A convenient synthesis of Δ7,8-Morphinan-6-one and its direct oxidation to 14-hydroxy-Δ7,8-morphinan-6-one

Article abstract of DOI:10.1016/S0960-894X(02)00280-9

Synthesis of Δ^7,8-morphinan-6-one by Grewe cyclization and bromoketalization reaction as crucial steps is described. Introduction of a hydroxyl group at 14-position is demonstrated by direct oxidation with MnO₂ in the presence of silica gel.

Full text of DOI:10.1016/S0960-894X(02)00280-9

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1981–1983
A Convenient Synthesis of D7,8-Morphinan-6-one and Its Direct
Oxidation to 14-Hydroxy-D7,8-morphinan-6-one
Daniele Passarella,* Alessandra Consonni, Alessandra Giardini,
Giordano Lesma and Alessandra Silvani
`
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano,
Via Venezian 21, 20133 Milan, Italy
Received 12 February 2002; revised 26 March 2002; accepted 23 April 2002
Abstract—Synthesis of Á7,8-morphinan-6-one by Grewe cyclization and bromoketalization reaction as crucial steps is described.
Introduction of a hydroxyl group at 14-position is demonstrated by direct oxidation with MnO2 in the presence of silica gel. # 2002
Elsevier Science Ltd. All rights reserved.
With increasing knowledge about agonistic and antago-
nistic activities of morphinan derivatives at opioid
receptors,1 the field of potential application for this
class of compounds is broadening and the demand of
novel procedures to obtain new analogues is rising.2
In this context, compounds containing the Á7,8 double
bond offer the possibility for further manipulations such
as the stereoselective introduction of a hydroxyl group
at C143 in the search for novel agonist and antagonists
ligands possessing opioid receptor affinity. Á7,8-Mor-
phinanones and 14-hydroxymorphinanones generally
derive from thebaine, the common starting material that
has only a low natural abundance.
As part of our program directed toward the synthesis of
nitrogen containing compounds with interesting
pharmacological activity, we present here a convenient
synthesis of 7,8-didehydro-6-morphinanone 1 as depic-
ted in Scheme 1 where the crucial steps are the Grewe
cyclization4 of an appropriate hexahydroisoquinoline
for the construction of the tetracyclic skeleton and a
bromoketalization for the creation of the unsaturated
ketone.5
*Corresponding author. Tel.: +39-02-5031-4080; fax: +39-02-5080-
14078; e-mail: daniele.passarella@unimi.it
Scheme 1.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00280-9

