from ethanol). H NMR
spectrum (CDCl3), δ, ppm: 2.22 c (6H, 2CH3N), 2.22 m
(2H, CH2), 2.39 m (2H, CH2), 6.56 s (2H, H3,4).
N-(2-Fluorophenethyl)maleimide (IIg). Yield 65%,
mp 138–140°C (from ethyl acetate). 1H NMR spectrum
(CDCl3), δ, ppm: 2.84 m (2H, CH2), 3.29 m (2H, CH2),
6.62 s (2H, H3,4), 6.90 m (2H, Ph), 7.18 m (2H, Ph).
Thebaine adducts with maleimides. To a solution
of 5 mmol of thebaine (I) in 15 ml of ethanol 5.2 mmol
of an appropriate maleimide in 10 ml of ethanol was
added. The reaction mixture was heated at reflux for 3–
9 h (TLC monitoring). On cooling the precipitated crystals
N-[2-(Cyclohex-1-enyl)ethyl]maleimide (IIh).
1
Yield 62%, mp 172–175°C (from ether). H NMR
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005

SHULTS et al.
1142
of adducts III–XI were filtered off, the mother liquor
was evaporated, and the oily compound obtained was
subjected to column chromatography on alkaline
aluminum oxide to isolate additionally 15–20% of the
adduct. Yields and spectral characteristics of N'-substitut-
ed [7α,8α,3',4']succinimido-6,14-endo-ethenotetrahydro-
thebaines III–XI are presented in Tables 1, 2. 19F NMR
spectrum, δ, ppm: 45.38 m (F4', VIII), 43.90 m (F2', IX).
51.92 d (C7), 52.08 q (C6 OCH3), 56.42 q (C3CH3O),
57.28 d (C9), 58.60 d (2CHN), 60.45 t, 63.65 t (CH2OH),
80.19 s (C6), 92.93 d (C5), 113.46 d (C2), 119.49 d (C1),
124.00 d (C19), 127.84 C (C11), 133.57 s (C12), 139.64 d
(C18), 141.89 C (C3), 147.67 s (C4), 172.50 s (C2'), 178.15
s (C5''). C33H47N3O7. Mass spectrum, m/z (Irel, %): 494
(100), 409 (46), 319 (63), 311 (39), 310 (73), 276 (64),
255 (57), 216 (34), 162 (37), 60 (55) and 42 (96).
[7α,8α,3',4']{N'-[(1S)-1-Hydroxymethyl-2-
methylpropyl]succinimido}-6,14-endo-etheno-
6,7,8,14-tetrahydrothebaine (XIV). To a solution of
1.0 g (2.42 mmol) of compound XII in 45 ml of freshly
distilled toluene was added under argon 0.25 g (2.4 mmol)
of S-valinol (XIII). The reaction mixture was boiled at
stirring for 2 h. Into the homogeneous solution obtained
0.48 g (4.8 mmol) of triethylamine and molecular sieves
(3 A) were added, and the reaction mixture was boiled
for another 17 h. On cooling the reaction mixture was
washed with water and dried with MgSO4. The solvent
was evaporated, the residue was crystallized from ethanol.
We filtered off 0.80 g (65%) of compound XIV. The
chromatography of the mother liquor on a column charged
with aluminum oxide afforded in succession 0.085 g
(7.2%) of adduct XIV and 0.29 g (20%) of 7α,8α-
bis{N'-[(1S)-1-hydroxymethyl-2-methylpropyl]-
aminocarbonyl}-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine (XV). mp 240–242°C (from
ethanol). IR spectrum, cm–1: 755, 797, 923, 986, 1012,
1040, 1055, 1083, 1107, 1146, 1156, 1210, 1252, 1499, 1537,
1568, 1598, 1654, 3075, 3384. UV spectrum, λmax, nm
[7α,8α,3',4']-N'-[4-(Bromobutoxy)phenethyl]-
succinimido-6,14-endo-etheno-6,7,8,14-tetra-
hydrothebaine (XVI). To a solution of 0.53 g (1 mmol)
of compound VII in 20 ml of CH2Cl2 was added 8 ml of
24% aqueous NaOH, 0.01 g of tetrabutylammonium
bromide, and 0.25 g (1.3 mmol) of 1,4-dibromobutane.
