Benzylation of morphinandienes and new aspects of their acid-catalyzed rearrangement to new aporphines

Article abstract of DOI:10.1016/j.tet.2008.04.069

The benzylation of thebaine and 6-demethoxythebaine resulted in different product mixtures. Explanations were given for both the observed differences in the ratio of 5β- versus 7-benzyl products and the deviation of the electronic structure of ring C of 7

Full text of DOI:10.1016/j.tet.2008.04.069

Tetrahedron 64 (2008) 5851–5860
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Benzylation of morphinandienes and new aspects of their acid-catalyzed
rearrangement to new aporphines
*
´
´
Attila Sipos , Sandor Berenyi
Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The benzylation of thebaine and 6-demethoxythebaine resulted in different product mixtures. Expla-
Received 21 February 2008
Received in revised form 4 April 2008
Accepted 17 April 2008
nations were given for both the observed differences in the ratio of 5b- versus 7-benzyl products and the
deviation of the electronic structure of ring C of 7-benzyl products. The acid-catalyzed rearrangement of
morphinan-5,8-dienes, 5,6- and 6,7-disubstituted morphinan-6,8-dienes was achieved and mechanistic
interpretations for the formation of new, potentially dopamine-active aporphines were provided.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 22 April 2008
Keywords:
Morphinan-5,8-dienes
5b-Substitution
6-Demethoxythebaine
Acid-catalyzed rearrangement
1. Introduction
investigated the relationship between the spatial size of the elec-
trophile partner and the change in the ratio of conventional 5
substituted versus 7-substituted products. On the basis of their
previous observations regarding the formation of 5 -trimethylsi-
lylthebaine with the conventional procedure, they applied alkyl-
arylsilyl chlorides with gradually increasing steric size to test the
b-
Thebaine (1) is the pharmaceutically most important, naturally
occurring morphinan-6,8-diene, as it is used in the synthesis of
a variety of opioid receptor agonist and antagonist compounds
utilized as major alternatives in the treatment of severe pain and
the management of drug dependence.1 Besides this application, 1 is
also an excellent starting compound to potent dopamine agonists
such as N-propyl-2-fluoronorapomorphine via its acid-catalyzed
rearrangement and further transformation.2 The structure of
thebaine (1) is frequently referred to as morphinandiene, as the
chemically most interesting ring C of the morphinan backbone
contains a conjugated diene motif, disregarding the fact that there
is not only one type of morphinandiene. Maat et al. first reported
the successful isolation and characterization of morphinan-5,8-
diene structure.3 It was the 7-methyl congener 2 that was formed in
the 5-methylation reaction of 6-demethoxythebaine (3) under
classic conditions elaborated by Gates and his colleagues (Fig. 1).4
The methanesulfonic acid-mediated rearrangement of mor-
b
H3C H
7
OCH3
8
6
14
5
9
N
N
H3C
H3C
O
O
10
3
1
OCH3
morphinan-5,8-diene structure
Figure 1. The structure of morphinandienes.
OCH3
2
1
2
morphinan-6,8-diene structure
Y
Y
X
Y
H
H
H
H
H
Cl
Br
phinan-6,8-dienes into apocodeines was investigated by Neu-
X
5
X
´
meyer’s and Berenyi’s groups (Scheme 1).
The 5
and well-studied subjects of morphinan chemistry; recent appli-
cation of 5 -substituted derivatives was reported for the prepara-
tion of
-selective opioid agonists.6 Coop and his co-workers7
1, 9 OCH3
b
-substitution has remained one of the frequently applied
N
H
N
3, 10
H
CH3SO2OH
H3C
H3C
O
OH
4, 11 Cl
5, 12 Br
b
d
OCH3
OCH3
6, 13
7, 14
8, 15
F
H
H
9-15
1, 3-8
* Corresponding author. Tel.: þ36 52 512900/22473; fax: þ36 52 512836.
E-mail address: asipos@puma.unideb.hu (A. Sipos).
Scheme 1. Acid-catalyzed rearrangement of morphinan-6,8-dienes.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.069

5852
A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
OCH3
OCH3
OCH3
N
N
N
H3C
H3C
H3C
O
O
O
OCH3
OCH3
OCH3
16c
16b
16a
R2
R1
PhMe2Si
R2
H
R
OCH3
R1
35%
47%
PhMe2Si
PhMe2Si PhMe2Si
N
RCl
H3C
Ph2MeSi
H
14%
62%
H
O
Ph2MeSi
Ph3Si
Ph2MeSi
64%
H
Ph3Si
OCH3
Scheme 2. The effect of the size of electrophile partner on the ratio of products.
effect of the steric bulk. It was confirmed that the 7-position was
favoured at the expense of the formation of the original 5-
substituted derivatives in the case of reactions of sterically large
electrophiles with thebaine anion 16 (Scheme 2).
In an attempt to rationalize our observations, DFT calculations
were performed to determine the electrophilic character of the
benzyl carbon atoms primarily relevant to the reaction. The cal-
culated net NBO (natural bond orbital) atomic charges of the benzyl
carbon atoms are collected in Table 2. The above-presented results
were found to be in good agreement with our expectations re-
garding the correlation between the electrophilic power of the
applied benzyl chlorides and the ratio of 5- and 7-substituted
products. The reactions of more reactive benzyl chlorides led to
a dominance of kinetic control, i.e., the reaction at the less sterically
hindered centre of the C ring.
2. Results and discussion
We aimed to carry out the syntheses, full structural character-
ization and ab initio evaluation of the formation of benzyl conge-
ners of thebaine (1) and 6-demethoxythebaine (3) in order to
explore the fundamental reasons for the difference in the electronic
structure of ring C of the resulting morphinan skeletons. Further-
more, the acid-catalyzed rearrangement of the benzyl derivatives of
morphinan-5,8-dienes and 6,7-disubstituted morphinan-6,8-di-
enes was also achieved forming novel benzylapocodeines.
Table 1
Yields in benzylations of thebaine (1)
Product
Isolated yielda (%)
Product ratio (17:18)
17a
18a
17b
18b
17c
18c
17d
18d
17e
18e
42
28
47
20
48
24
40
29
42
30
1.5:1
2.1. Benzylation of morphinandienes
2.35:1
2:1
On the basis of our preliminary studies, Gates’ procedure4 for
the generation of thebaine anion 16 was modified in order to in-
crease the amount of the resulting 7-substituted morphinandienes
in the product mixture (Scheme 3). After dissolving morphi-
nandiene 1 or 3 in dry THF, it was cooled to ꢀ78 ꢁC and treated with
1.2 equiv of tert-BuLi. We reduced the amount of the anion-forming
agent from 1.5 to 2.0 equiv4,7 and applied a more reactive one. The
benzylation of 16 was carried out with a variety of benzyl chlorides.
The amount of benzyl chloride was also reduced from 1.5 to
1.2 equiv. The modification involved the extension of the mixing
time after the 2 h-long warm-up period from ꢀ78 ꢁC to room
temperature, however, as it was concluded henceforth, it had
a beneficial effect on the work-up of the crude products than
a favourable thermal influence on the reaction itself.
1.38:1
1.4:1
a
Average of three reactions.
Table 2
Net NBO atomic charges for benzyl carbon atoms as obtained from B3LYP/6-31G
calculations
*
R
Atomic charge (e)
Difference (%)
H
2-Cl
2-F
2-CF3
4-NO2
0.0341
0.0314
0.0338
0.0442
0.0465
0
ꢀ7.9
ꢀ0.9
29.6
36.4
The isolated yields of 5
b
- and 7-benzylthebaines 17a–e and
18a–e are collected in Table 1.
R
R
H
OCH3
O
OCH3
OCH3
R
17a, 18a
N
N
N
1. t-BuLi, THF, -78 °C
2.
H3C
H3C
H3C
O
O
2-Cl
2-F
17b, 18b
17c, 18c
+
R
Cl
OCH3
OCH3
OCH3
17d, 18d 2-CF3
17e, 18e 4-NO2
1
17a-e
18a-e
Scheme 3. Formation of 5b- and 7-benzylthebaines 17a–e and 18a–e.

A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
5853
Figure 3. Determining NOE correlations presented on the structure of 20a optimized
at the B3LYP/6-31G level.
*
Figure 2. Representative structures of optimized TS of benzyl chloride with thebaine-
5-anion 16a and thebaine-7-anion 16b (green represents chlorine).
et al.11 They reported most recently the synthesis and character-
ization of a stable ortho-deprotonated carbamate dimer containing
Li–O and Li–N dative bonds and DFT calculations explaining the
formation of this product. The comparison between the bond
lengths and angles around the centres of the kinetically and ther-
In order to estimate the extent of steric hindrance in the case
of thebaine-5-anion 16a and thebaine-7-anion 16b, a model was
established using the Gaussian 98 program to optimize transition
´
state (TS) structures at the B3LYP/6-31G
*
level for benzyl chloride
modynamically most probable monomer of Garcıa et al. and our
with both nucleophiles (Fig. 2 and Table 3).8,9
The weaker the electrophilic character of the benzyl chloride,
the higher the ratio of the thermodynamically more stable
complex towards C5-lithiation revealed significant similarity.
The benzylation of 6-demethoxythebaine (3) was performed
according to the same methodology in order to compare the
structure and the proportion of the isolated products. Compound
3 was synthesized using the original procedure reported by our
research group in 1982.5b It was found in each run that the crude
product mixtures contained three components, two benzylated
morphinans and some unreacted diene 3. The 1D and 2D NMR
spectroscopic characterization of the two products proved that
5b-substituted derivative in the product mixture. Referring to the
calculated NBO atomic charges, 2-CF3– and 4-NO2–benzyl chlorides
were found to be more reactive partners whereas 2-Cl, 2-F and
unsubstituted benzyl chlorides were less reactive, which were in
accordance with the observed product ratios.
We also considered the possibility of a direct ortho-metalation-
like (DoM)10 lithium-coordination to the methoxy group, depro-
tonation and lithiation of 5- and 7-positions as the initiation of the
benzylation procedure and as an explanation of the observed
product ratios. Taking into consideration the two important factors
of the evolution of DoM, steric hindrance and charge deactivation
properties, thebaine (1) was found to be an appropriate partner for
this mechanism. The complexes formed using tert-BuLi and com-
benzylation was taken place again at 5
besides the expected 5 -benzyl-6-demethoxythebaines 19a–e, we
found -benzyl-morphinan-5,8-diene-type products 20a–e
(Scheme 4). The 7 -position of the benzyl moiety was confirmed by
NOE correlations observed between benzyl hydrogens and C15–Ha/
16–Ha as presented on the optimized structure of 20a (Fig. 3). As
b- and 7-positions, however,
b
7
b
b
C
was mentioned in Section 1, these facts and the analytical data for
20a–e were in accord with Maat’s observation3 regarding the
methylation of 3.
The ratio of the isolated products 19a–e and 20a–e is summa-
rized in Table 4.
pound 1 towards a potential 5b- and 7-lithiation were investigated
as a starting point. It was found that the formation of a complex
involving the coordination of lithium to both C6–methoxy and C4–
O–C5 etheral oxygen atoms and C5 carbon as the reactive centre is
much more probable with respect to the calculated formation
These data suggested the loss of thermodynamic dominance of
properties of the structures optimized at the B3LYP/6-31G
*
level.
5b
-benzyl product versus 7
b-benzyl one in comparison to the
Moreover, we compared our data to the calculation results of Garcı´a
benzylation of thebaine (1). This observation was confirmed by the
Table 3
Calculated parameters of optimized TS of benzyl chloride with thebaine-5-anion 16a and thebaine-7-anion 16b
Substrate
Nucleophile
Bond angle (ꢁ) Cl/CBn/CRC
Mulliken charge
Cl
Distance (Å)
CBn
CRC
Cl/CBn
CBn/CRC
Benzyl chloride
16a
16b
154
173
ꢀ0.387
ꢀ0.391
0.625
0.656
ꢀ0.712
ꢀ0.735
2.47
2.61
1.97
2.07
CRC¼charge carrier C atom of ring C; CBn¼benzyl C atom.
R
H
R
R
19a, 20a
H
N
N
N
1. t-BuLi, THF, -78 °C
2. R
H3C
H3C
H3C
19b, 20b 2-Cl
19c, 20c 2-F
19d, 20d 2-CF3
19e, 20e 4-NO2
O
O
O
+
Cl
OCH3
19a-e
OCH3
20a-e
OCH3
3
Scheme 4. Benzylation of 6-demethoxythebaine (3).

5854
A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
Table 4
of regioisomers, although we are aware the fact that the influence
Observed yields in benzylations of 6-demethoxythebaine (3)
of co-solvents and additives could have dramatic influences on the
outcome of such alkylations. In other words these benzylations
were proven to be an effective procedure in the synthesis of po-
tentially dopamine-active aporphinoids.
Product
Isolated yielda (%)
Product ratio (19:20)
19a
20a
26
56
10
1:2.15
Unreacted diene 3
19b
20b
23
58
12
1:2.52
1:2.62
1:2.40
1:2.63
2.2. Acid-catalyzed rearrangements
Unreacted diene 3
It was decided to study the acid-catalyzed rearrangement of the
morphinan-5,8-diene-type products 20a–b. The procedure was
performed in line with our original procedure elaborated for the
morphinan-6,8-dienes as presented in Section 1. It involved the
heating of the methanesulfonic acid solution of the diene 20a–e for
30 min. In both cases we obtained a single component crude
product. After isolation and full characterization of these products
we concluded that this type of reaction resulted in 3-benzylapo-
codeines 22a–b (Scheme 5).
19c
20c
21
55
11
Unreacted diene 3
19d
20d
25
60
6
Unreacted diene 3
19e
20e
24
63
8
Unreacted diene 3
a
Reported yields are averages of three reactions and were calculated for 19a–e
and 20a–e on the basis of the reacted amount of diene 3.
R
R
calculated data for the heat of formation of 19a–e and 20a–e, and
explained by the electronic and conformational effects of the ab-
sence of the 6-methoxy group. On the one hand, the absence of the
6-OMe led to the loss of a clearly favourable energetic character of
the conjugated 6,8-type diene structure having a stabilizing O-
ether moiety at the 6-position over a hypothetical product struc-
ture with a cumulated 5,8-diene structure and O-ethers at positions
5 and 6. On the other hand, the main effect of the loss of 6-OMe on
the conformation of the ring C of the morphinan-5,8-diene-7-anion
21 was the occurrence of a more stable, less stretched boat con-
formation in comparison to thebaine-7-anion 16b (Fig. 4).
However, no remarkable conformational change was observed
at the ring C of the morphinan-6,8-diene skeleton during the
elimination of the 6-OMe function of thebaine-5-anion 16a. On the
basis of these reasons, the remarkable change in the product ratios
was a clear consequence of the growth of the importance of the
kinetic effect of the reactions via the change in the conformational
background of the reaction, besides the loss of the thermodynamic
one. The modification of the electronic structure of ring C of the 7-
benzyl products (18a–e vs 20a–e) was originated directly from the
electronic modification of the target ring affected by the loss of the
6-methoxy moiety.
H
4
B
3
R
2
1
5
A
20a, 22a
H
C
A
6a
N
N
CH3SO2OH
H3C
N
B
H3C
20b, 22b 2-Cl
C
H
O
O
90 °C, 30 min
11 OH
10
7
D
8
OCH3
OCH3
9
22a-b
20a-b
Scheme 5. Acid-catalyzed rearrangement of morphinan-5,8-dienes 20a–b.
The conventional explanation5a,12 for the acid-catalyzed rear-
rangement of the thebaine-like molecules involves the proton-
promoted cleavage of the C5–O ether bond as the first step,
resulting in a cation at ring C. Meanwhile the bridgehead bond of
ring N at the fusion of rings B and C relocates from 13-position to
14-position. As the next steps of the mechanism, a series of electron
pair shifts take place at ring C in order to form the aromatic
structure; these rearrangements are terminated with a further re-
location of ring N from 14-position to 8-position of the late mor-
phinan backbone. The aporphine skeleton is stabilized by a proton
release. This general theory was applied for the morphinan-5,8-
diene structure presuming an acid-catalyzed isomerization of the
5,8-diene structure into the more stable conjugated 6,8-diene in-
termediate (Scheme 6).
In order to further study the capabilities of acid-catalyzed
rearrangement on morphinandiene backbone and to obtain a novel
class of semisynthetic aporphines, we performed the rearrange-
ments of some representatives of the newly synthesized 5,6- and
6,7-disubstituted morphinan-6,8-dienes (Schemes 7 and 8).
In the backbone rearrangement of both groups of disubstituted
morphinandienes 17–18 we found the formation of the corre-
sponding 1,2- or 2,3-disubstituted apocodeines 23–24 in high yield.
The presence of two substituents or the relative steric bulk on the C
ring of the morphinans has no disturbing effect on these acid-cat-
alyzed reactions. The mechanism of them is considered to be the
same as the generally accepted one for morphinan-6,8-dienes.
With respect to the significant dopamine D2 affinity of 2-
methoxy- and 2-phenylapomorphines and the interpretation of
their activity2a the presented 1,2- and 2,3-disubstituted aporphi-
noids 23 and 24 are neuropharmacologically interesting hybrids
bearing the H-bond acceptor ability and the large lipophilic moiety
in the proximity of the 2-position of the aporphine skeleton. Due to
this consideration the extension of the synthetic procedures and
the detailed pharmacological study of the existing compounds are
in progress.
In summary of the results of benzylations we emphasize that
these reactions give rise to some new precursors to semisynthetic
aporphinoids with hitherto unknown substitution patterns on the
A-ring. The overall conversion of the starting morphinandienes 1
and 3 into the benzylated ones was found to be very high. These are
the main reasons for not focussing on the optimization of the ratio
Figure 4. Optimized structure for thebaine-7-anion 16b and morphinan-5,8-diene-7-
anion 21 at the B3LYP/6-31G level.
*

A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
5855
-H+
H
R
H
R
R
H
H
H
H
H
acid-catalyzed
isomerization
+H+
-H+
+H+
N
N
N
H
H
OH
H3C
H3C
H3C
O
O
OCH3
OCH3
OCH3
20a-b
R
H
H
N
H3C
H
OH
OCH3
22a-b
Scheme 6. Suggested mechanism for the acid-catalyzed rearrangement of morphinan-5,8-dienes.
OCH3
OCH3
R
R
N
N
R
H
CH3SO2OH
H3C
H3C
O
17a, 23a
17b, 23b
OH
2-Cl
OCH3
OCH3
17a-b
23a-b
Scheme 7. Acid-catalyzed rearrangement of 5,6-disubstituted morphinan-6,8-dienes 17a–b.
R
R
Merck 5554 Kieselgel 60 F254 foils using chloroform/methanol¼8:2
mobile phase; the spots were visualized with Dragendorff’s re-
agent. 1H and 13C NMR spectra were recorded on a Bruker AM 360
(360 and 90.6 MHz, respectively), chemical shifts are reported in
OCH3
OCH3
R
H
18a, 24a
18b, 24b
N
N
parts per million (d) from internal TMS and coupling constants (J)
CH3SO2OH
H3C
H3C
O
2-Cl
are measured in hertz. Signal assignments are based on standard
APT, DEPT, HSQC, HMQC and 1H–1H COSY experiments. Abbrevia-
tions s, d, t, m and br are used to designate singlet, doublet, triplet,
multiplet and broad, respectively. Mass spectra (EI and HRMS,
70 eV, m/z) were obtained on a Jeol DX 303/DA 5000 instrument.
Elementary analyses were carried out on a Perkin–Elmer 2400 CHN
analyzer. Compounds were purified by column chromatography
using Merck Kieselgel 60 (230–400 mesh). IR spectra were recorded
on Perkin–Elmer 283 B spectrometer.
OH
OCH3
OCH3
18a-b
24a-b
Scheme 8. Acid-catalyzed rearrangement of 6,7-disubstituted morphinan-6,8-dienes
18a–b.
3. Conclusion
We presented the benzylation of thebaine (1) and 6-deme-
thoxythebaine (3) resulting in different product mixtures. Expla-
nations were given for either the observed differences in the ratio
4.2. Chemistry
of 5b- versus 7-benzyl products or the deviation of the electronic
4.2.1. General procedure for the benzylation of morphinans
structure of ring C of 7-benzyl products starting from 1 or 3. The
acid-catalyzed rearrangement of 7-benzyl-morphinan-5,8-dienes
20a–b was achieved and a mechanistic interpretation of the for-
mation of 3-benzylapocodeines 22a–b was provided. The same
rearrangement of 5,6- and 6,7-disubstituted morphinans yielded
a novel class of semisynthetic aporphinoids with disubstituted
A-rings. All the presented aporphines have the possibility of
remarkable dopamine binding activity considering the same
properties of 2-methoxy- and 2-phenylapomorphines. The pre-
sented benzylation data could serve as starting consideration of
the development of opioid-active compounds derived via 5- or 7-
substituted morphinandienes or dopaminergic apomorphines with
mono- or disubstituted ring A.
To a stirred solution of 1 g of thebaine (1) or 1 g of 6-demethoxy-
thebaine (3) in 80 mL of dry THF, cooled to ꢀ78 ꢁC, was added 1.7 M
tert-BuLi (in pentane, 1.2 equiv). The mixture was stirred for 30 min
before benzyl chloride (1.2 equiv) was added. The solutionwas stirred
at ꢀ78 ꢁC for 1 h before it was allowed to come to room temperature
over 2 h and stirred at ambient temperature for further 2 h. Thework-
up was performed in line with Gates’ method,4 products were sepa-
rated by means of column chromatography (dichloromethane/
methanol/concentrated ammonium hydroxide¼90:9:1).
4.2.1.1. 5b-Benzyl-3,6-dimethoxy-4,5a-epoxy-17-methyl-6,7,8,14-tet-
radehydro-morphinan (17a). Compound 17a and compound 18a
were separated by means of column chromatography. Compound
17a was the first eluted component. Yellow cubic crystals were
obtained by crystallization from toluene/methanol¼8:2; mp: 126–
128 ꢁC (lit.4 124 ꢁC from anhydrous ether); yield: 542 mg (42%);
4. Experimental protocols
4.1. General
CHN anal. calcd for C26H27NO3: C, 77.58; H, 7.01; N, 3.48. Found: C,
25
77.60; H, 7.09; N, 3.52; [
a
]
D
ꢀ376 (c 0.1, chloroform); Rf (90%
Melting points were determined with a Kofler hot-stage appa-
ratus. Thin layer chromatography was performed on precoated
CH2Cl2/9% CH3OH/1% concentrated ammonium hydroxide): 0.47;
nmax (KBr disc): 2940, 2880, 1640, 1150, 1100; MS (EI): m/z (%) 402

5856
A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
(Mþþ1, 100), 387 (87), 312 (64); HRMS (EI) m/z (%) calculated for
(Mþþ1, 100), 411 (65), 387 (76), 305 (32); HRMS (EI) m/z (%) cal-
culated for C27H27F3NOþ3 : 470.1938 (MþþH), found: 470.1950
(MþþH, 100); dH (360 MHz, CDCl3): 7.27–7.10 (4H, m, Bn aromatic),
6.51, 6.48 (2H, 2d, C1–H, C2–H, J1–2 8.2), 5.64 (1H, d, C8–H, J7–8 6.2),
4.87 (1H, d, C7–H, J7–8 6.2), 3.99–3.82 (7H, m, C5–CH2–, C9–H, C3–
C
26H28NOþ3 : 402.2064 (MþþH), found: 402.2049 (MþþH, 100); dH
(360 MHz, CDCl3): 7.22–7.04 (5H, m, Bn aromatic), 6.61, 6.59 (2H,
2d, C1–H, C2–H, J1–2 8.2), 5.66 (1H, d, C8–H, J7–8 6.8), 4.84 (1H, d, C7–
H, J7–8 6.8), 3.84–3.76 (6H, m, C9–H, C5–CH2–, C3–OCH3), 3.34 (3H, s,
C6–OCH3), 3.09–2.19 (7H, m, C10–Ha, C10–Hb, C16–Ha, C16–Hb,
–NCH3), 2.08–1.93 (2H, m, C15–Ha, C15–Hb); dC (50.3 MHz, CDCl3):
157.25 (C6), 147.22 (C3), 144.53 (C4), 136.37–108.61 (10C, aromatic,
C8, C14), 92.34 (C6), 88.11 (C5), 64.61 (C9), 54.44 (C6–OCH3), 52.34
(C3–OCH3), 48.83 (C16), 45.88 (C13), 42.01 (NCH3), 39.12 (C5–CH2–),
35.64 (C15), 32.68 (C10).
OCH3), 3.44 (3H, s, C6–OCH3), 3.10–1.88 (9H, m, C10–Ha, C10–Hb, C15
Ha, C15–Hb, C16–Ha, C16–Hb, –NCH3); dC (50.3 MHz, CDCl3): 153.54
(C6), 145.34 (C3), 144.23 (C4), 134.21–108.56 (10C, aromatic, C8, C14
–
,
–CF3), 93.21 (C6), 87.54 (C5), 66.87 (C9), 55.43 (C6–OCH3), 53.56 (C3–
OCH3), 49.21 (C16), 44.76 (C13), 43.05 (NCH3), 39.40 (C5–CH2), 36.65
(C15), 31.98 (C10).
4.2.1.2. 5
b
-(2-Chlorobenzyl)-3,6-dimethoxy-4,5
a
-epoxy-17-methyl-
4.2.1.5. 3,6-Dimethoxy-4,5a-epoxy-17-methyl-5b-(4-nitrobenzyl)-
6,7,8,14-tetradehydro-morphinan (17b). Compound 17b and com-
pound 18b were separated by means of column chromatography.
Compound 17b was the first eluted component. Pale yellow cubic
crystals were obtained by crystallization from toluene/meth-
anol¼8:2; mp: 118–120 ꢁC; yield: 657 mg (47%); CHN anal. calcd for
6,7,8,14-tetradehydro-morphinan (17e). Compound 17e and com-
pound 18e were separated by means of column chromatography.
Compound 17e was the first eluted component. Pale brown cubic
crystals were obtained by crystallization from toluene/meth-
anol¼8:2; mp: 131–133 ꢁC; yield: 602 mg (42%); CHN anal. calcd
C
26H26ClNO3: C, 71.47; H, 6.23; N, 3.21. Found: C, 71.52; H, 6.18; N,
for C26H26N2O5: C, 69.94; H, 5.87; N, 6.27. Found: C, 69.87; H, 6.09;
25
25
3.15; [
a]
ꢀ312 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
N, 6.31; [
a
]
D
ꢀ411 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
D
concentrated ammonium hydroxide): 0.46; nmax (KBr disc): 2930,
2900, 1640, 1380, 1170, 1090, 710; MS (EI): m/z (%) 436 (Mþþ1, 100),
384 (51), 334 (43); HRMS (EI) m/z (%) calculated for C26H27ClNOþ3 :
436.1574 (MþþH), found: 436.1566 (MþþH, 100); dH (360 MHz,
CDCl3): 7.18–7.01 (4H, m, Bn aromatic), 6.68, 6.63 (2H, 2d, C1–H, C2–
H, J1–2 8.0), 5.69 (1H, d, C8–H, J7–8 6.6), 4.91 (1H, d, C7–H, J7–8 6.6),
3.90–3.80 (6H, m, C9–H, C5–CH2–, C3–OCH3), 3.40 (3H, s, C6–OCH3),
3.14–2.21 (7H, m, C10–Ha, C10–Hb, C16–Ha, C16–Hb, –NCH3), 2.11–2.01
(2H, m, C15–Ha, C15–Hb); dC (50.3 MHz, CDCl3): 158.92 (C6), 145.76
(C3), 144.98 (C4), 138.67–110.11 (10C, aromatic, C8, C14), 90.45 (C6),
87.34 (C5), 66.68 (C9), 54.23 (C6–OCH3), 51.47 (C3–OCH3), 49.66
(C16), 46.06 (C13), 43.74 (NCH3), 40.21 (C5–CH2–), 36.98 (C15), 34.16
(C10).
concentrated ammonium hydroxide): 0.49; nmax (KBr disc): 2920,
2990, 1640, 1530, 1350, 1150, 1130; MS (EI): m/z (%) 447 (Mþþ1, 12),
401 (100), 373 (67), 307 (43); HRMS (EI) m/z (%) calculated for
C
26H27N2Oþ5 : 447.1914 (MþþH), found: 447.1924 (MþþH, 12); dH
(360 MHz, CDCl3): 7.87–7.65 (2H, dd, Bn aromatic, A2B2, J 6.4 and
1.1), 7.52–7.44 (2H, dd, Bn aromatic, A2B2, J 6.3 and 1.1), 6.52, 6.47
(2H, 2d, C1–H, C2–H, J1–2 8.0), 5.84 (1H, d, C8–H, J7–8 6.1), 4.97 (1H, d,
C7–H, J7–8 6.1), 3.83–3.73 (6H, m, C5–CH2–, C3–OCH3), 3.66 (1H, dd,
C9–H, J9–10a 6.0, J9–10b 3.2), 3.43 (3H, s, C6–OCH3), 3.37–2.11 (7H, m,
C10–Ha, C10–Hb, C16–Ha, C16–Hb, –NCH3), 2.02–1.86 (2H, m, C15–Ha,
C15–Hb); dC (50.3 MHz, CDCl3): 156.32 (C6), 145.21 (C3), 143.77 (C4),
139.15–106.98 (10C, aromatic, C8, C14), 90.87 (C6), 85.43 (C5), 67.45
(C9), 56.10 (C6–OCH3), 53.43 (C3–OCH3), 50.08 (C16), 45.87 (C13),
43.65 (NCH3), 39.62 (C5–CH2), 36.34 (C15), 33.12 (C10).
4.2.1.3. 3,6-Dimethoxy-4,5a-epoxy-5b-(2-fluorobenzyl)-17-methyl-
6,7,8,14-tetradehydro-morphinan (17c). Compound 17c and com-
pound 18c were separated by means of column chromatography.