1982
D. Passarella et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1981–1983
Scheme 3.
room temperature. After one night, the addition of
EtOH/Et2O allowed to obtain a white solid of the imi-
nium chloride salt (yield 67%) that was converted to the
tetrahydroisoquinoline 6d by reduction with NaBH4 in
MeOH (yield 97%). The Birch reaction (Li, NH3, THF–
tBuOH 1:1, À78 ꢀC) occurred at the methoxy sub-
stituted phenyl ring, as expected, and was accompanied
by hydrogenolysis of the benzyloxy group to give com-
pound 7b (95% yield). Subsequent reaction of 7b with
HCOOEt in DMF at 80 ꢀC gave compound 4d (95%
yield).
Scheme 2.
The first retrosynthetic analysis identified as ideal sub-
strate for the Grewe cyclization the hexahydro-
isoquinoline 4a that we planned to obtain by Birch
reduction of the corresponding tetrahydroisoquinoline
6a6 (Scheme 2).
The submission of 6a to Birch conditions (Li, NH3,
THF–tBuOH 1:1, À78 ꢀC) caused the undesired reduc-
tion of both phenyl rings.
The Grewe cyclization of derivative 4d (80% sulfuric
acid and Et2O at 25 ꢀC) proceeded with trans addition
to the double bond with the smoothly formation of
C12–C13 bond and afforded the N-formyl-2-hydroxy-
6-morphinanone 8 (82% yield)10 (Scheme 3).
In order to reduce the susceptibility of reduction in the
second phenyl ring we introduced an electron-rich sub-
stituent on position 3 (for the sake of simplicity we use
for the intermediates the numbering system of the target
morphinan skeleton).
Compound 8 was submitted to hydrolysis of formyl
group (HCl, MeOH, 70 ꢀC) to give 9 (96% yield). The
subsequent reductive N-methylation with formaldehyde
in the presence of Pd/C gave compound 10 (40% yield)
that by introduction of 5-chloro-1-phenyl-1H-tetrazole,
(K2CO3, DMF, rt) gave the corresponding derivative 11
(65% yield). Hydrogenation reaction of 11 in formic
acid in the presence of Pd/C gave the expected com-
pound 3 (74% yield).10b, 11 It was possible to change the
order of the described steps to obtain compound 11. We
achieved the introduction of the phenyltetrazole on the
N-formylated compound using the same conditions
described to give 12 (50% yield). The hydrolysis of the
formyl group (85% yield) gave 13. Compound 11 was
obtained by reductive methylation of 13 (59% yield).
The first choice was the methoxy group, but when
compound 6b7 was submitted to Birch conditions we
observed again reduction of both phenyl rings. We then
moved to the preparation of compound 6c that by Birch
reduction gave the desired hexahydroisoquinoline 7a.8
Reaction of 7a with HCOOEt in DMF at 80 ꢀC gave
compound 4c (95% yields). Our efforts to induce Grewe
cyclization of compound 4c with 80% sulfuric at 25 ꢀC
or orthophosphoric acid at 135 ꢀC were unsuccessful
even though examples of this type are reported in the
literature.8
We reasoned that position 12 was not sufficiently acti-
vated by the presence of OH group at position 3, and
for this reason we supposed a successful reaction when
the OH group was at position 2. The condensation
reaction of 3-methoxyphenylethylamine and 3-benzyl-
oxyphenylacetic acid9 was maintained at 200 ꢀC for 5 h
to give the amide 5d (80%) that was submitted to Bis-
chler–Napieralski cyclization in CH2Cl2 with PCl5 at
This alternative preparation presents similar total yield
as the first sequence (8–9–10–11) but several chromato-
graphic purifications are required. The next goal in our
plan was the introduction of Á7,8 double bond, a task
that was accomplished by a sequence of reactions start-
ing with a bromoketalization step that proceeded regio-
selectively to give 212 as a mixture of diastereoisomers

