On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

Article abstract of DOI:10.1007/s11172-011-0086-y

An improved method for the synthesis of 8-[(1E)-2-phenylethenyl]codeinone dimethyl ketal was described. The ability of [(1E)-2-phenylethenyl] substituent to stabilize effectively the π-system of the ring C is responsible for the essential difference in both the reactivity and the compositions of products formed in the reactions of the corresponding substituted and unsubstituted codeinone and thebaine derivatives.

Full text of DOI:10.1007/s11172-011-0086-y

Russian Chemical Bulletin, International Edition, Vol. 60, No. 3, pp. 557—560, March, 2011
557
On the features of reactivity of 8ꢀ[(1E)ꢀ2ꢀphenylethenyl]ꢀsubstituted thebaine
and codeinone derivatives
S. K. Moiseev, I. V. Shishkov, and V. N. Kalinin
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6549. Eꢀmail: vkalin@ineos.ac.ru
An improved method for the synthesis of 8ꢀ[(1E)ꢀ2ꢀphenylethenyl]codeinone dimethyl
ketal was described. The ability of [(1E)ꢀ2ꢀphenylethenyl] substituent to stabilize effectively the
πꢀsystem of the ring C is responsible for the essential difference in both the reactivity and the
compositions of products formed in the reactions of the corresponding substituted and unsubstiꢀ
tuted codeinone and thebaine derivatives.
Key words: morphinan alkaloids, 8ꢀ[(1E)ꢀ2ꢀphenylethenyl]codeinone dimethyl ketal,
8ꢀ[(1E)ꢀ2ꢀphenylethenyl]thebaine, hydrolysis, dehydrobromination.
Thevinone (1a) is a key intermediate on the synthetic
route from natural alkaloid thebaine (2a) toward orvinols
(3a), so called "semiꢀsynthetic" opioid derivatives exhibitꢀ
ing marked affinity to opioid receptors (e.g., buprenorꢀ
phine, diprenorphine, ethorphine, dihydroethorphine).1,2
Therefore, compounds 3a for decades are the subjects for
intense search for potent analgetics for treatment of severe
and chronic pain with decreased level of unwanted side
effects. Compound 1a is formed by [4+2] cycloaddition of
AcCH=CH2 to diene system of 2a and serve as the starting
compound for the synthesis of large scope of thevinols 3b,
Oꢀdemethylation of the latter leading to compounds 3a.
A variety of compounds 3b and 3a resulted mainly from
altering the substituents R2 and R3. However, recently,
modification of the C(6)—C(14)ꢀetheno or ꢀethano bridge
of compounds 3 became of interest. Functionalization of
these positions can be achieved by either preliminary inꢀ
troduction of the substituent at the positions 7 or 8 of
diene 2a (which correspond to positions 18 and 19 of adꢀ
duct 1a) followed by [4+2] cycloaddition3 or by modificaꢀ
tion of the ethene bridge in the Diels—Alder adduct.4,5
Recently, in the framework of the design of novel proꢀ
cedures for the modification of the C ring of the morphiꢀ
nan alkaloids, we carried out the Pdꢀcatalyzed Heck reacꢀ
tion of codeine (4a) and PhCH=CHBr to give 7,8ꢀdiꢀ
hydroꢀ8βꢀ[(1E)ꢀ2ꢀphenylethenyl]codeinone (5a), from
which 8ꢀ[(1E)ꢀ2ꢀphenylethenyl]codeinone dimethyl ketꢀ
al (6a) was synthesized in four steps.6 It was found that
ketal 6a bearing conjugated diene system reacts with diꢀ
enophiles to give adducts 7 including 19ꢀ[(1E)ꢀ2ꢀphenylꢀ
ethenyl]thevinone (1b) (in the reaction with AcCH=CH2)
instead of the expected 7,8ꢀfused compounds. The use of
ketal 6a as "masked" 8ꢀ[(1E)ꢀ2ꢀphenylethenyl]thebaine
(2b) opens the route toward derivatives of compounds 3
substituted at the position 19. Moreover, the hydrolysis of
ketal 6a and subsequent reduction of the carbonyl group
afforded 8ꢀ[(1E)ꢀ2ꢀphenylethenyl]codeinone (4b), which
in the "ordinary" Diels—Alder reaction gives derivatives
with the additional cycle fused to the C ring at the posiꢀ
tions C(7)—C(8).6
Thus, ketal 6a is the key intermediate toward both
the 7,8ꢀfused derivatives of morphinan alkaloids and deꢀ
1, 2: R = H (a), transꢀCH=CHPh (b)
3: R1 = H (a), Me (b); Z∼Z = CH2CH2, CH=CH
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 544—547, March, 2011.
1066ꢀ5285/11/6003ꢀ557 © 2011 Springer Science+Business Media, Inc.

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Moiseev et al.
rivatives of thevinols and orvinols 3 substituted at the
position 19.
4a → 5a, while next three steps can be carried out without
purification of the intermediates; compound 6a can easily
be purified by recrystallization.
In the present work we report the shorter and more
efficient synthetic pathway toward ketal 6a and describe
the role of the (1E)ꢀ2ꢀphenylethenyl moiety at the posiꢀ
tion C(8) as structural factor that significantly effects the
chemical behavior of the corresponding derivatives and,
specifically, brings about unique properties of ketal 6a.
If required, ketal 6a can be used for the synthesis of
compound 2b, which is the substituted analog of 2a.6 Alꢀ
though, it is not mandatory because Diels—Alder adducts
7 substituted at the position 19 can be prepared directly
from compound 6a. It was suggested6 that formation of
adducts 7 in the reactions of dimethyl ketal 6a with dienoꢀ
philes instead of the expected 7,8ꢀfused compounds is due
to triene 2b that formed from 6a by elimination of MeOH
under reaction conditions used (reflux in toluene). In this
case, triene 2b is the true substrate of cycloaddition.
We studied in detail the composition of the reaction
mixture formed upon refluxing ketal 6a in toluene without
dienophile. Indeed, triene 2b was formed under these conꢀ
ditions. After 5 h, the reaction reached the equilibrium
with 6a : 2b = 1 : 4. Ease of methanol elimination in this
case can obviously be explained by the gain upon the forꢀ
mation of extended system of the conjugated πꢀbonds in
compound 2b, which included diene fragment of the ring
C and phenylethenyl moiety in the position C(8). Thus,
the presence in the codeinone derivatives of the type of
ketal 6a the substituents at the position C(8) capable of
effective π,πꢀconjugation with the C—C multiple bonds of
the ring C turned them into "masked" thebaine derivatives.
Conversely, equilibrium between compounds 6a and 2b
upon refluxing in toluene suggests that the presence of
aboveꢀmentioned substituents at position C(8) of diene 2a
Results and Discussion
According to the known procedure,6 ketal 6a was preꢀ
pared form ketone 5a in four steps, which include transꢀ
formation of 5a by the action of HC(OMe)3 in MeOH
into ketal 5b, treatment of 5b with TsOH in anhydrous
conditions to give enol ether 8, conversion of the later by
treatment with MeOBr in MeOH into bromide 5c, which
in the reaction with ButOK in DMSO at ambient temperꢀ
ature afforded ketal 6a.
We managed to shorten the synthetic route and preꢀ
pare ether 8 from ketone 5a in one step in 82% yield. The
modified procedure involved treatment of ketone 5a with
the excess of sodium hydride in DMF at ambient temperꢀ
ature followed by alkylation of the sodium enolate with
dimethyl sulfate at –5 °C. Besides the reducing the synꢀ
thetic route, the essential advantage of the developed proꢀ
cedure to produce ketal 6a is that the only step of the four
on the pathway from codeine (4a) to ketal 6a, which reꢀ
quired purification of the intermediate is the reaction
4: R1 = Me, R2 = H (a); R1 = Me, R2 = transꢀCH=CHPh (b); R1 = R2 = H (c)
5: R1 + R2 = O; R3 = transꢀCH=CHPh, X = H (a); R1 = R2 = OMe; R3 = transꢀCH=CHPh, X = H (b);
R
1 = R2 = OMe, R3 = transꢀCH=CHPh, X = Br (c); R1 = R2 = OMe, R3 = H, X = Br (d)
6: R1 = R2 = OMe, R3 = transꢀCH=CHPh (a); R1 + R2 = O, R3 = transꢀCH=CHPh (b); R1 = R2 = OMe, R3 = H (c);
1 + R2 = O, R3 = H (d)
R

Thebaine and codeinone derivatives
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
559
should facilitate ready conversion of these compounds into
the corresponding codeinone derivatives under the action
of compounds HX with sufficient acidity. Moreover, it is
natural to expect that the compounds bearing 8ꢀphenylꢀ
ethenyl substituent could easier be involved in the reactions
proceeding via formation of carbocation at C(8) atom.
Therefore, with the task to determine how strong could
be the effect of 2ꢀphenylethenyl substituent at the C(8)
atom in the corresponding chemical transformations of
the compound of this series, we studied the reaction, which
resulted in the formation of the πꢀsystem in the ring C
capable of effective conjugation with the 8ꢀ(2ꢀphenylꢀ
ethenyl) group, namely, elimination of HBr from bromide
5c and hydrolysis of ketal 6a. In addition, the chemical
behavior of 8ꢀ(2ꢀphenylethenyl)ꢀsubstituted derivatives
was compared with previously described properties of the
corresponding compounds unsubstituted at the C(8) atom.
Both studied reactions are of practical interest due to the
relevance to the synthesis of opium alkaloid thebaine (2a),
which is the most valuable from the synthetic point of
view and is very scarce due to low natural content (and
consequently its derivatives) from more affordable row
materials — morphine (4c) or codeine (4a). For this reaꢀ
son, both the elimination of HBr from bromide 5d and
hydrolysis (acidolysis) of codeinone dimethyl ketal (6c)
were studied in detail in the framework of the developed
earlier procedure for the preparation of 2a from codeinone
(6d), which is readily available from 4a.7,8
Reaction of bromide 5d with ButOK in DMSO at higher
temperature (120 °C) afforded thebaine (2a) in nearly
quantitative yield.8 However, reaction of bromide 5c with
ButOK under the same conditions resulted in a complex
product mixture. Probably, these conditions is too severe
for triene 2b.
Thebaine (2a) is formed from dimethyl ketal 6c under
the action of POCl3 in pyridine at 90 °C.7 Diene 6a, as it
was mentioned above, readily afforded the corresponding
derivative 2b substituted at position 8 by refluxing in toluene.
Comparison of the results of hydrolysis of dimethyl
ketals 6a and 6c provided even stronger evidence of the
effect of the substituent at the C(8) atom. All attempts to
synthesize compound 2a by the acidolysis of dimethyl ketꢀ
al 6c were unsatisfactory from the practical point of view.
The action of anhydrous TsOH and, conversely, aqueous
acid (3 M AcOH) on dimethyl ketal 6c resulted in ketone
6d as the only product instead of 2a. At the same time,
hydrolysis of ketal 6c by the action of TsOH with strictly
controlled water content furnished the mixtures of comꢀ
pounds 2a and 6d in different ratios; besides, the maxiꢀ
mum yield of 2a (40%) was obtained in the presence of
3 mol.% of water.
In case of hydrolysis of ketal 6a, the opposite pattern
was observed. Hydrolysis of ketal 6a in acetic acid gave
triene 2b (65%) as the main product; the yield of ketone 6b
was only 28%. Hydrolysis of ketal 6a in 3.5% aqueous HCl
afforded ketone 6b in the yield of 75%, although, triene 2b
formed in significant amount (16%). However, preparaꢀ
tive synthesis of 6b, which is necessary for the synthesis of
codeine 4b substituted at the position 8 (see Ref. 6), reꢀ
quires the use of 20% aqueous HCl, under these condiꢀ
tions only traces of 2b formed. These results can be exꢀ
plained as follows. According to the general mechanism of
Ketal 6c can be synthesized from bromide 5d by both
the prolonged refluxing with potassium tertꢀamylate in
tertꢀamyl alcohol7 and the action of ButOK in DMSO at
60 °C.8 Similar reaction of 8ꢀ[(1E)ꢀ2ꢀphenylethenyl]ꢀ
substituted bromide 5c with ButOK in DMSO proceeded
at ambient temperature to give ketal 6a.6
Scheme 1