The reaction mixture was stirred at room temperature
for 24 h, then diluted with 50 ml of water, and the reaction
products were extracted into dichloromethane. The
organic solution was washed in succession with water
and saturated NaCl solution, dried over MgSO4, and the
solvent was evaporated in a vacuum. The obtained crude
product (0.8 g) was ground into amorphous powder in a
mixture acetone −hexane. On recrystallization from ethyl
acetate we isolated 0.54 g (82%) of compound XVI. UV
spectrum, λmax, nm (log å): 220 (4.21), 250 (2.48), 278
(1.88).
[7α,8α,3',4']-N'-{4-[4-(2-Aminoethoxy)butoxy]-
phenethyl}- and [7α,8α,3',4']-N'-{4-[4-(2-hydroxy-
ethylamino)butoxy]phenethyl}succinimido-6,14-
endo-etheno-6,7,8,14-tetrahydrothebaines (XVII,
XVIII). To a solution of 0.65 g (1 mmol) of compound
XVI in 30 ml 0.82 g of K2CO3, and the reaction mixture
was heated at reflux for 8th till complete disappearance
of the initial compound (TLC monitoring). On cooling the
precipitate was filtered off, washed with acetone, the
compound acetone solution was evaporated in a vacuum,
the residue was subjected to chromatography on aluminum
oxide. We isolated 0.18 g (29%) of amine XVII and
1
(log ε): 215 (4.26), 245 (3.28), 286 (2.18). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 0.80 d (3H, CH3,
J 7.0), 0.86 d (3H, CH3, J 7.0), 1.01 d (3H, CH3, J 7.0),
1.07 d (3H, CH3, J 7.0), 1.63 m [1H, CH(i-Pr)],
1.81 d.d.d (1H, H15, J 13.5, 4.2 and 1.4), 1.99 m [1H,
CH(i-Pr)], 2.06 d.d.d (1H, H15, J 13.5, 10.2 and 3.1),
2.32 s [3H, (CH3N)], 2.41 m (1H, H16, J 12.2, 10.3 and
1.4), 2.45 m (1H, H10), 2.51 d.d.d (1H, H16, Jgem 12.2,
0.23 g (37%) of compound XVIII. UV spectrum, λmax
,
vic 4.2 and 1.5), 3.03 m (1H, CH), 3.16 d (1H, H10β, Jgem
nm (log å): 215 (4.26), 245 (3.28), 286 (2.18) (XVII);
222 (4.32), 245 (2.28), 284 (2.98) (XVIII).
J
18.6), 3.28 d (1H, H7, J 11.6), 3.39 d.d (1H, CH, J 7.6
and 5.3), 3.56 s (3H, CH3OC6), 3.55 m and 3.76 m (2H,
CH2), 3.67 m (1H, CH), 3.79 s (3H, CH3OC3), 3.81 d
(1H, H9α, J 6.4), 4.08 d (1H, H8, J 11.6), 4.62 d (1H, H5β,
J 1.3), 5.82 d (1H, H19, J 8.7), 5.90 d.d (1H, H18, J 8.7
and 1.3), 6.10 m (2H, NH), 6.52 d (1H, H1, J 8.2), 6.60 d
(1H, H2, J 8.2). 13C NMR spectrum (CDCl3), δ, ppm:
17.88 q, 18.52 q, 19.01 q, 19.54 q (CH3), 22.36 t (C10),
28.58 d, 29.73 d [CH(i-Pr)], 32.92 t (C15), 43.43 q (CH3N),
43.88 s (C13), 45.22 t (C16), 47.28 s (C14), 50.30 d (C8),
Reduction of adducts III, VII, and XVI by LiAlH4.
To a solution of 2.5 mmol of adducts III or VII in 20 ml
of anhydrous THF was added by small portions in an
argon flow 0.2 g of LiAlH4. The reaction mixture was
heated at reflux for 6–8 h (TLC monitoring). On cooling
0.2 ml of water was cautiously added to the reaction
mixture, the mixture was stirred for 20 min, the precipitate
formed was filtered off, boiled with THF (3×10 ml), the
mother liquors were combined, washed with a saturated
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THEBAINE ADDUCTS WITH MALEIMIDES. SYNTHESIS AND TRANSFORMATIONS
1143
NaCl solution, the organic layer was separated, dried with
MgSO4, and evaporated in a vacuum. The residue was
subjected to column chromatography on aluminum oxide.
Thus we isolated N'-substituted [7α,8α,3'4']pyrroli-
dino-6,14-endo-etheno-6,7,8,14-tetrahydro-
thebaines (XIX–XXI).
reaction mixture at room temperature for 12 h resulted
in formation of chromatographically individual 6-de-
methyloripavine XXIX. The samples for analysis of all
compounds were recrystallized from appropriate solvents
(Table 1).
The study was carried out under financial support of
the Russian Foundation for Basic Research (grant no.
01-03-32431) and INTAS grant no.97-12060.
Reduction of adducts V and VI by NaBH4. In
50 ml of anhydrous THF was dissolved 5.9 mmol of
succinimides V and VI, the solution was cooled to 0°C,
and at stirring in an argon flow 2.24 g (59 mmol) of
NaBH4 was added. The reaction mixture was stirred at
room temperature for 4 h, then 3 ml (5.9 mmol) of 2.2 M
solution of HCl in ethanol was added dropwise. The
reaction mixture was stirred for 2 h, then poured in 50 ml
of saturated NaHCO3 solution. The organic layer was
separated, the water layer was extracted with chloroform
(3×50 ml). The combined organic solutions were dried
over MgSO4 and evaporated in a vacuum. The residue
was was subjected to column chromatography on
aluminum oxide. Thus we isolated N-substituted
[7α,8α,3'4']-(2'α-hydroxy-5'-oxopyrrolidino)-6,14-
endo-etheno-6,7,8,14-tetrahydrothebaines (XXII,
XXIII).
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O-Demethylation of compounds III, IV, XIV, XIX,
XX, and XXIII. To a solution of 2 mmol of compound in
20 ml of chloroform was added at stirring 1 M solution of
ΒΒr3 in 20 ml of chloroform. The reaction mixture was
stirred at room temperature for 3 h, then poured into the
cooled to 3–5°C diluted (1:1) solution of ammonium
hydroxide, and the mixture was stirred at 0°C for 30 min.
The organic layer was separated, the water layer was
extracted with chloroform (2×15 ml). The combined
organic solutions were washed with a saturated NaCl
solution, and dried over MgSO4. The magnesium sulfate
was filtered off, and the solution was passed through
a bed (5.0 g) of alkaline aluminum oxide, evaporated,
and the residue was ground with ether. We isolated
N-substituted [7α,8α,3',4']pyrrolidino-6,14-endo-
ethenotetrahydrooripavines XXIV and XXV, 6-demethyl-
N-substituted [7α,8α,3',4']-succinimido-6,14-endo-
ethenotetrahydrooripavines XXVI, XXVII, and XXIX,
[7α,8α,3',4']{N'-[(1S)-1-hydroxymethyl-2-methylpropyl]-
succinimido}-6-demethyl-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine (XXVIII), and [7α,8α,3',4'](N'-
phenethyl-2'α-hydroxy-5'-oxo)-pyrrolidino-6,14-endo-
ethenotetrahydrothebaine (XXX). Compounds XXVIII
and XXIX were separated by column chromatography
on aluminum oxide. The treating of succinimide XIV
with BBr3 under the above conditions and keeping the
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1144
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RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005