D. Passarella et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1981–1983
1983
(dry ethylene glycol, bromine, 70 ꢀC, 50% yield).13 The
dehydrobromination of a-bromo ketal 2 with DBU in
DMSO failed to give the desired product thus the use of
tBuOK in DMSO at 85 ꢀC was preferred.14 The result-
ing compound 14 was reacted with 3 N HCl in MeOH
(reflux) to provide the enone 1 (yield 87%).15
loids; Brossi, A., Ed.; Academic: New York and London,
1994; Vol. 45, Chapter 2, p 127. (c) Novak, B. H.; Hudlicky,
T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem.
2000, 4, 343. (d) For a recent synthesis of morphine, see
Nagata, H.; Miyazawa, N.; Ogasawara, K. Chem. Commun.
2001, 1094.
3. (a) Coop, A.; Rice, K. C. Tetrahedron 1999, 55, 11429. (b)
Ninan, A.; Sainsbury, M. Tetrahedron 1992, 49, 6709.
4. Palmer, D. C.; Strauss, M. J. Chem. Rev. 1977, 77, 1.
5. Garbish, E. W., Jr. J. Org. Chem. 1965, 30, 2109.
6. Stambach, J. F.; Jung, L. Tetrahedron 1985, 41, 169.
7. Chakravarti, J. Indian Chem. Soc. 1932, 9, 573.
8. Olieman, C.; Nagelhout, Ph.; de Groot, A. D.; Maat, L.;
Beyerman, H. C. Recl. Trav. Chim. Pays-Bas 1978, 97, 127.
9. 3- And 4-benzyloxyphenylacetic acid were obtained by
reaction of benzyl bromide with 3- and 4-hydroxyphenylacetic
acid in THF in the presence of NaH at 70 ꢀC (yields 90–93%).
10. (a) Schmidhamer, H.; Brossi, A. Can. J. Chem. 1982,
60, 3055. (b) Schmidhamer, H.; Jacobsen, A. E.; Brossi, A.
Heterocycles 1982, 17, 391.
The availability of compound 1 gave us the opportunity
to study the oxidation to 14-hydroxy derivative. This
reaction has been described, on morphine related deri-
vatives, using a variety of two-steps procedures via for-
mation of a diene system followed by oxidation.16
We preferred a direct procedure that offers the advan-
tage of less synthetic steps and overcomes the necessity
for the isolation of a diene intermediate. The use of
MnO2 as oxidant in the presence of silica gel afforded
the stereoselective introduction of the hydroxyl group at
position C14.3,17
11. Hussey, B. J.; Johnstone, R. A. W.; Entwistle, I. D.
Tetrahedron 1982, 38, 3775.
To confirm the structure of the obtained compound 15
1
12. A stirred solution of ketone 3 (156 mg, P.M.=255.35 g/
mol, 0.61 mmol) in dry ethylene glycol was treated with bro-
mine (168 mg, P.M.=159.82 g/mol, 1.05 mmol, d=3.119 g/
mL, 54 mL) at 70 ꢀC. After 2 h, anhydrous K2CO3 was added
to the reaction mixture. The mixture was diluted with water
and extracted with AcOEt to give after chromatographic
purification (CH2Cl2/EtOH with 5% NH4OH 25:1) com-
pound 14. Kozikowski, A. P.; Park, P. J. Org. Chem 1990, 55,
4668.
13. The bromination of morphinan-6-one was also studied by
Tada et al. with HBr and pyridinium hydrobromide per-
bromide Sawa, K. Y.; Kobayashi, M.; Tada, H. Heterocycles
1984, 22, 2575.
14. (a) For the introduction of Á7,8 double bound on a mor-
phine system, see: White, J. D.; Hrnaciar, P.; Stappenbeck, F.
J. Org. Chem. 1999, 64, 7871. (b) Weller, D. D.; Rapoport,
H. J. J. Med. Chem. 1976, 19, 1171. (c) Iijima, I.; Rice, K. C.
Heterocycles 1977, 6, 1157. (d) Gates, M.; Tschudi, G. J. Am.
Chem. Soc. 1952, 74, 1109.
the H NMR signal of H-8 appeared at d 5.69 as doub-
let (J=10 Hz) while in the starting compound it
appeared as doublet of doublet (d 5.73, J=10, 3 Hz).
In summary, we have developed a practical synthesis of
7,8-didehydro-6-morphinanone 1 with a high-yield
sequence of reactions and the first direct oxidation at
C14 of a morphinan compound. The insertion of a
hydroxyl group into the 14-position of morphine like
structures, generally gives compounds with interesting
pharmacological activity;1 for this reason, compound 15
encourages its use as a suitable synthon for the pre-
paration of new pharmacologically active compounds.
Acknowledgement
15. 7,8-Didehydro-6-morphinanone 1: 1H NMR (DMSO-d6)
d 7.25–7.05 (4H, m, ArH), 6.90 (1H, bd, J=10 Hz, H-7), 5.73
(1H, dd, J=10, 3 Hz; H-8), 2.35 (3H, s, N–Me), 3.40–1.80
(10H, m).
The authors would like to thank GlaxoSmithKline
S.p.A Milano (Italy) for financial support.
16. (a) Seki, I. Chem. Pharm. Bull. 1970, 18, 671. (b) Schartz,
M. A.; Wallace, R. A. J. Med. Chem. 1981, 24, 1525.
17. A suspension of compound 1 (68 mg, 0.27 mmol) and
MnO2 (680 mg) in CH2Cl2 (10 mL) was stirred for 1 day at
40 ꢀC. When the disappearance of starting compound was
complete silica-gel (200 mg, Merck, 60H) was added and the
stirring was maintained for 1 day at 40 ꢀC. The mixture was
filtered and the residue was washed with CH2Cl2 containing
1% of MeOH. Evaporation gave the title compound.
7,8-Didehydro-14-hydroxy-6-morphinanone 15 (yield 59%):
1H NMR (CDCl3) diagnostic signals d 7.35–7.00 (4H, m,
ArH), 6.61 (1H, bd, J=10 Hz, H-7), 5.69 (1H, d, J=10, Hz;
H-8). Low EIMS: 269 (M+).
References and Notes
1. Synthetic morphinans are levorphanol and dex-
tromethorphan that have analgesic and/or antitussive activity.
For a general review on morphinans, see: (a) Brossi, A. In The
Chemistry and Biology of Isoquinoline Alkaloids; Phillipson, J.
D., Roberts, M. F., Zenk, M. H., Eds.; Springer: Berlin, 1985;
p 171.
2. (a) For a recent synthesis of 3,4-dimethoxy-6-morphin-
anone derivative, see Yamada, O.; Ogasawara, K. Org. Lett.
2000, 2, 2785. (b) For general review for the synthesis of mor-
phine, see: Szantay, C.; Dornyei, G.; Blasko, G. In The Alka-