Synthetic transformations of isoquinoline alkaloids. Synthesis of new dihydrothebaine-hydroquinone derivatives

Article abstract of DOI:10.1007/s11172-007-0190-1

1-Bromo-and 1-iodo-6,14-endo-ethenodihydrothebaine-hydroquinones were obtained. The Heck reactions of these halides with various olefins were studied.

Full text of DOI:10.1007/s11172-007-0190-1

Russian Chemical Bulletin, International Edition, Vol. 56, No. 6, pp. 1252—1260, June, 2007
1252
Synthetic transformations of isoquinoline alkaloids.
Synthesis of new dihydrothebaineꢀhydroquinone derivatives*
V. T. Bauman, E. E. Shults,ꢀ M. M. Shakirov, and G. A. Tolstikov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: schultz@nioch.nsc.ru
1ꢀBromoꢀ and 1ꢀiodoꢀ6,14ꢀendoꢀethenodihydrothebaineꢀhydroquinones were obtained.
The Heck reactions of these halides with various olefins were studied.
Key words: 6,14ꢀendoꢀethenotetrahydromorphinanes, dihydrothebaineꢀhydroquinone, alkaꢀ
loids, bromination, iodination, olefins, the Heck reaction, indolizines.
6,14ꢀendoