Michael reactions of benzylimines derived from morphinan-6-ones: Synthesis of pyrrolo- and pyridinomorphinans

Article abstract of DOI:10.1002/1522-2675(200206)85:6<1790::AID-HLCA1790>3.0.CO;2-G

The benzylimines 15 derived from oxymorphones 14 and generated in situ reacted with Michael acceptors (methyl methacrylate, maleic anhydride, and α-methylene-γ-butyrolactone) to give opioid ligands 16, 17, and 19-21 having pyrrole- or pyridine-derived ring systems (see Scheme 3). The product of the reaction with maleic anhydride displayed a surprising preference for the 2-hydroxypyrrole form 19 rather than for the tautomeric 1,6-dihydro-2H-pyrrol-2-one form 24, resulting from the stability of the C(6)=C(7) bond in oxymorphone and related structures.

Full text of DOI:10.1002/1522-2675(200206)85:6<1790::AID-HLCA1790>3.0.CO;2-G

1
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Helvetica Chimica Acta ± Vol. 85 (2002)
Michael Reactions of Benzylimines Derived from Morphinan-6-ones:
Synthesis of Pyrrolo- and Pyridinomorphinans
b
a
a
a
b
by Shefali ), Sanjay K. Srivastava ), Lee D. Hall ), John W. Lewis ), Stephen M. Husbands* )
a) School of Chemistry, University of Bristol, Bristol, BS8 1TS
b) Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY
The benzylimines 15 derived from oxymorphones 14 and generated in situ reacted with Michael acceptors
(
1
methyl methacrylate, maleic anhydride, and a-methylene-g-butyrolactone) to give opioid ligands 16, 17, and
9 ± 21 having pyrrole- or pyridine-derived ring systems (see Scheme 3). The product of the reaction with maleic
anhydride displayed a surprising preference for the 2-hydroxypyrrole form 19 rather than for the tautomeric 1,6-
dihydro-2H-pyrrol-2-one form 24, resulting from the stability of the C(6)ˆC(7) bond in oxymorphone and
related structures.
Introduction. ± The indolomorphinan structure has become a major focus of
interest in opioid medicinal chemistry since the discovery of naltrindole (NTI; 1), the
first nonpeptide d-opioid-receptor-selective antagonist [1]. It was hypothesised that the
5
5
indole ring mimics the phenylalanine residue of [Met ]- and [Leu ]enkephalins, which
are endogenous d-opioid receptor ligands. N-Benzylnaltrindole (BNTI; 2) is a potent d
antagonist with selectivity for the d -subtype and long duration of action in vivo when
2
administered intracerebroventricularly (icv) [2].

Helvetica Chimica Acta ± Vol. 85 (2002)
1791
The indole moiety of naltrindole has been replaced by a number of structurally
diverse heterocycles. These studies have tended to focus on the introduction of a phenyl
ring into the morphinan structure in similar or slightly different positions compared to
NTI or benzylidenenaltrexone (BNTX; 3), a d -selective antagonist [3]. Examples
1
include 4 ± 7 [4 ± 7]. Compared to naltrindole, the new ligands typically have been of
limited selectivity, in particular for d/m.
Our aim was to develop chemistry that would give access to a range of analogues of
these ligands having pyrrole- or pyridine-derived rings to which potential opioid
receptor binding groups could be attached. We were attracted to recent literature
reports of the reactions of ketone-derived imines (as their secondary enamine
tautomers) with Michael acceptors [8 ± 10]. Pfau und Ribiere [11] had demonstrated
that cyclohexanimines 8 reacted with dimethyl maleate and maleic anhydride to give
1,5-dihydro-2H-pyrrol-2-ones 9 related to indole-3-acetic acid (Scheme 1). In reactions
with these reagents, Pfau et al. [9] showed that the N-benzylimine 10 derived from 2-
methylcyclohexanone gave pyrrolone and pyridinone derivatives 11 ± 13 (Scheme 2), in
which the more substituted enamine tautomer was involved in the addition, and the
products showed high diastereoselectivity.
Scheme 1
i) r.t. ii) 2008.
Our interest was heightened by the knowledge that the morphinan-6-ones and their
imine counterparts react readily as their enol and enamine tautomers [7][12]. This
suggested that the benzylimines derived from oxymorphone (14a) and naltrexone (14b)
could react similarly with Michael acceptors, giving access to a range of pyrrolo- and
pyridino-derived morphinans.
We here report the results of investigations of the reaction of the N-benzyl- and N-
methylimines of oxymorphones generated in situ with several activated olefins.

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Helvetica Chimica Acta ± Vol. 85 (2002)
Scheme 2
i) Maleic anhydride, 0 ± 208, 10 min. ii) Methyl methacrylate, 1008, 3d. iii) Methyl crotonate, 1208, 5d.
Results. ± Initially, the procedure of Lim et al. [8] with oxymorphone (ˆ4,5a-
epoxy-3,14-dihydroxy-17-methylmorphinan-6-one; 14a) was followed, but we were
unable to purify the benzylimine 15a, which decayed on silica-gel columns. However, it
was found that, under one-pot conditions somewhat similar to those described by
Meyer [13], but allowing the imine to form before introduction of the appropriate
Michael acceptor and using powdered 4-ä molecular sieves to suppress reaction of the
electrophile with amine [8], the desired cyclized Michael adducts were obtained in
good yield. Thus, the reaction of the benzyl- and methylimines derived from
oxymorphone (14a) and naltrexone ((ˆ17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihy-
droxymorphinan-6-one; 14b) with methyl methacrylate (ˆ methyl 2-methylprope-
noate) and maleic anhydride (ˆ(2Z)-but-2-enedioic acid anhydride) gave 16, 17, and
19 (via 18) in ca. 40% yields by means of the one-pot procedure (Scheme 3). In the
latter case, the solvent EtOH reacted with the initially formed carboxylic acid to afford
the ethyl ester. The only other material found in the reaction mixtures was unreacted
ketone and imine, showing that addition of amine to the Michael acceptor reagents was
effectively inhibited. The procedure was also used with a-methylene-g-butyrolactone
(
2
ˆ4,5-dihydro-3-methylenefuran-2(3H)-one) as Michael acceptor to give pyridinones
0 and 21, analogous in structure to 16 and 17, in 69% yield (combined). Methyl
crotonate (ˆ methyl (2E)-but-2-enoic acid) when used under identical conditions gave
only a trace amount (< 5%) of impure product, whereas reaction with ethyl acrylate
(
ˆethyl propenoate) gave 60 ± 70% of 22. Thus, it appears that the addition is hindered
by the presence of a substituent at C(b). The only other example where a b-substituent
was present was in the reaction with maleic anhydride. Here the substituent is part of
the ring system and thus held in the (Z)-configuration, whereas, in methyl crotonate,
the b-methyl group is in the (E)-configuration. In each case where diastereoisomers

Helvetica Chimica Acta ± Vol. 85 (2002)
1793
Scheme 3
1
2
i) R NH , EtOH, 4-ä molecular sieves, TsOH. ii) Methyl methacrylate, EtOH, 4-ä molecular sieves, TsOH. iii)
Maleic anhydride, EtOH, 4-ä molecular sieves, TsOH. iv) a-Methylene-g-butyrolactone, EtOH, 4-ä molecular
sieves, TsOH. v): Ethyl acrylate, EtOH, 4-ä molecular sieves.

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Helvetica Chimica Acta ± Vol. 85 (2002)
could be formed, they did so in approximately equivalent amounts. These could be
separated by repeated, careful silica-gel column chromatography, except in the cases of
16b, 16c, and 17c.
The structures of pyridinones 16, 17, 20, and 21 were assigned from NMR and X-ray
1
data. In no H-NMR spectrum was there evidence for a vinyl proton, but, in each case,
the C(5) proton was present and appeared as a singlet, indicating that no proton was
present at C(6), thus ruling out products of type 23. The configuration of the side chain
in the pyridinone ring of 16, 17, 20, and 21 was assigned from the X-ray crystal-structure
analysis of 21a, which showed that the hydroxyethyl group occupies the 5'b-position; a
similar configuration for the 5'-methyl group of 17a is assumed based on comparison of
NMR spectra.
The structure of the dihydropyrrolone product of the maleic anhydride reaction was
expected to be 24 on the basis of the normally preferred structure of dihydropyrrolones
including that of the product 9 of the equivalent reaction with cyclohexanimines (see
Scheme 1). Both the 1,6-dihydro-2H-pyrrol-2-one structure 24 (with C(7)ˆC(4') and
the 1,3-dihydro-2H-pyrrol-2-one structure 18 (with C(6)ˆC(7)) have a tertiary C-atom
at C(4') (24) or C(6) (18) that were not detected by DEPT NMR. Confirmation of this
1
1
assignment was obtained from H, H-COSY analysis of the side-chain CH protons,
2
establishing that these were not coupled to any others within the molecule.
Discussion. ± The imines derived from 4,5-epoxymorphinan-6-ones and generated
in situ reacted smoothly with the Michael acceptors to give adducts that, as expected,
cyclized under the reaction conditions. The structures of the products 16 and 17 from
the reaction with methyl methacrylate differed from that reported from the reaction of
N-benzyl-2-methylcyclohexanimine with methyl methacrylate (see 12 in Scheme 2)
with respect to the position of the olefinic bond. In the latter case, the CˆC bond is
trisubstituted and exocyclic with respect to the pyridinone ring, whereas in 16, 17 it is
tetrasubstituted and endocyclic. The reasons for this difference are the steric strain that
would be created by the presence of a C(5)ˆC(6) bond and the inherent stability of the
C(6)ˆC(7) bond in derivatives of oxymorphones.
In the reactions with methyl methacrylate and a-methylene-g-butyrolactone, both
a- and b-epimers were formed. The lack of diastereoselectivity of the cyclizations was
in contrast to the work of Pfau et al. [9], who constructed a model for Michael reactions
of the N-benzyl-2-methylcyclohexanimine with maleic anhydride, methyl methacrylate,
and methyl crotonate. The model involved a chair-like geometry for the reactant
complex with concomitant CÀC bond-formation and intramolecular H-transfer. The

Helvetica Chimica Acta ± Vol. 85 (2002)
1795
lack of diastereoselectivity observed in the current work is likely to be related to the use
of a protic solvent in the reaction. Thus, intramolecular proton transfer will be
competing with proton transfer from the solvent, whereas Pfau et al. [9] were able to
conduct their Michael-type addition in the absence of solvent. It is also possible that the
extended reaction time may allow epimerization of the final product and/or uncyclized
intermediate. This was investigated in part by refluxing 21a in EtOH in the presence of
TsOH (4-methylbenzenesulfonic acid) and molecular sieves. No epimerization was
observed.
Reaction with maleic anhydride was predicted [7] to give 18 (Scheme 3). However,
it was shown that, in the present case, the tautomeric 5'-hydroxypyrrole structure 19 is
favored so that the chiral center at C(4') is lost. As mentioned earlier, the unusual
preference for the hydroxypyrrole structure most likely is due to the stability of the
C(6)ˆC(7) bond in naltrexone-derived structures [12]. This was manifested in the acid-
catalysed dehydration of the initial product 26 in the annulation of naltrexone
(
Scheme 4) [12]. The dehydration product at room temperature was the a,b-
unsaturated ketone 27 (with C(6)ˆC(6')), but this was converted to the C(6)ˆC(7)
isomer 28 under reflux conditions. Thus, the C(6)ˆC(7) structure 18 would be preferred
to the expected C(7)ˆC(4') isomer 24 with aromatization to 19 giving added stability.
Scheme 4
In conclusion, imines derived from morphinan-6-ones were again shown to react
readily as their enamine tautomers, confirming the stability of the C(6)ˆC(7) bond in
the morphinan series. The isolation of the 5'-hydroxypyrrole derivative 19 provides
further evidence for this stability. The one-pot-reaction conditions allowed rapid access
to morphinans having pyrrole- and pyridine-derived ring systems. The functionalized
side chains will allow ready elaboration and the generation of further series of opioid-
receptor ligands.

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Helvetica Chimica Acta ± Vol. 85 (2002)
This work was supported by NIDA (OTDP, Division of Treatment Research and Development), Grant
DA07315.
Experimental Part
General. Reagents and solvents were purchased from Aldrich or Lancaster and used as received. Org. solns.
were dried (Na SO ) and evaporated with a B¸chi rotary evaporator at low pressure. Yields are of purified
2
4
product and were not optimized. Compounds were converted to their hydrochloride salts by dissolving in
MeOH and adding HCl/MeOH. M.p.: Reichert hot-stage apparatus; uncorrected. The compounds were
routinely checked for their purity by TLC: aluminium sheets coated with silica gel 60 F254 (Merck) 5% MeOH/
CH
2
Cl
2
with 1% NH
4
OH; visualization by UV light and I
Cl
2
vapour. Column chromatography (CC): flash silica
1
13
gel 60 (Fluka, mesh 220 ± 240) and 2.5% MeOH/CH
JNM-GX-FT-300 spectrometer; at 300 ( H) and 75 ( C) MHz and r.t.; chemical shifts d in ppm rel. to SiMe
2
13
2
with 1% NH
4
OH. H- and C-NMR Spectra: Jeol
1
4
(
(
ˆ0 ppm) as internal standard, J in Hz. EI-MS: Fission-Auto spectrometer with electron-impact ionization
70 eV); in m/z (% rel. int.). Elemental analyses: Carlo-Erba EA-1108 analyser; results within Æ0.4% of the
theoretical values.
1
'-Benzyl-6,7-didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-5'a,17-dimethylpyrido[2',3':6,7]morphin-
an-6'(1'H)-one (16b) and 1'-Benzyl-6,7-didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-5'b,17-dimethylpyr-
ido[2',3':6,7]morphinan-6'(1'H)-one (17b). Asoln. of oxymorphone ( 14a, 0.25 g, 0.84 mmol), benzylamine
(0.1 ml, 0.88 mmol) and TsOH ¥ H
2
O (1 mg) in EtOH (3 ml) was refluxed in the presence of 4-ä molecular
sieves under N for 3 h. Methyl methacrylate (0.1 ml, 0.88 mmol) was added and reflux continued overnight. The
2
mixture was then cooled, filtered, and evaporated, and the resultant solid washed with hexane to leave crude 16b
and 17b, which were purified by CC: 0.15 g (41%) of 16b and ca. 0.07 g of 17b (isolated as a mixture with 16b).
1
Data of 16b: R
f
0.68. M.p. 227 ± 2298. H-NMR (CD
2
Cl
); 4.85 (s, HÀC(5)); 4.55 (d, J ˆ 16.7, 1 H, PhCH
d, J ˆ 18.7, 1 HÀC(10)); 2.72 (d, J ˆ 6.3, HÀC(9)); 2.57 (m, 1 H); 2.08 (m, 11 H); 1.43 (m, 1 H); 1.05 (d, J ˆ
2
): 7.18 (m, PhCH
2
); 6.54 (d, J ˆ 8.0, HÀC(2)); 6.48
(
(
6
1
1
d, J ˆ 8.0, HÀC(1)); 5.47 (d, J ˆ 16.7, 1 H, PhCH
2
2
); 3.05
1
3
2 2
.4, Me). C-NMR (CD Cl ): 173.53, 142.93; 139.63; 139.15; 131.62; 128.91; 128.72; 128.35; 127.13; 126.43;
25.49; 119.34; 119.24; 117.27; 86.13; 70.36; 64.18; 46.24; 45.43; 44.53; 43.06; 36.82; 34.98; 34.27; 31.60; 22.39;
5.25. EI-MS: 458 (100, M , 91 (80). Anal. calc. for C28
‡
H
30
N
2
O
4
¥ HCl ¥ 1.75 H
2
O (526.5): C 63.87, H 6.60, N 5.32;
found: C 64.10, H 7.00, N 5.10.