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Moiseev et al.
wise, and the reaction mixture was stirred at –5—0 °C for 1 h.
Then the mixture was poured into the mixture of ice and 25%
aqueous ammonia, stirred for 5 min, the products were extracted
with diethyl ether (200 mL) with vigorous stirring for 30 min.
The organic layer was separated, washed with water (2×100 mL),
dried with Na2SO4, and the solvent was removed in vacuo to give
compound 8 (2.25 g, purity ~95% according to the 1H NMR
data), foam, which crystallized at standing. The product can be
used on the next steps without further purification. Analytically
pure compound 8 was obtained by recrystallization from hepꢀ
tane—ethyl acetate (5 : 1), physicochemical characteristics and
NMR 1H spectra are identical to those given in literature.6
the ketal hydrolysis, in the acidic media, compound 6a
gives the C(6)ꢀcarbocation 9a, which is prone to reꢀ
arrangement into the C(8)ꢀcarbocation 9b additionally staꢀ
bilized by 8ꢀ[(1E)ꢀ2ꢀphenylethenyl] moiety. In this case,
formation of a mixture of two products is the result of the
competitive processes of the nucleophilic attack of water
on cation 9a to give 6b and the stabilization of cation 9b by
elimination of the proton from the position C(14) to give
2b (Scheme 1). Possible attack of a water molecule on
cation 9a can be disregarded since it resulted in epimeric
C(8) alcohols, which are, for the obvious reasons, in equiꢀ
librium with carbocation 9b under acidic conditions of
hydrolysis. In the case of ketal 6c, which contains no subꢀ
stituent capable of addition stabilizing the carbocationic
center at the C(8) atom, the formation of C(8)ꢀcation
analogous to 9b is less favorable as compared with the
corresponding C(6)ꢀcation making the preparation of theꢀ
baine (2a) in preparative yields impossible.
References
1. A. F. Casy, R. T. Parfitt, Opioid Analgesics. Chemistry and
Receptors, Plenum Press, New York—London, 1986.
2. G. R. Lenz, S. M. Evans, D. E. Walters, A. J. Hopfinger,
in Opiates, Academic Press, Orlando—London, 1986.
3. W. Chen, D. A. Parrish, J. R. Deschamps, A. Coop, Helv.
Chim. Acta, 2005, 88, 822.
4. H. Wu, D. Bernard, W. Chen, G. D. Strahan, J. R. Desꢀ
champs, D. A. Parrish, J. W. Lewis, A. D. MacKerell, A. Coop,
J. Org. Chem., 2005, 70, 1907.
5. H. Wu, T. A. Smith, H. Huang, J. B. Wang, J. R. Deschamps,
A. Coop, Bioorg. Med. Chem. Lett., 2007, 17, 4829.
6. V. N. Kalinin, I. V. Shishkov, S. K. Moiseev, E. E. Shults,
G. A. Tolstikov, N. I. Sosnina, P. V. Petrovskii, K. A. Lysꢀ
senko, H. Schmidhammer, Helv. Chim. Acta, 2006, 44, 861.
7. H. Rapoport, C. H. Lovell, H. R. Reist, M. E. Warren, Jr.,
J. Am. Chem. Soc., 1967, 89, 1942.
In summary, the 8ꢀ[(1E)ꢀ2ꢀphenylethenyl] moiety
and, obviously, other substituents at the C(8) atom capable
of effective πꢀconjugation can affect the chemical behavior
of the codeinone and thebaine derivatives, which are the
key intermediates in the synthesis of potent physiologicalꢀ
ly active compounds of orvinol and morphinone series.
Experimental
(5α,8β)ꢀ6,7ꢀDidehydroꢀ3,6ꢀdimethoxyꢀ17ꢀmethylꢀ8ꢀ[(1E)ꢀ
2ꢀphenylethenyl]ꢀ4,5ꢀepoxymorphinan (8). To a solution of comꢀ
pound 5a (2.67 g, 6.66 mmol) in anhydrous DMF (34 mL), NaH
(0.40 g, 9.99 mmol, 60% dispersion in mineral oil) was added.
The reaction mixture was stirred at ~20 °C until nearly clear
solution was formed (20—30 min). The mixture was cooled to
–10 °C, dimethyl sulfate (0.95 mL, 9.99 mmol) was added dropꢀ
8. D. D. Weller, H. Rapoport, J. Med. Chem., 1976, 19, 1171.
Received March 29, 2010;
in revised form November 13, 2010