Compound 17c was the first eluted component. Bright yellow cubic
crystals were obtained by crystallization from toluene/meth-
anol¼8:2; mp: 123–125 ꢁC; yield: 627 mg (48%); CHN anal. calcd
4.2.1.6. 7-Benzyl-3,6-dimethoxy-4,5a-epoxy-17-methyl-6,7,8,14-tet-
radehydro-morphinan (18a). Compound 17a and compound 18a
were separated by means of column chromatography. Compound
18a was the second eluted component. Off-white, plate-shaped
crystals were obtained by crystallization from toluene/meth-
anol¼8:2; mp: 142–144 ꢁC; yield: 361 mg (28%); CHN anal. calcd
for C26H26FNO3: C, 74.44; H, 6.25; N, 3.33. Found: C, 74.50; H, 6.19;
25
N, 3.35; [
a]
ꢀ334 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
for C26H27NO3: C, 77.58; H, 7.01; N, 3.48. Found: C, 77.66; H, 7.12; N,
D
25
concentrated ammonium hydroxide): 0.38; nmax (KBr disc): 2910,
2880, 1660, 1310, 1150, 1100; MS (EI): m/z (%) 420 (Mþþ1, 100), 366
(67), 354 (54), 321 (34); HRMS (EI) m/z (%) calculated for
3.44; [
a
]
ꢀ456 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
D
concentrated ammonium hydroxide): 0.23; nmax (KBr disc): 2900,
2850, 1240, 1140; MS (EI): m/z (%) 402 (Mþþ1, 100), 364 (62), 322
(67), 288 (40); HRMS (EI) m/z (%) calculated for C26H28NOþ3 :
402.2064 (MþþH), found: 402.2063 (MþþH, 100); dH (360 MHz,
CDCl3): 7.17–7.00 (5H, m, Bn aromatic), 6.51, 6.48 (2H, 2d, C1–H, C2–
H, J1–2 8.0), 5.77 (1H, s, C8–H), 4.22 (1H, s, C5–H), 3.91–3.83 (4H, m,
C9–H, C3–OCH3), 3.61 (3H, s, C6–OCH3), 3.32 (2H, s, C7–CH2–), 3.18–
2.26 (7H, m, C10–Ha, C10–Hb, C16–Ha, C16–Hb, –NCH3), 2.12–2.01 (2H,
m, C15–Ha, C15–Hb); dC (50.3 MHz, CDCl3): 154.21 (C6), 147.56 (C3),
145.89 (C4), 131.02–110.67 (10C, aromatic, C8, C14), 99.23 (C7), 86.45
(C5), 61.72 (C9), 56.64 (C6–OCH3), 53.38 (C3–OCH3), 50.83 (C16),
44.36 (C13), 41.09 (NCH3), 38.29 (C7–CH2–), 34.04 (C15), 30.94 (C10).
C
26H27FNOþ3 : 420.1969 (MþþH), found: 420.1979 (MþþH, 100); dH
(360 MHz, CDCl3): 7.06–6.87 (4H, m, Bn aromatic), 6.62, 6.55 (2H,
2d, C1–H, C2–H, J1–2 8.1), 5.80 (1H, d, C8–H, J7–8 6.5), 5.01 (1H, d, C7–
H, J7–8 6.5), 3.94–3.86 (6H, m, C5–CH2–, C3–OCH3), 3.74 (1H, dd,
C9–H, J9–10a 6.1, J9–10b 3.4), 3.37 (3H, s, C6–OCH3), 3.19–2.17 (7H, m,
C
C
10–Ha, C10–Hb, C16–Ha, C16–Hb, –NCH3), 2.07–1.89 (2H, m, C15–Ha,
0
15–Hb); dC (50.3 MHz, CDCl3): 159.44 (C2 ), 155.43 (C6), 144.87 (C3),
143.45 (C4), 136.91–106.32 (9C, aromatic, C8, C14), 91.63 (C6), 86.84
(C5), 67.21 (C9), 55.16 (C6–OCH3), 52.03 (C3–OCH3), 49.34 (C16),
45.07 (C13), 43.32 (NCH3), 40.01 (C5–CH2), 35.23 (C15), 32.45 (C10).
4.2.1.4. 3,6-Dimethoxy-4,5a-epoxy-17-methyl-6,7,8,14-tetradehydro-
4.2.1.7. 7-(2-Chlorobenzyl)-3,6-dimethoxy-4,5a-epoxy-17-methyl-
5
b
-(2-trifluoro-methylbenzyl)-morphinan (17d). Compound 17d
6,7,8,14-tetradehydro-morphinan (18b). Compound 17b and com-
pound 18b were separated by means of column chromatography.
Compound 18b was the second eluted component. Off-white,
plate-shaped crystals were obtained by crystallization from tolu-
ene/methanol¼8:2; mp: 134–136 ꢁC; yield: 280 mg (20%); CHN
and compound 18d were separated by means of column chroma-
tography. Compound 17d was the first eluted component. Dark
yellow cubic crystals were obtained by crystallization from toluene/
methanol¼8:2; mp: 132–137 ꢁC; yield: 603 mg (40%); CHN anal.
calcd for C27H26F3NO3: C, 69.07; H, 5.58; N, 2.98. Found: C, 69.12; H,
anal. calcd for C26H26ClNO3: C, 71.47; H, 6.23; N, 3.21. Found: C,
25
25
5.61; N, 3.01; [
a
]
ꢀ363 (c 0.1, chloroform); Rf (90% CH2Cl2/9%
71.40; H, 6.14; N, 3.15; [
a]
ꢀ404 (c 0.1, chloroform); Rf (90%
D
D
CH3OH/1% concentrated ammonium hydroxide): 0.56; nmax (KBr
disc): 2920, 2860, 1650, 1420, 1340, 1120; MS (EI): m/z (%) 470
CH2Cl2/9% CH3OH/1% concentrated ammonium hydroxide): 0.26;
nmax (KBr disc): 2890, 2810, 1630, 1350, 1180, 720; MS (EI): m/z (%)

A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
5857
436 (Mþþ1, 100), 371 (67), 356 (56), 312 (34); HRMS (EI) m/z (%)
calculated for C26H27ClNO3þ: 436.1574 (MþþH), found: 436.1561
(MþþH, 100); dH (360 MHz, CDCl3): 7.11–7.02 (4H, m, Bn aromatic),
6.58, 6.54 (2H, 2d, C1–H, C2–H, J1–2 8.1), 5.80 (1H, s, C8–H), 4.09 (1H,
s, C5–H), 3.88–3.75 (4H, m, C9–H, C3–OCH3), 3.54 (3H, s, C6–OCH3),
3.30 (2H, s, C7–CH2–), 3.34–2.08 (8H, m, C10–Ha, C10–Hb, C15–Hb,
CH2Cl2/9% CH3OH/1% concentrated ammonium hydroxide): 0.31;
nmax (KBr disc): 2930, 2890, 1660, 1550, 1520, 1360, 1150, 1120; MS
(EI): m/z (%) 447 (Mþþ1, 4), 401 (100), 369 (74), 354 (55), 302 (23);
HRMS (EI) m/z (%) calculated for C26H27N2Oþ5 : 447.1914 (MþþH),
found: 447.1909 (MþþH, 4); dH (360 MHz, CDCl3): 8.01–7.89 (2H,
dd, Bn aromatic, A2B2, J 6.3 and <1), 7.52–7.44 (2H, dd, Bn aromatic,
A2B2, J 6.5 and <1), 6.54, 6.49 (2H, 2d, C1–H, C2–H, J1–2 8.2), 5.80
(1H, s, C8–H), 4.21 (1H, s, C5–H), 3.91 (3H, s, C3–OCH3), 3.82–3.71
(4H, m, C9–H, C6–OCH3), 3.38 (2H, s, C7–CH2–), 3.31–2.00 (8H, m,
C
16–Ha, C16–Hb, –NCH3), 1.98 (1H, td, C15–Ha, J15a,15b;16a,16b 11.4,
J15a,15b 4.5); dC (50.3 MHz, CDCl3): 151.27 (C6), 146.76 (C3), 145.01
(C4), 128.44–108.37 (10C, aromatic, C8, C14), 97.66 (C7), 88.24 (C5),
61.04 (C9), 55.18 (C6–OCH3), 53.30 (C3–OCH3), 49.93 (C16), 43.92
(C13), 41.25 (NCH3), 40.09 (C7–CH2–), 35.53 (C15), 32.45 (C10).
C
10–Ha, C10–Hb, C15–Hb, C16–Ha, C16–Hb, –NCH3), 1.91 (1H, td, C15
–
Ha, J15a,15b;16a,16b 10.4, J15a,15b 4.3); dC (50.3 MHz, CDCl3): 162.23 (C6),
0
0
147.19 (C3), 146.31 (C4), 144.54 (C4 ), 141.78 (C1 ), 130.07–111.82 (8C,
aromatic, C8, C14), 99.21 (C7), 89.49 (C5), 60.09 (C9), 56.36 (C6–
OCH3), 53.49 (C3–OCH3), 51.45 (C16), 43.89 (C13), 41.10 (NCH3), 39.62
(C7–CH2–), 35.21 (C15), 33.23 (C10).
4.2.1.8. 3,6-Dimethoxy-4,5a-epoxy-7-(2-fluorobenzyl)-17-methyl-
6,7,8,14-tetradehydro-morphinan (18c). Compound 17c and com-
pound 18c were separated by means of column chromatography.
Compound 18c was the second eluted component. Pale yellow,
plate-shaped crystals were obtained by crystallization from tolu-
ene/methanol¼8:2; mp: 127–129 ꢁC; yield: 323 mg (24%); CHN
4.2.1.11. 5b-Benzyl-4,5a-epoxy-3-methoxy-17-methyl-6,7,8,14-tetra-
dehydro-morphinan (19a). Compound 19a and compound 20a
were separated by means of column chromatography. Compound
19a was the first eluted component. Off-white, plate-shaped crys-
tals were obtained by crystallization from toluene/methanol¼6:4;
mp: 116–118 ꢁC; yield: 309 mg (26%) and 100 mg of unreacted di-
anal. calcd for C26H26FNO3: C, 74.44; H, 6.25; N, 3.33. Found: C,
25
74.39; H, 6.32; N, 3.37; [
a
]
D
ꢀ424 (c 0.1, chloroform); Rf (90%
CH2Cl2/9% CH3OH/1% concentrated ammonium hydroxide): 0.19;
nmax (KBr disc): 2890, 2870, 1630, 1330, 1080; MS (EI): m/z (%) 420
(Mþþ1, 100), 366 (54), 342 (32), 307 (74); HRMS (EI) m/z (%) cal-
ene 3 also was recovered; CHN anal. calcd for C25H25NO2: C, 80.83;
25
culated for
C
26H27FNOþ3 : 420.1969 (MþþH), found: 420.1957
H, 6.78; N, 3.77. Found: C, 80.73; H, 6.70; N, 3.82; [
a
]
ꢀ321 (c 0.1,
D
(MþþH, 100); dH (360 MHz, CDCl3): 7.02–6.87 (4H, m, Bn aromatic),
6.51, 6.48 (2H, 2d, C1–H, C2–H, J1–2 8.2), 5.68 (1H, s, C8–H), 4.03 (1H,
s, C5–H), 3.91–3.85 (4H, m, C9–H, C3–OCH3), 3.61 (3H, s, C6–OCH3),
3.46 (2H, s, C7–CH2–), 3.27–2.02 (8H, m, C10–Ha, C10–Hb, C15–Hb,
chloroform); Rf (90% CH2Cl2/9% CH3OH/1% concentrated ammo-
nium hydroxide): 0.59; nmax (KBr disc): 2880, 2860, 1610, 1140; MS
(EI): m/z (%) 372 (Mþþ1, 100), 357 (47), 321 (66); HRMS (EI) m/z (%)
calculated for C25H26NOþ2 : 372.1958 (MþþH), found: 372.1964
(MþþH, 100); dH (360 MHz, CDCl3): 7.14–7.01 (5H, m, Bn aromatic),
6.65, 6.61 (2H, 2d, C1–H, C2–H, J1–2 8.1), 5.84–5.72 (3H, m, C6–H, C7–
H, C8–H), 3.84–3.76 (6H, m, C9–H, C5–CH2–, C3–OCH3), 3.12–2.09
(8H, m, C10–Ha, C10–Hb, C15–Hb, C16–Ha, C16–Hb, –NCH3), 1.90 (1H,
td, C15–Ha, J15a,15b;16a,16b 11.1, J15a,15b 4.5); dC (50.3 MHz, CDCl3):
147.56 (C3), 145.89 (C4), 138.37–108.17 (10C, aromatic, C6, C7, C8,
C
16–Ha, C16–Hb, –NCH3), 1.84 (1H, td, C15–Ha, J15a,15b;16a,16b 10.6,
0
J15a,15b 4.3); dC (50.3 MHz, CDCl3): 161.11 (C2 ), 160.67 (C6), 146.10
(C3), 145.79 (C4), 133.65–110.67 (9C, aromatic, C8, C14), 98.89 (C7),
88.27 (C5), 61.56 (C9), 56.05 (C6–OCH3), 53.78 (C3–OCH3), 51.12
(C16), 44.12 (C13), 41.78 (NCH3), 35.33 (C15), 33.27 (C10), 27.62 (C7–
CH2–).
C14), 86.75 (C5), 62.67 (C9), 56.49 (C6–OCH3), 50.17 (C16), 49.34 (C13),
4.2.1.9. 3,6-Dimethoxy-4,5a-epoxy-17-methyl-6,7,8,14-tetradehydro-
41.56 (NCH3), 40.67 (C5–CH2–), 35.89 (C15), 33.09 (C10).
7-(2-trifluoro-methylbenzyl)-morphinan (18d). Compound 17d and
compound 18d were separated by means of column chromatog-
raphy. Compound 18d was the second eluted component. Yellow,
plate-shaped crystals were obtained by crystallization from tolu-
ene/methanol¼8:2; mp: 141–143 ꢁC; yield: 437 mg (29%); CHN
4.2.1.12. 5b-(2-Chlorobenzyl)-4,5a-epoxy-3-methoxy-17-methyl-
6,7,8,14-tetradehydro-morphinan (19b). Compound 19b and com-
pound 20b were separated by means of column chromatography.
Compound 19b was the first eluted component. Pale yellow, plate-
shaped crystals were obtained by crystallization from toluene/
methanol¼6:4; mp: 111–113 ꢁC; yield: 291 mg (23%) and 120 mg of
unreacted diene 3 also was recovered; CHN anal. calcd for
anal. calcd for C27H26F3NO3: C, 69.07; H, 5.58; N, 2.98. Found: C,
25
69.00; H, 5.64; N, 3.06; [
a]
ꢀ423 (c 0.1, chloroform); Rf (90%
D
CH2Cl2/9% CH3OH/1% concentrated ammonium hydroxide): 0.23;
nmax (KBr disc): 2910, 2870, 1670, 1420, 1340, 1130; MS (EI): m/z (%)
470 (Mþþ1, 100), 441 (78), 408 (34), 374 (72), 332 (32); HRMS (EI)
m/z (%) calculated for C27H27F3NOþ3 : 470.1938 (MþþH), found:
470.1930 (MþþH, 100); dH (360 MHz, CDCl3): 7.23–7.18 (2H, m, Bn
aromatic), 7.10–7.04 (2H, m, Bn aromatic), 6.63, 6.57 (2H, 2d, C1–H,
C2–H, J1–2 7.9), 5.85 (1H, s, C8–H), 3.99 (1H, s, C5–H), 3.84 (3H, s, C3–
OCH3), 3.71–3.63 (4H, m, C9–H, C6–OCH3), 3.31 (2H, s, C7–CH2–),
3.15–2.00 (8H, m, C10–Ha, C10–Hb, C15–Hb, C16–Ha, C16–Hb, –NCH3),
1.87 (1H, td, C15–Ha, J15a,15b;16a,16b 11.0, J15a,15b 4.4); dC (50.3 MHz,
CDCl3): 159.44 (C6), 147.45 (C3), 146.10 (C4), 133.21–109.34 (9C, ar-
omatic, C8, C14, –CF3), 98.54 (C7), 89.65 (C5), 61.67 (C9), 56.34 (C6–
OCH3), 53.10 (C3–OCH3), 51.04 (C16), 44.12 (C13), 41.39 (NCH3), 35.34
(C15), 33.78 (C10), 31.42 (C7–CH2–).
C
25H24ClNO2: C, 73.97; H, 5.96; N, 3.45. Found: C, 73.91; H, 5.97; N,
25
3.40; [
a
]
D
ꢀ356 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
concentrated ammonium hydroxide): 0.64; nmax (KBr disc): 2900,
2810, 1640, 1360, 1140, 720; MS (EI): m/z (%) 406 (Mþþ1, 100), 391
(84), 360 (60); HRMS (EI) m/z (%) calculated for C25H25ClNOþ2 :
406.1568 (MþþH), found: 406.1564 (MþþH, 100); dH (360 MHz,
CDCl3): 7.16–7.06 (4H, m, Bn aromatic), 6.56, 6.52 (2H, 2d, C1–H, C2–
H, J1–2 7.9), 5.91 (1H, dd, C7–H, J1 6.6, J2 6.8); 5.80–5.71 (2H, m, C6–H,
C8–H), 3.78–3.64 (6H, m, C9–H, C5–CH2–, C3–OCH3), 3.21–2.11 (8H,
m, C10–Ha, C10–Hb, C15–Hb, C16–Ha, C16–Hb, –NCH3), 1.94 (1H, td,
C15–Ha, J15a,15b;16a,16b 10.6, J15a,15b 4.2); dC (50.3 MHz, CDCl3): 147.32
0
(C3), 146.16 (C4), 143.56 (C2 ), 136.45–109.23 (9C, aromatic, C6, C7, C8,
C14), 85.42 (C5), 62.75 (C9), 56.33 (C6–OCH3), 49.69 (C16), 49.11 (C13),
42.14 (NCH3), 41.23 (C5–CH2–), 36.03 (C15), 33.34 (C10).
4.2.1.10. 3,6-Dimethoxy-4,5a-epoxy-17-methyl-7-(4-nitrobenzyl)-
6,7,8,14-tetradehydro-morphinan (18e). Compound 17e and com-
pound 18e were separated by means of column chromatography.
Compound 18e was the second eluted component. Dark yellow,
plate-shaped crystals were obtained by crystallization from tolu-
ene/methanol¼8:2; mp: 148–150 ꢁC; yield: 430 mg (30%); CHN
4.2.1.13. 4,5a-Epoxy-5b-(2-fluorobenzyl)-3-methoxy-17-methyl-
6,7,8,14-tetradehydro-morphinan (19c). Compound 19c and com-
pound 20c were separated by means of column chromatography.
Compound 19c was the first eluted component. Pale grey, plate-
shaped crystals were obtained by crystallization from toluene/
methanol¼6:4; mp: 118–120 ꢁC; yield: 259 mg (21%) and 110 mg of
unreacted diene 3 also was recovered; CHN anal. calcd for
anal. calcd for C26H26N2O5: C, 69.94; H, 5.87; N, 6.27. Found: C,
25
69.99; H, 6.11; N, 6.19; [
a
]
ꢀ476 (c 0.1, chloroform); Rf (90%
D

5858
A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
C25H24FNO2: C, 77.10; H, 6.21; N, 3.60. Found: C, 77.14; H, 6.27; N,
was recovered; CHN anal. calcd for C25H252N5 O2: C, 80.83; H, 6.78; N,
3.77. Found: C, 80.87; H, 6.79; N, 3.84; [
ꢀ67 (c 0.1, chloroform);
25
3.51; [
a
]
ꢀ399 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
a]
D
D
concentrated ammonium hydroxide): 0.53; nmax (KBr disc): 2900,
2880, 1600, 1350, 1070; MS (EI): m/z (%) 390 (Mþþ1, 100), 375 (65),
323 (54); HRMS (EI) m/z (%) calculated for C25H25FNOþ2 : 390.1864
(MþþH), found: 390.1860 (MþþH, 100); dH (360 MHz, CDCl3): 7.10–
6.94 (4H, m, Bn aromatic), 6.45, 6.42 (2H, 2d, C1–H, C2–H, J1–2 8.3),
5.95 (1H, dd, C7–H, J1 6.5, J2 6.6); 5.81–5.74 (2H, m, C6–H, C8–H),
Rf (90% CH2Cl2/9% CH3OH/1% concentrated ammonium hydroxide):
0.34; nmax (KBr disc): 2920, 2880, 1650, 1420, 1120; MS (EI): m/z (%)
372 (Mþþ1, 100), 357 (73), 318 (32); HRMS (EI) m/z (%) calculated
for C25H26NOþ2 : 372.1958 (MþþH), found: 372.1950 (MþþH, 100);
dH (360 MHz, CDCl3): 7.20–7.09 (5H, m, Bn aromatic), 6.51, 6.49 (2H,
2d, C1–H, C2–H, J1–2 7.9), 5.34 (1H, d, C8–H, J7a–8 5.5), 4.78 (1H, d, C6–
H, J6–7a 4.9), 3.84–3.77 (4H, m, C9–H, C3–OCH3), 3.31 (1H, dd, C7–H,
3.82–3.71 (6H, m, C9–H, C5–CH2–, C3–OCH3), 3.21–2.04 (9H, m, C10
–
Ha, C10–Hb, C15–Ha, C15–Hb, C16–Ha, C16–Hb, NCH3); dC (50.3 MHz,
J7a–8 5.5, J6–7a 4.9), 3.14–2.09 (10H, m, C5–CH2–, C10–Ha, C10–Hb, C15–
0
CDCl3): 158.34 (C2 ), 147.45 (C3), 146.23 (C4), 135.12–110.78 (9C,
Hb, C16–Ha, C16–Hb, –NCH3), 1.97 (1H, td, C15–Ha, J15a,15b;16a,16b 10.8,
J15a,15b 4.3); dC (50.3 MHz, CDCl3): 161.12 (C5), 146.49 (C3), 145.31
aromatic, C6, C7, C8, C14), 86.01 (C5), 61.76 (C9), 56.52 (C6–OCH3),
50.44 (C16), 49.76 (C13), 42.56 (NCH3), 36.32 (C15), 33.49 (C10), 32.10
(C5–CH2–).