1
Data of 17b (mixture with 16b): R
f
0.68. H-NMR (CDCl ): 7.17 (m, 10 H, PhCH
3
2
); 6.77 ± 6.66 (m, 2 H,
2
HÀC(2)); 6.63 ± 6.51 (m, 2 H, 2 HÀC(1)); 5.53 ± 5.49 (m, 2 H, PhCH
2
); 5.03 (s, 2 H, 2 HÀC(5)); 4.76 ± 4.72
‡
(
m, 2 H, PhCH
2
); 1.12 (d, J ˆ 6.8, 3 H, Me); 0.96 (d, J ˆ 7.2, 3 H, Me). FAB-MS: 459 (82, [M ‡ 1] ).
1
'-Benzyl-17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-5'a-methylpyri-
do[2',3':6,7-]morphinan-6'(1'H)-one (16a) and 1'-Benzyl-17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-
4
1
',5'-dihydro-3,14-dihydroxy-5'b-methylpyrido[2',3':6,7]morphinan-6'(1'H)-one (17a). As described for 16b/
7b, from naltrexone (14b; 0.50 g, 1.47 mmol), benzylamine (0.18 ml, 1.47 mmol) and methyl methacrylate
(
0.15 ml, 1.47 mmol): 0.06 g (20%) of 16a and 0.05 g (17%) of 17a.
1
Data of 16a: R
f
0.78. M.p. 207 ± 2098. H-NMR (CD
2
Cl
2
): 7.30 (m, PhCH
2
); 6.59 (d, J ˆ 8.1, HÀC(2)); 6.51
); 3.11
(
(
(
d, J ˆ 8.1, HÀC(1)); 5.44 (d, J ˆ 16.6, 1 H, PhCH
2
); 4.99 (s, HÀC(5)); 4.76 (d, J ˆ 16.6, 1 H, PhCH
2
d, J ˆ 6.4, HÀC(9)); 3.05 (d, J ˆ 18.5, 1 HÀC(10)); 2.62 (m, 2 H); 2.11 (m, 8 H); 1.50 (m, 2 H); 0.98
m, HÀC(19)); 0.81 (d, J ˆ 6.0, Me); 0.49 (m, 2 H, HÀC(20), HÀC(21)); 0.11 (m, 2 H, HÀC(20),
1
3
HÀC(21)). C-NMR (CD
2 2
Cl ): 174.26; 142.89; 139.66; 139.38; 131.83; 128.92; 127.16; 125.45; 119.46; 118.25;
1
9
17.24; 86.56; 70.55; 62.55; 61.83; 59.75; 47.05; 44.64; 43.92; 43.81; 37.95; 35.36; 33.73; 31.93; 31.10; 22.95; 15.32;
‡
.72; 4.02; 3.94. EI-MS: 498 (100, M ), 91 (80). Anal. calc. for C31
34 2 4 2
H N O ¥ HCl ¥ 2 H O (571.11): C 65.20,
H 6.88, N 4.91; found: C 65.12, H 6.77, N 4.61.
1
Data of 17a: R
f
0.84. M.p. 215 ± 2208. H-NMR (CDCl
3
): 7.40 ± 7.2 (m, PhCH
); 5.0 (s, HÀC(5)); 4.77 (d, J ˆ 16.4, 1 H, PhCH
d, J ˆ 5.6, HÀC(9)); 3.04 (d, J ˆ 18.4, 1 HÀC(10)); 2.8 (m, 1 HÀC(10)); 2.41 ± 1.4 (m, 13 H); 1.20 (d, 3 H, J ˆ
.8, Me); 0.83 ± 0.80 (m, HÀC(19)); 0.54 ± 0.51 (m, 2 H, HÀC(20), HÀC(21)); 0.12 ± 0.005 (m, 2 H, HÀC(20),
2
); 6.65 (d, J ˆ 8.0, HÀC(2));
6
(
6
.51 (d, J ˆ 7.6, HÀC(1)); 5.51 (d, J ˆ 16.4, 1 H, PhCH
2
2
); 3.14
1
3
HÀC(21)). C-NMR (CDCl
3
): 173.52; 142.63; 139.25; 138.78; 131.35; 128.80; 128.67; 127.01; 126.23; 119.21;
18.76; 117.08; 86.44; 70.34; 61.57; 59.72; 46.93; 44.86; 43.88; 37.13; 35.20; 34.40; 31.71; 23.29; 15.61; 9.78; 4.50;
1
4
‡
.17. FAB-MS: 499 (100, [M ‡ 1] ), 91 (60). Anal. calc. for C31
34 2 4 2
H N O ¥ HCl ¥ 2 H O (571.11): C 65.20, H 6.88,
N 4.91; found: C 64.8, H 6.94, N 4.75.
,7-Didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-1',5'a,17-trimethylpyrido[2',3':6,7]morphinan-
'(1'H)-one (16c) and 6,7-Didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-1',5'b,17-trimethylpyri-
6
6

Helvetica Chimica Acta ± Vol. 85 (2002)
1797
in
do[2',3':6,7]morphinan-6'(1'H)-one (17c). As described for 16b/17b, from 14a (0.5 g, 1.66 mmol), 2m MeNH
2
MeOH (1.66 mmol, 1.0 ml), and methyl methacrylate (0.18 ml, 1.66 mmol): 0.2 g (32%) of 16c/17c, which could
1
not be separated by CC. R
2
(
f
0.4. H-NMR (CDCl
3
): 6.65 ± 6.61 (m, 2 H, 2 HÀC(2)); 6.52 ± 6.48 (m, 2 H,
HÀC(1)); 5.14 (s, 2 H, 2 HÀC(5)); 3.21 (s, 6 H, 2 MeNC); 2.33 (s, 6 H, 2 MeN); 1.05 (d, J ˆ 3.2, 3 H, Me); 0.66
‡
d, J ˆ 3.6, 3 H, Me). EI-MS: 382 (100, M ).
1
'-Benzyl-6,7-didehydro-4,5a-epoxy-3,5',14-trihydroxy-17-methyl-1'H-pyrrolo[2',3':6,7]morphinan-4'-acetic
Acid Ethyl Ester (19a). As described for 16b/17b, from 14a (0.6 g, 1.99 mmol), benzylamine (0.24 ml, 2 mmol),
1
and maleic anhydride (0.19 g, 2 mmol): 0.22 g (21%) of 19a. R
m, PhCH
PhCH
); 4.55 (d, J ˆ 15.9, 1 H, PhCH
f
0.56. M.p. 179 ± 1818. H-NMR (CD
2
Cl
2
): 7.17
(
2
); 6.54 (d, J ˆ 8.0, HÀC(2)); 6.34 (d, J ˆ 8.0, HÀC(1)); 6.06 (s, HÀC(5)); 4.76 (d, J ˆ 15.9, 1 H,
); 3.95 (q, J ˆ 7.1, MeCH O); 3.16 (m, 3 H); 3.0 (m, 2 H); 2.5 (m, 10 H);
O). C-NMR (CD Cl ): 170.56; 143.10; 142.99; 141.28; 138.32; 135.95; 128.75; 127.73;
2
2
2
1
3
1
.07 (t, J ˆ 7.1, MeCH
2
2
2
1
27.38; 122.04; 118.68; 72.98; 62.92; 61.39; 46.97; 43.34; 42.51; 42.47; 31.82; 31.51; 30.96; 29.39; 24.95; 14.24. EI-
‡
MS: 516 (50, M ), 91 (100). Anal. calc. for C30
32 2 6 2
H N O ¥ HCl ¥ 1.75 H O (584.57): C 61.63, H 6.28, N 4.78; found:
C 61.69, H 5.88, N 4.90.
1
'-Benzyl-17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3,5',14-trihydroxypyrrolo[2',3':6,7]morphinan-
4
'-acetic Acid Ethyl Ester (19b). As described for 16b/17b, from 14b (0.50 g, 1.47 mmol), benzylamine (0.16 ml,
1
1
(
1
3
2
.5 mmol), and maleic anhydride (0.15 g, 1.5 mmol): 0.34 g (40%) of 19b. R
CD Cl ): 7.24 (m, PhCH
5.8, 1 H, PhCH
); 4.59 (d, J ˆ 15.8, 1 H, PhCH
.25 (d, J ˆ 16.9, 1 H, CH CO Et); 3.08 (d, J ˆ 5.9, HÀC(9)); 3.03 (d, J ˆ 18.7, 1 H, HÀC(10)); 2.77 (m, 5 H);
.36 (m, 2 H); 2.14 (m, 2 H); 1.65 (m, 1 H); 1.15 (t, J ˆ 7.1, MeCH O); 0.80 (m, HÀC(19)); 0.51 (m, 2 H,
Cl ): 170.60; 142.99; 142.69; 141.72;
38.35; 135.98; 128.80; 127.88; 127.74; 127.45; 121.86; 119.22; 118.69; 114.12; 73.10; 61.44; 60.50; 59.49; 45.07;
f
0.65. M.p. 191 ± 1938. H-NMR
2
2
2
); 6.61 (d, J ˆ 8.2, HÀC(2)); 6.43 (d, J ˆ 8.2, HÀC(1)); 6.16 (s, HÀC(5)); 4.86 (d, J ˆ
2
2
); 4.04 (q, J ˆ 7.1, MeCH O); 3.27 (d, J ˆ 16.9, 1 H, CH CO Et);
2
2
2
2
2
2
1
3
HÀC(20), HÀC(21)); 0.10 (m, 2 H, HÀC(20), HÀC(21)). C-NMR (CD
2
2
1
4
‡
3.40; 32.49; 31.46; 29.48; 25.49; 14.28; 9.72; 4.02. EI-MS: 556 (50, M ), 91 (100). Anal. calc. for C33
O (615.64): C 64.38, H 6.47, N 4.55; found: C 64.13, H 6.52, N 4.32.
'-Benzyl-17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-5'a-(2-hydroxy-
36 2 6
H N O ¥
HCl ¥ 1.25 H
2
1
ethyl)pyrido[2',3':6,7]morphinan-6'(1'H)-one (20a) and 1'-Benzyl-17-(cyclopropylmethyl)-6,7-didehydro-4,5a-
epoxy-4',5'-dihydro-3,14-dihydroxy-5'b-(2-hydroxyethyl)pyrido[2',3':6,7]morphinan-6'(1'H)-one (21a): As de-
scribed for 16b/17b, from 14b (0.5 g, 1.46 mmol), benzylamine (0.16 ml, 1.46 mmol), and a-methylene-g-
butyrolactone (0.13 ml, 1.46 mmol): 0.13 g (26%) of 20a and 0.17 g (33%) of 21a.
1
Data of 20a: R
f
0.69. M.p. 200 ± 2028. H-NMR (CDCl
3
): 7.19 (m, PhCH
2
); 6.59 (d, J ˆ 8.0, HÀC(2)); 6.47
(
(
(
(
1
3
d, J ˆ 8.0, HÀC(1)); 5.42 (d, J ˆ 16.5, 1 H, PhCH
2
); 4.93 (s, HÀC(5)); 4.75 (d, J ˆ 16.5, 1 H, PhCH
2
); 3.52
m, 1 H); 3.07 (d, J ˆ 6.4, HÀC(9)); 2.97 (d, J ˆ 18.8, 1 H, HÀC(10)); 2.54 (m, 3 H); 2.15 (m, 8 H); 1.78
dd, J ˆ 6.0, 1 H); 1.55 (m, 1 H); 1.33 (m, 2 H); 0.75 (m, HÀC(19)); 0.45 (m, 2 H, HÀC(20), HÀC(21)); 0.03
1
3
m, 2H, HÀC(20), HÀC(21)). C-NMR (CDCl
3
): 174.23; 143.08; 139.36; 138.32; 131.44; 128.81; 128.10; 127.11;
26.19; 126.07; 125.23; 119.53; 118.95; 117.96; 86.14; 69.94; 61.34; 60.98; 59.53; 46.73; 44.56; 43.59; 38.81; 37.72;
‡
2.75; 31.95; 31.16; 23.02; 9.47; 4.11; 3.83. EI-MS: 528 (100, M ), 91 (90). Anal. calc. for C32
36 2 5
H N O ¥ HCl ¥ 0.75
H
2
O (578.62): C 66.43, H 6.71, N 4.84; found: C 66.60, H 6.66, N 4.66.
1
Data of 21a: R
f
0.75. M.p. 255 ± 2568. H-NMR (CDCl
3
): 7.33 ± 7.17 (m, PhCH
); 4.98 (s, HÀC(5)); 4.79 (d, J ˆ 16.6, 1 H, PhCH
CH
OH); 3.13 (d, J ˆ 6.3, HÀC(9)); 3.04 (d, J ˆ 18.6,
HÀC(10)); 2.64 ± 2.60 (m, 1 HÀC(10)); 2.5 ± 2.0 (m, 8 H, 1 HÀC(8), CH (15), CH (16), CH (18), 1 H,
CH OH); 1.7 (m, 1 H, CH CH
OH); 1.55 (br. d, 1 HÀC(8)); 0.80 ± 0.79 (m, HÀC(19)); 0.52 ± 0.50 (m, 2 H,
2
); 6.65 (d, J ˆ 8.0, HÀC(2));
6
3
1
.53 (d, J ˆ 8.0, HÀC(1)); 5.55 (d, J ˆ 16.8, 1 H, PhCH
2
2
); 3.8 ±
.7 (m, 1 H, CH CH OH); 3.67 ± 3.57 (m, 1 H, CH
2
2
2
2
2
2
2
CH
2
2
2
2
1
3
HÀC(20), HÀC(21)); 0.11 ± 0.10 (m, 2 H, HÀC(20), HÀC(21)). C-NMR (CDCl
3
): 173.81; 142.56; 139.39;
1
3
38.23; 128.63; 126.87; 125.94; 119.06; 117.18; 85.71; 70.19; 61.29; 59.34; 46.55; 45.50; 43.0; 40.0; 36.5; 32.80;
‡
2.47; 31.34; 30.90; 22.83; 9.32; 3.95; 3.65. EI-MS: 528 (100, M ), 91 (80). Anal. calc. for C32
.5 H O (592.05): C 64.91, H 6.80, N 4.72; found: C 65.12, H 6.46, N 4.59.
'-Benzyl-6,7-didehydro-4,5a-epoxy-3,14-dihydroxy-4',5'-dihydro-5'a-(2-hydroxyethyl)-17-methylpyri-
36 2 5
H N O ¥ HCl ¥
1
2
1
do[2',3':6,7]morphinan-6'(1'H)-one (20b) and 1'-Benzyl-6,7-didehydro-4,5a-epoxy-3,14-dihydroxy-4',5'-dihy-
dro-5'b-(2-hydroxyethyl)-17-methylpyrido[2',3':6,7]morphinan-6'(1'H)-one (21b). As described for 16b/17b,
from 14a (0.5 g, 1.66 mmol), benzylamine (0.19 ml, 1.66 mmol), and a-methylene-g-butyrolactone (0.14 ml,
1
.66 mmol): 0.07 g (12%) of 20b and 0.12 g (21%) of 21b.