0
(C4), 140.11 (C1 ), 138.32 (C14), 134.59–108.47 (9C, aromatic, C6, C8),
61.84 (C9), 56.34 (C6–OCH3), 51.14 (C16), 43.24 (C5–CH2–), 41.67
(C13), 41.18 (NCH3), 37.56 (C7), 34.39 (C15), 31.69 (C10).
4.2.1.14. 4,5
a-Epoxy-3-methoxy-17-methyl-6,7,8,14-tetradehydro-
5b
-(2-trifluoromethylbenzyl)-morphinan (19d). Compound 19d and
4.2.1.17. 7b-(2-Chlorobenzyl)-4,5a-epoxy-3-methoxy-17-methyl-
compound 20d were separated by means of column chromatog-
raphy. Compound 19d was the first eluted component. Off-white,
plate-shaped crystals were obtained by crystallization from tolu-
ene/methanol¼6:4; mp: 129–131 ꢁC; yield: 367 mg (25%) and
60 mg of unreacted diene 3 also was recovered; CHN anal. calcd for
5,6,8,14-tetradehydro-morphinan (20b). Compound 19b and com-
pound 20b were separated by means of column chromatography.
Compound 20b was the second eluted component. Pale yellow,
cubic crystals were obtained by crystallization from toluene/
methanol¼1:1; mp: 127–129 ꢁC; yield: 736 mg (58%) and 120 mg
of unreacted diene 3 also was recovered; CHN anal. calcd for
C
26H24F32N5O2: C, 71.06; H, 5.50; N, 3.19. Found: C, 71.01; H, 5.55; N,
3.20; [
a
]
D
ꢀ432 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
C25H24ClNO2: C, 73.97; H, 5.96; N, 3.45. Found: C, 74.04; H, 6.04; N,
25
concentrated ammonium hydroxide): 0.64; nmax (KBr disc): 2900,
2870, 1640, 1410, 1350, 1130; MS (EI): m/z (%) 440 (Mþþ1, 100), 425
(61), 379 (87), 351 (56); HRMS (EI) m/z (%) calculated for
3.41; [
a
]
D
ꢀ43 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
concentrated ammonium hydroxide): 0.44; nmax (KBr disc): 2920,
2870, 1640, 1350, 1450, 1130, 720; MS (EI): m/z (%) 406 (Mþþ1, 100),
391 (78), 377 (89), 352 (48); HRMS (EI) m/z (%) calculated for
C
26H25F3NOþ2 : 440.1832 (MþþH), found: 440.1821 (MþþH, 100); dH
(360 MHz, CDCl3): 7.28–7.21 (2H, m, Bn aromatic), 7.11–7.07 (2H, m,
Bn aromatic), 6.56, 6.52 (2H, 2d, C1–H, C2–H, J1–2 8.1), 5.84 (1H, dd,
C7–H, J1 7.0, J2 6.8); 5.79–5.73 (2H, m, C6–H, C8–H), 3.84–3.69 (6H,
m, C9–H, C5–CH2–, C3–OCH3), 3.27–2.01 (9H, m, C10–Ha, C10–Hb,
C
25H25ClNOþ2 : 406.1568 (MþþH), found: 406.1575 (MþþH, 100); dH
(360 MHz, CDCl3): 7.16–7.03 (4H, m, Bn aromatic), 6.56, 6.52 (2H,
2d, C1–H, C2–H, J1–2 8.0), 5.29 (1H, d, C8–H, J7a–8 5.2), 4.65 (1H, d,
C6–H, J6–7a 5.1), 3.90–3.79 (4H, m, C9–H, C3–OCH3), 3.37 (1H, dd, C7–
H, J7a–8 5.2, J6–7a 5.1), 3.27–2.04 (11H, m, C5–CH2–, C10–Ha, C10–Hb,
C
15–Ha, C15–Hb, C16–Ha, C16–Hb, NCH3); dC (50.3 MHz, CDCl3): 147.21
(C3), 146.45 (C4), 133.83–107.12 (10C, aromatic, C6, C7, C8, C14, CF3),
86.34 (C5), 61.20 (C9), 56.91 (C6–OCH3), 51.12 (C16), 50.07 (C13), 41.87
(NCH3), 37.24 (C5–CH2–), 36.07 (C15), 33.54 (C10).
C
15–Ha, C15–Hb, C16–Ha, C16–Hb, –NCH3); dC (50.3 MHz, CDCl3):
0
163.08 (C5), 146.23 (C3), 144.27 (C4), 141.48 (C1 ), 137.67 (C14),
133.17–108.78 (9C, aromatic, C6, C8), 61.23 (C9), 56.93 (C6–OCH3),
51.08 (C16), 41.89 (C13), 41.03 (NCH3), 37.28 (C7), 34.59 (C5–CH2–),
33.67 (C15), 30.12 (C10).
4.2.1.15. 4,5a-Epoxy-3-methoxy-17-methyl-5b-(4-nitrobenzyl)-
6,7,8,14-tetradehydro-morphinan (19e). Compound 19e and com-
pound 20e were separated by means of column chromatography.
Compound 19e was the first eluted component. Yellow, plate-sha-
ped crystals were obtained by crystallization from toluene/meth-
anol¼1:1; mp: 121–123 ꢁC; yield: 327 mg (24%) and 80 mg of
unreacted diene 3 also was recovered; CHN anal. calcd for
4.2.1.18. 4,5a-Epoxy-7b-(2-fluorobenzyl)-3-methoxy-17-methyl-
5,6,8,14-tetradehydro-morphinan (20c). Compound 19c and com-
pound 20c were separated by means of column chromatography.
Compound 20c was the second eluted component. Pale yellow,
cubic crystals were obtained by crystallization from toluene/
methanol¼1:1; mp: 133–135 ꢁC; yield: 678 mg (55%) and 110 mg of
unreacted diene 3 also was recovered; CHN anal. calcd for
C
25H24N2O4: C, 72.10; H, 5.81; N, 6.73. Found: C, 72.01; H, 5.87; N,
25
6.67; [
a]
ꢀ408 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
D
concentrated ammonium hydroxide): 0.67; nmax (KBr disc): 2910,
2880,1660,1540,1510,1360,1120,1110; MS (EI): m/z (%) 417 (Mþþ1,
12), 371 (100), 356 (59); HRMS (EI) m/z (%) calculated for
C25H24FNO2: C, 77.10; H, 6.21; N, 3.60. Found: C, 77.02; H, 6.25; N,
25
3.66; [
a]
ꢀ78 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
D
concentrated ammonium hydroxide): 0.32; nmax (KBr disc): 2910,
2860, 1620, 1460, 1340, 1040; MS (EI): m/z (%) 390 (Mþþ1, 100), 375
(87), 361 (89), 334 (34); HRMS (EI) m/z (%) calculated for
C
25H25N2Oþ4 : 417.1809 (MþþH), found: 417.1814 (MþþH, 12); dH
(360 MHz, CDCl3): 8.09–7.90 (2H, dd, Bn aromatic, A2B2, J 6.1 and
<1), 7.64–7.47 (2H, dd, Bn aromatic, A2B2, J 6.5 and <1), 6.59, 6.55
(2H, 2d, C1–H, C2–H, J1–2 8.0), 5.84–5.73 (3H, m, C6–H, C7–H, C8–H),
C
25H25FNOþ2 : 390.1864 (MþþH), found: 390.1856 (MþþH, 100); dH
(360 MHz, CDCl3): 7.09–6.93 (4H, m, Bn aromatic), 6.50, 6.47 (2H,
2d, C1–H, C2–H, J1–2 8.1), 5.39 (1H, d, C8–H, J7a–8 5.5), 4.88 (1H, d, C6–
H, J6–7a 5.3), 3.92–3.81 (4H, m, C9–H, C3–OCH3), 3.44 (1H, dd, C7–H,
3.81–3.65 (6H, m, C9–H, C5–CH2–, C3–OCH3), 3.30–2.03 (9H, m, C10
–
Ha, C10–Hb, C15–Ha, C15–Hb, C16–Ha, C16–Hb, –NCH3); dC (50.3 MHz,
0
0
CDCl3): 146.43 (C3), 145.65 (C4), 142.12 (C4 ), 139.10 (C1 ), 131.67–
109.82 (8C, aromatic, C6, C7, C8, C14), 85.69 (C5), 61.17 (C9), 56.43 (C6–
OCH3), 51.67 (C16), 50.98 (C13), 43.24 (C5–CH2–), 41.36 (NCH3), 35.43
(C15), 32.81 (C10).
J7a–8 5.5, J6–7a 5.3), 3.26–1.98 (11H, m, C5–CH2–, C10–Ha, C10–Hb, C15–
Ha, C15–Hb, C16–Ha, C16–Hb, –NCH3); dC (50.3 MHz, CDCl3): 163.66
0
(C5), 159.14 (C2 ), 147.11 (C3), 143.73 (C4), 136.23 (C14), 133.40–109.69
(9C, aromatic, C6, C8), 61.73 (C9), 56.23 (C6–OCH3), 51.48 (C16), 41.45
(C13), 40.66 (NCH3), 35.19 (C7), 34.08 (C5–CH2–), 32.99 (C15), 31.49
(C10).
4.2.1.16. 7b-Benzyl-4,5a-epoxy-3-methoxy-17-methyl-5,6,8,14-tetra-
dehydro-morphinan (20a). Compound 19a and compound 20a
were separated by means of column chromatography. Compound
20a was the second eluted component. Yellow, cubic crystals were
obtained by crystallization from toluene/methanol¼1:1; mp: 124–
126 ꢁC; yield: 665 mg (56%) and 100 mg of unreacted diene 3 also
4.2.1.19. 4,5
a-Epoxy-3-methoxy-17-methyl-5,6,8,14-tetradehydro-
7b
-(2-trifluoro-methylbenzyl)-morphinan (20d). Compound 19d
and compound 20d were separated by means of column chroma-
tography. Compound 20d was the second eluted component.

A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
5859
Off-white, cubic crystals were obtained by crystallization from
toluene/methanol¼1:1; mp: 130–132 ꢁC; yield: 881 mg (60%) and
60 mg of unreacted diene 3 also was recovered; CHN anal. calcd for
(1H, td, C6a–H, J6a–7a 10.5, J6a–7b 2.8), 3.87 (3H, s, C10–OCH3), 3.81 (2H,
s, C3–CH2–), 3.22–2.41 (9H, m, C4–Ha, C4–Hb, C5–Ha, C5–Hb, C7–Ha, C7–
Hb, –NCH3); dC (50.3 MHz, CDCl3): 146.49 (C9), 144.12 (C10), 141.63
0
C
26H24F32N5O2: C, 71.06; H, 5.50; N, 3.19. Found: C, 71.09; H, 5.53; N,
(C1 ), 138.54–113.17 (15C, aromatic), 61.24 (C6a), 56.47 (C10–OCH3),
3.18; [
a
]
ꢀ48 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
54.74 (C5), 41.18 (NCH3), 40.24 (C3–CH2–), 35.51 (C7), 32.10 (C4).
D
concentrated ammonium hydroxide): 0.44; nmax (KBr disc): 2920,
2870, 2840, 1630, 1460, 1420, 1350, 1130; MS (EI): m/z (%) 440
(Mþþ1, 100), 382 (78), 366 (62), 340 (50); HRMS (EI) m/z (%) cal-
culated for C26H25F3NOþ2 : 440.1832 (MþþH), found: 440.1837
(MþþH, 100); dH (360 MHz, CDCl3): 7.35–7.28 (2H, m, Bn aromatic),
7.17–7.09 (2H, m, Bn aromatic), 6.57, 6.54 (2H, 2d, C1–H, C2–H, J1–2
8.0), 5.30 (1H, d, C8–H, J7a–8 5.0), 4.91 (1H, d, C6–H, J6–7a 5.1), 3.87–
3.72 (4H, m, C9–H, C3–OCH3), 3.35 (1H, dd, C7–H, J7a–8 5.0, J6–7a 5.1),
4.2.2.2. (ꢀ)-R-3-(2-Chlorobenzyl)-11-hydroxy-10-methoxy-apor-
phine (22b). Pale yellow, needle-shaped crystals; mp: 233–235 ꢁC
(ether); yield: 730 mg (73%); CHN anal. calcd for C25H24ClNO2: C,
25
73.97; H, 5.96; N, 3.45. Found: C, 74.07; H, 6.01; N, 3.44; [
a
]
ꢀ147
D
(c 0.1, chloroform); Rf (chloroform/methanol¼8:2): 0.51; nmax (KBr
disc): 3560, 3080, 2950, 1630, 1590, 1480, 1300, 1120, 730; MS (EI):
m/z (%) 406 (Mþþ1, 100), 391 (62), 361 (71), 332 (21); HRMS (EI)
m/z (%) calculated for C25H25ClNOþ2 : 406.1568 (MþþH), found:
406.1560 (MþþH, 100); dH (360 MHz, CDCl3): 7.12–7.03 (5H, m, Bn
aromatic, C1–H), 6.89 (1H, d, C2–H, J1–2 8.1), 6.55, 6.52 (2H, 2d, C8–H,
C9–H, J8–9 8.0), 6.24 (1H, br s, OH), 4.21 (1H, td, C6a–H, J6a–7a 10.1,
J6a–7b 3.0), 3.81 (2H, s, C3–CH2–), 3.74 (3H, s, C10–OCH3), 3.31–2.44
(9H, m, C4–Ha, C4–Hb, C5–Ha, C5–Hb, C7–Ha, C7–Hb, –NCH3); dC
3.23–1.94 (11H, m, C5–CH2–, C10–Ha, C10–Hb, C15–Ha, C15–Hb, C16
–
Ha, C16–Hb, –NCH3); dC (50.3 MHz, CDCl3): 160.16 (C5), 146.34 (C3),
144.70 (C4), 137.29 (C14), 134.39–110.26 (10C, aromatic, C6, C8, CF3),
61.24 (C9), 56.79 (C6–OCH3), 51.30 (C16), 42.08 (C13), 41.63 (NCH3),
36.51 (C5–CH2–), 35.03 (C7), 32.39 (C15), 30.98 (C10).
0
4.2.1.20. 4,5
a
-Epoxy-3-methoxy-17-methyl-7
b
-(4-nitrobenzyl)-
(50.3 MHz, CDCl3): 145.67 (C9), 143.20 (C10), 142.69 (C1 ), 137.89–
5,6,8,14-tetradehydro-morphinan (20e). Compound 19e and com-
pound 20e were separated by means of column chromatography.
Compound 20e was the second eluted component. Off-white, cubic
crystals were obtained by crystallization from toluene/meth-
anol¼1:1; mp: 140–142 ꢁC; yield: 858 mg (63%) and 80 mg of
unreacted diene 3 also was recovered; CHN anal. calcd for
112.59 (15C, aromatic), 61.07 (C6a), 56.23 (C10–OCH3), 55.01 (C5),
42.03 (NCH3), 35.56 (C7), 33.28 (C3–CH2–), 32.54 (C4).
4.2.2.3. (ꢀ)-R-1-Benzyl-11-hydroxy-2,10-dimethoxy-aporphine
(23a). White, plate-shaped crystals; mp: 178–182 ꢁC (ether); yield:
710 mg (71%); CHN anal. calcd for C26H272N5O3: C, 77.78; H, 6.78; N,
C
25H24N2O4: C, 72.10; H, 5.81; N, 6.73. Found: C, 72.12; H, 5.85; N,
3.49. Found: C, 77.84; H, 6.85; N, 3.44; [
a
]
ꢀ62 (c 0.1, chloroform);
D
25
6.72; [
a
]
ꢀ48 (c 0.1, chloroform); Rf (90% CH2Cl2/9% CH3OH/1%
Rf (chloroform/methanol¼8:2): 0.43; nmax (KBr disc): 3470, 3010,
2830, 1620, 1530, 1510, 1440; MS (EI): m/z (%) 402 (Mþþ1, 78), 387
(100), 343 (38); HRMS (EI) m/z (%) calculated for C25H28NOþ3 :
402.2069 (MþþH), found: 402.2071 (MþþH, 78); dH (360 MHz,
CDCl3): 7.22–7.04 (5H, m, Bn aromatic), 6.61, 6.56 (2H, 2d, C8–H, C9–
D
concentrated ammonium hydroxide): 0.51; nmax (KBr disc): 2920,
2870, 2860,1650,1540,1440,1330,1110; MS (EI): m/z (%) 417 (Mþþ1,
4), 371 (100), 356 (42), 321 (43); HRMS (EI) m/z (%) calculated for
C
25H25N2Oþ4 : 417.1809 (MþþH), found: 417.1800 (MþþH, 4); dH
(360 MHz, CDCl3): 8.14–7.94 (2H, dd, Bn aromatic, A2B2, J 6.6 and
<1), 7.78–7.61 (2H, dd, Bn aromatic, A2B2, J 6.1 and <1), 6.52, 6.48
(2H, 2d, C1–H, C2–H, J1–2 8.3), 5.42 (1H, d, C8–H, J7a–8 5.4), 4.84 (1H, d,
C6–H, J6–7a 4.9), 3.90–3.81 (4H, m, C9–H, C3–OCH3), 3.47 (1H, dd, C7–
H, J7a–8 5.4, J6–7a 4.9), 3.30–2.07 (10H, m, C5–CH2–, C10–Ha, C10–Hb,
H, J8–9 8.0), 6.33 (1H, s, C3–H), 6.02 (1H, br s, OH), 4.29 (1H, td, C6a–
H, J6a–7a 9.7, J6a–7b 2.4), 3.78 (3H, s, C10–OCH3), 3.71 (3H, s, C2–OCH3),
3.68 (2H, s, C1–CH2–), 3.41–2.35 (9H, m, C4–Ha, C4–Hb, C5–Ha, C5–
Hb, C7–Ha, C7–Hb, –NCH3); dC (50.3 MHz, CDCl3): 154.23 (C2), 147.78
(C9), 146.27 (C10), 137.12–112.66 (15C, aromatic), 6.87 (C6a), 57.12
(C2–OCH3), 56.34 (C10–OCH3), 52.71 (C5), 40.81 (NCH3), 34.56 (C7),
32.56 (C4), 30.24 (C1–CH2–).
C
15–Hb, C16–Ha, C16–Hb, –NCH3), 1.97 (1H, td, C15–Ha, J15a,15b;16a,16b
11.1, J15a,15b 4.5); dC (50.3 MHz, CDCl3): 161.84 (C5),146.37 (C3),145.11
0
0
(C4 ), 144.47 (C1 ), 143.74 (C4), 138.44 (C14), 135.10–109.82 (8C, aro-
matic, C6, C8), 61.44 (C9), 56.10 (C6–OCH3), 51.67 (C16), 43.58 (C5–
CH2–), 42.21 (C13), 41.83 (NCH3), 34.70 (C7), 32.67 (C15), 31.27 (C10).
4.2.2.4. (ꢀ)-R-1-(2-Chlorobenzyl)-11-hydroxy-2,10-dimethoxy-apor-
phine (23b). Yellow, plate-shaped crystals; mp: 168–171 ꢁC (ether);
yield: 740 mg (74%); CHN anal. calcd for C26H26ClNO3: C, 71.63; H,
25
4.2.2. General procedure for acid-catalyzed rearrangement of
dienes
6.01; N, 3.21. Found: C, 71.57; H, 6.09; N, 3.27; [
a]
D
ꢀ81 (c 0.1,
chloroform); Rf (chloroform/methanol¼8:2): 0.52; nmax (KBr disc):
3520, 3010, 2960, 1600, 1580, 1500, 1340, 1120, 740; MS (EI): m/z (%)
436 (Mþþ1, 91), 421 (100), 398 (67), 337 (32); HRMS (EI) m/z (%)
calculated for C26H27ClNO3þ: 436.1679 (MþþH), found: 436.1670
(MþþH, 91); dH (360 MHz, CDCl3): 7.16–7.02 (4H, m, Bn aromatic),
6.63, 6.60 (2H, 2d, C8–H, C9–H, J8–9 8.3), 6.44 (1H, s, C3–H), 6.12 (1H, br
s, OH), 4.29(1H, td, C6a–H, J6a–7a 9.9, J6a–7b 2.7), 3.84 (3H, s, C10–OCH3),
3.81 (2H, s, C1–CH2–), 3.77 (3H, s, C2–OCH3), 3.43–2.41 (9H, m, C4–Ha,
C4–Hb, C5–Ha, C5–Hb, C7–Ha, C7–Hb, –NCH3); dC (50.3 MHz, CDCl3):
A mixture of the diene (1.00 g) and 98% methanesulfonic acid
(5 mL) was stirred for 20 min at 0 ꢁC and then for 30 min at 90–
95 ꢁC (the progress of the reaction was followed by TLC). After
completion the reaction mixture was added dropwise, with stirring
and external ice cooling, to a solution of potassium hydrogen car-
bonate (10 g) in water (50 mL). After extraction with chloroform
(3ꢂ15 mL), the combined organic extracts were washed with sat-
urated brine, dried (MgSO4) and concentrated under vacuum to
yield crude apocodeine. Recrystallization from anhydrous ether
gave pure apocodeine.
0
161.12 (C2),149.56 (C9),146.32 (C10),141.43 (C1 ),139.56–114.51 (14C,
aromatic), 61.44 (C6a), 56.23–56.01 (C10–OCH3, C10–OCH3), 53.78
(C5), 42.11 (NCH3), 35.10 (C7), 32.52 (C4), 29.16 (C1–CH2–).
4.2.2.1. (ꢀ)-R-3-Benzyl-11-hydroxy-10-methoxy-aporphine (22a). Off-
white, needle-shaped crystals; mp: 212–214 ꢁC (ether); yield:
4.2.2.5. (ꢀ)-R-3-Benzyl-11-hydroxy-2,10-dimethoxy-aporphine
(24a). Off-white, plate-shaped crystals; mp: 167–169 ꢁC (ether);
yield: 800 mg (80%); CHN anal. calcd for C26H27NO3: C, 77.78; H,
790 mg (79%); CHN anal. calcd for C25H25NO2: C, 80.83; H, 6.78; N,
25
3.77. Found:C,80.73;H, 6.83;N, 3.71;[
a
]
ꢀ124 (c 0.1, chloroform); Rf
D
25
(chloroform/methanol¼8:2): 0.61; nmax (KBr disc): 3550, 3050, 2940,
2840, 1630,1590,1480, 1300,1120; MS (EI): m/z (%) 372 (Mþþ1, 100),
342 (46), 308 (30); HRMS (EI) m/z (%) calculated for C25H26NOþ2 :
372.1958 (MþþH), found: 372.1966 (MþþH, 100); dH (360 MHz,
CDCl3): 7.18–7.04 (6H, m, Bn aromatic, C1–H), 6.84 (1H, d, C2–H, J1–2
8.4), 6.59, 6.55 (2H, 2d, C8–H, C9–H, J8–9 7.9), 6.12 (1H, br s, OH), 4.17
6.78; N, 3.49. Found: C, 77.73; H, 6.82; N, 3.50; [
a]
ꢀ101 (c 0.1,
D
chloroform); Rf (chloroform/methanol¼8:2): 0.61; nmax (KBr disc):
3580, 3100, 2870, 2810, 1640, 1500, 1350; MS (EI): m/z (%) 402
(Mþþ1, 100), 387 (78), 351 (89); HRMS (EI) m/z (%) calculated for
C
25H26NOþ2 : 402.2069 (MþþH), found: 402.2066 (MþþH, 100); dH
(360 MHz, CDCl3): 7.14–7.04 (5H, m, Bn aromatic), 6.53, 6.50 (2H,

5860
A. Sipos, S. Bere´nyi / Tetrahedron 64 (2008) 5851–5860
2d, C8–H, C9–H, J8–9 8.0), 6.47 (1H, s, C1–H), 6.20 (1H, br s, OH), 4.26
(1H, td, C6a–H, J6a–7a 10.0, J6a–7b 2.6), 3.87 (3H, s, C10–OCH3), 3.84
(3H, s, C2–OCH3), 3.75 (2H, s, C3–CH2–), 3.37–2.34 (9H, m, C4–Ha,
C4–Hb, C5–Ha, C5–Hb, C7–Ha, C7–Hb, –NCH3); dC (50.3 MHz, CDCl3):
References and notes
1. Review on the chemistry of morphinandienes: Bere´nyi, S.; Csutora´s, Cs.; Sipos,
A. Curr. Med. Chem. 2008, 15. doi:10.2174/156801405774330421
2. (a) Review on the chemistry and pharmacology of aporphines: Zhang, A.;
Zhang, Y.; Branfman, A. R.; Baldesarini, R. J.; Neumeyer, J. L. J. Med. Chem. 2007,
50, 171; Zhang, A.; Neumeyer, J. L.; Baldessarini, R. J. Chem. Rev. 2007, 107, 274;
(b) Ramsby, S.; Neumeyer, J. L.; Grigoriadis, D.; Seeman, P. J. Med. Chem. 1989,
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Cs.; Kula, N. S.; Zhang, K.; Baldessarini, R. J.; Neumeyer, J. L. Bioorg. Med. Chem.
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0
156.56 (C2), 146.59 (C9), 145.36 (C10), 142.48 (C1 ), 139.66–115.25
(14C, aromatic), 61.30 (C6a), 56.40–56.09 (C2–OCH3, C10–OCH3),
55.03 (C5), 42.45 (NCH3), 35.57 (C7), 33.24 (C3–CH2–), 33.44 (C4).
4.2.2.6. (ꢀ)-R-3-(2-Chlorobenzyl)-11-hydroxy-2,10-dimethoxy-apor-
phine (24b). Pale yellow, plate-shaped crystals; mp: 173–175 ꢁC
(ether); yield: 730 mg (73%); CHN anal. calcd for C26H26ClNO3: C,
25
71.63; H, 6.01; N, 3.21. Found: C, 71.67; H, 6.04; N, 3.30; [
a
]
ꢀ111
D
(c 0.1, chloroform); Rf (chloroform/methanol¼8:2): 0.65; nmax (KBr
disc): 3520, 2940,1660,1600,1440,1330,1140, 730; MS (EI): m/z (%)
436 (Mþþ1, 100), 421 (89), 400 (14), 376 (71), 356 (27); HRMS (EI)
m/z (%) calculated for C26H27ClNOþ3 : 436.1679 (MþþH), found:
436.1677 (MþþH, 100); dH (360 MHz, CDCl3): 7.18–7.07 (4H, m, Bn
aromatic), 6.60, 6.57 (2H, 2d, C8–H, C9–H, J8–9 8.1), 6.39 (1H, s, C1–
H), 6.13 (1H, br s, OH), 4.24 (1H, td, C6a–H, J6a–7a 9.7, J6a–7b 2.5), 3.87
(3H, s, C10–OCH3), 3.81 (2H, s, C3–CH2–), 3.76 (2H, s, C3–CH2–),
3.36–2.40 (9H, m, C4–Ha, C4–Hb, C5–Ha, C5–Hb, C7–Ha, C7–Hb,
–NCH3); dC (50.3 MHz, CDCl3): 154.12 (C2), 146.60 (C9), 144.67 (C10),
3. Woudenberg, R. H.; Piet, D. P.; Sinnema, L.; Lie, T. S.; Maat, L. Recl. Trav. Chim.
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Hung. 1982, 110, 363; (c) Bere´nyi, S.; Makleit, S.; Hosztafi, S.; Molna´r, I. Acta
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1985, 120, 201; (e) Berenyi, S.; Sipos, A.; Szabo, I.; Kalai, T. Synth. Commun. 2007,
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Commun. 2007, 37, 2549; (g) Sipos, A.; Kiss, B.; Schmidt, E.; Greiner, I.; Berenyi,
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0
142.34 (C1 ), 139.29–115.78 (14C, aromatic), 62.00 (C6a), 56.23–
6. Biyashev, D.; Monory, K.; Benyhe, S.; Schutz, J.; Koch, M.; Schmidhammer, H.;
Borsodi, A. Helv. Chim. Acta 2001, 83, 2015; Schu¨tz, J.; Dersch, C. M.; Horel, R.;
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56.20 (C2–OCH3, C10–OCH3), 55.56 (C5), 42.36 (NCH3), 34.89 (C7),
33.34 (C3–CH2–), 32.26 (C4).
4.3. Computational procedure
We have carried out the geometry optimization at Becke’s three-
parameter hybrid (B3LYP)13 levels in the DFT with the basis set 6-
7. Chen, W.; Parrish, D. A.; Deschamps, J. R.; Coop, A. Helv. Chim. Acta 2005, 88,
822.
31G
using Gaussian 98.9 The solvent effect was not considered. We
*
8. Lee, J.-G.; Jeong, H. Y.; Lee, H. Bull. Korean Chem. Soc. 2002, 24, 369.
9. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.;
Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Mo-
rokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J.-L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.3; Gaussian: Pittsburgh,
assumed that the morphinans 1 or 3 and the benzyl chlorides were
far apart in the initial state. After optimizing the TS structure, vi-
brational calculation was performed to confirm that the TS had only
one imaginary vibrational frequency. Intrinsic reaction coordinate
calculation was also carried out to ensure that the TS connected the
initial and the intended final states. The reported net atomic
charges were obtained for the geometry optimized structures using
the NBO (natural bond orbital) analysis implemented in Gaussian
98 package. Mulliken population analyses for optimized TS struc-
tures were calculated by Fragment Reassociation method.8
PA, 1998; The model for thebaine (1) obtained at the B3LYP/6-31G level was
*
very much in accord with X-ray data (ref.: Mahler, C. H.; Stevens, E. D.; Tundell,
M.-L.; Nolan, S. P. Acta Crystallogr. C 1996, 52, 3193 ) for compound 1.
10. Snieckus, V. Chem. Rev. 1990, 90, 879.
11. Garcı´a, F.; McPartlin, M.; Morey, J. V.; Nobuto, D.; Kondo, Y.; Naka, H.; Uchiyama,
Acknowledgements
M.; Wheatley, A. E. H. Eur. J. Org. Chem. 2008, 11, 644.
´
´
12. Berenyi, S.; Czirjak, M.; Makleit, S. J. Chem. Soc., Perkin Trans. 1 1993,
2137.
The authors are grateful to the Hungarian National Science
Foundation (Grant OTKA reg. Nos. T049436 and NI61336) for the
financial support.
13. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (b) Becke, A. D. Phys. Rev. A 1998,
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