1
Data of 20b: R
d, J ˆ 8.0, HÀC(1)); 5.47 (d, J ˆ 16.6, 1 H, PhCH
m, CH CH
OH); 3.14 (d, J ˆ 18.6, 1 HÀC(10)); 2.89 (d, J ˆ 6.2, HÀC(9)); 2.65 (m, 1 HÀC(10)); 2.51 ± 2.06
2 3
m, 11 H); 1.58 ± 1.5 (m, 2 H); 1.38 ± 1.25 (m, CH CH OH). C-NMR (CDCl ): 174.14; 142.96; 139.38; 138.17;
f
0.84. M.p. 200 ± 2058. H-NMR (CDCl
3
): 7.30 (m, PhCH
2
); 6.59 (d, J ˆ 8.0, HÀC(2)); 6.56
(
(
(
2
); 4.99 (s, HÀC(5)); 4.81 (d, J ˆ 16.4, 1 H, PhCH
2
); 3.6 ± 3.56
2
2
1
3
2

1
798
Helvetica Chimica Acta ± Vol. 85 (2002)
1
4
31.06; 128.71; 127.93; 127.0; 126.08; 125.97; 119.49; 118.67; 117.97; 85.85; 70.01; 63.85; 61.35; 60.81; 45.88; 45.23;
‡
4.46; 42.98; 38.64; 37.53; 32.60; 31.74; 30.95; 30.67; 22.27. EI-MS: 488 (100, M ). Anal. calc. for C29
32 2 5
H N O ¥
HCl ¥ 1.25 H
2
O (547.56): C 63.6, H 6.52, N 5.11; found: C 63.5, H 6.21, N 5.24.
1
Data of 21b: R
f
0.87. M.p. 2808. H-NMR (CDCl
3
): 7.30 (m, PhCH
); 4.96 (s, HÀC(5)); 4.77 (d, J ˆ 16.8, 1 H, PhCH
OH); 3.62 ± 3.57 (m, 1 H, CH CH
OH); 3.13 (d, J ˆ 18.4, 1 HÀC(10)); 2.81 (d, J ˆ 6.0,
HÀC(9)); 2.60 (dd, J ˆ 6.4, 18.8, 1 HÀC(10)); 2.46 ± 2.21 (m, 9 H); 2.20 ± 2.0 (m, 3 H); 1.69 ± 1.63 (m, 1 H,
2
); 6.65 (d, J ˆ 8.0, HÀC(2)); 6.55 (d, J ˆ
8
.0, HÀC(1)); 5.54 (d, J ˆ 16.8, 1 H, PhCH
2
2
); 3.76 ± 3.71
(
m, 1 H, CH CH
2
2
2
2
1
3
2 2 3
CH CH OH); 1.55 ± 1.51 (m, 1 H). C-NMR (CDCl ): 173.65; 142.37; 139.28; 138.05; 130.62; 128.53; 128.37;
1
3
26.73; 125.83; 124.34; 118.98; 118.91; 117.16; 85.56; 70.39; 63.78; 61.34; 45.96; 45.11; 44.75; 42.98; 39.19; 36.57;
‡
32 2 5 2
2.87; 32.55; 31.22; 22.23. EI-MS: 488 (100, M ), 91 (70). Anal. calc. for C29H N O ¥ HCl ¥ H O (543.06):
C 64.14, H 6.50, N 5.16; found: C 64.0, H 6.62, N 5.23.
,7-Didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-5'a-(2-hydroxyethyl)-1',17-dimethylpyrido[2',3':6,7]-
morphinan-6'(1'H)-one (20c) and 6,7-Didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-5'b-(2-hydroxyethyl)-
6
1
',17-dimethylpyrido[2',3':6,7]morphinan-6'(1'H)-one (21c). As described for 16b/17b, from 14a (0.6 g,
1
.99 mmol), 2m MeNH in MeOH (1.99 mmol, 1.26 ml), and a-methylene-g-butyrolactone (0.17 ml,
2
1
.99 mmol): 0.08 g (14%) of 20c and 0.14 g (21%) of 21c.
1
Data of 20c: R
f
0.79. M.p. 255 ± 2608. H-NMR (CDCl
3
): 7.25 (m, PhCH
CH
OH); 3.28 (s, MeN); 3.16 (d, J ˆ 18.8,
HÀC(10)); 2.85 (d, J ˆ 6.4, HÀC(9)); 2.66 ± 2.47 (m, 4 H); 2.38 (s, MeN); 2.29 ± 2.27 (m, 2 H); 2.05 (br. s,
2
); 6.68 (d, J ˆ 8.0, HÀC(2)); 6.56
(
d, J ˆ 8.0, HÀC(1)); 5.29 (d, HÀC(5)); 3.47 ± 3.42 (m, CH
2
2
1
2
1
2
1
3
H); 1.65 ± 1.45 (m, 2 H); 1.2 ± 1.0 (m, CH
2 2 3
CH OH). C-NMR (CDCl ): 174.09; 143.19; 139.79; 131.30; 128.32;
24.93; 119.77; 118.38; 117.82; 85.55; 70.26; 64.08; 60.71; 46.19; 45.56; 43.42; 38.43; 37.75; 32.79; 31.35; 29.24;
2.61. EI-MS: 412 (100). Anal. calc. for C23
H
28 2 5 2 2 2
N O ¥ HCl ¥ 0.25 H O ¥ 0.5 CH Cl (496.84): C 56.8, H 6.18, N 5.63;
found: C 57.2, H 5.84, N 5.78.
Data of 21c: R
1
f
0.83. M.p. 265 ± 2678. H-NMR (CDCl
3
): 7.25 (m, PhCH
CH OH); 3.57 ± 3.52 (m, 1 H, CH
.28 (s, MeN); 3.16 (d, J ˆ 18.8, 1 HÀC(10)); 2.84 (d, J ˆ 6.4, HÀC(9)); 2.65 ± 2.59 (dd, J ˆ 6.8, 18.8,
HÀC(10)); 2.46 (d, J ˆ 7.2, 1 H, CH N); 2.42 (s, MeN); 2.38 ± 2.27 (m, 5 H); 2.25 ± 2.19 (m, 1 H, CH CH OH);
): 173.73;
2
); 6.67 (d, J ˆ 8.0, HÀC(2)); 6.56
(
3
1
d, J ˆ 8.0, HÀC(1)); 5.19 (s, HÀC(5)); 3.74 ± 3.69 (m, 1 H, CH
2
2
2
CH OH);
2
2
2
2
1
3
1
1
3
0
.99 ± 1.83 (m, 2 H); 1.65 (d, J ˆ 9.2, 1 H, CH
2 2 2 3
N); 1.58 ± 1.53 (m, 1 H, CH CH OH). C-NMR (CDCl
42.74; 139.73; 130.85; 128.96; 124.52; 119.27; 118.54; 117.64; 85.54; 70.66; 64.08; 61.57; 46.24; 45.49; 43.32;
‡
9.13; 36.61; 33.33; 32.71; 31.69; 29.52; 22.54. FAB-MS: 413 (100, [M ‡ 1] ). Anal. calc. for C23
28 2 5
H N O ¥ HCl ¥
.5 H
2
O ¥ 0.5 CH
2 2
Cl (501.34): C 56.29, H 6.22, N 5.58; found: C 56.1, H 6.10, N 5.64.
6
,7-Didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-1',17-dimethylpyrido[2',3':6,7]morphinan-6'(1'H)-
one (22a). As described for 16b/17b, from 14a (0.3 g, 0.99 mmol), 2m MeNH
and ethyl acrylate (0.11 ml, 0.99 mmol): 0.16 g (45%) of 22a. R
2
in MeOH (0.49 ml, 0.99 mmol)
1
f
0.5. M.p. 270 ± 2758. H-NMR (CDCl
3
): 6.68
(
d, J ˆ 8.4, HÀC(2)); 6.55 (d, J ˆ 8.4, HÀC(1)); 5.18 (s, HÀC(5)); 3.28 (s, MeN); 3.15 (d, J ˆ 18.8, 1 HÀC(10));
2
.83 (d, J ˆ 6.4, HÀC(9)); 2.61 (dd, J ˆ 18.8, 6.8, 1 HÀC(10)); 2.50 ± 2.11 (m, 10 H); 2.0 ± 1.6 (m, 3 H).
1
3
C-NMR (CDCl
5.89; 45.16; 42.99; 36.44; 31.36; 30.42; 28.67; 25.58; 22.20. FAB-MS: 369.1 (100, [M ‡ 1]). Anal. calc. for
¥ HCl ¥ 1.5 H O ¥ 0.5 CH Cl (475.33): C 54.32, H 6.14, N 5.89; found: C 54.2, H 6.01, N 6.15.
'-Benzyl-6,7-didehydro-4,5a-epoxy-4',5'-dihydro-3,14-dihydroxy-17-methylpyrido[2',3':6,7]morphinan-
3
): 170.37; 142.54; 139.47; 130.64; 128.82; 124.25; 118.84; 117.68; 117.29; 85.49; 70.33; 63.77;
4
C
21
H
24
N
2
O
4
2
2
2
1
6
'(1'H)-one (22b). As described for 16b/17b, from 14a (0.5 g, 1.66 mmol), benzylamine (0.19 ml, 1.66 mmol),
1
and ethyl acrylate (0.18 ml, 1.66 mmol): 0.4 g (60%) of 22b. R
f
0.5. M.p. 185 ± 1868. H-NMR (CDCl
); 6.63 (d, J ˆ 8.0, HÀC(2)); 6.54 (d, J ˆ 8.0, HÀC(1)); 5.43 (d, J ˆ 16.8, 1 H, PhCH
3
): 7.35 ± 7.18
); 4.89
); 3.14 (d, J ˆ 18.6, 1 HÀC(10)); 2.81 (d, J ˆ 6.3, HÀC(9)); 2.63 ± 2.55
(
(
(
1
4
m, PhCH
s, HÀC(5)); 4.86 (d, J ˆ 16.8, 1 H, PhCH
m, 2 H); 2.41 ± 1.98 (m, 11 H); 1.56 ± 1.51 (br. d, 1 H). C-NMR (CDCl
2
2
2
1
3
3
): 170.61; 142.52; 139.34; 138.59;
30.88; 128.76; 127.17; 126.82; 125.92; 124.64; 119.05; 118.74; 117.15; 86.11; 70.33; 63.82; 46.20; 45.07; 44.33;
‡
2.95; 36.76; 31.13; 30.80; 26.08; 22.11. EI-MS: 444 (100, M ), 91 (76). Anal. calc. for C27
28 2 4 2
H N O ¥ HCl ¥ 3.5 H O
(
544.04): C 59.6, H 6.66, N 5.14; found: C 59.9, H 6.31, N 5.28.
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Received February 22, 2002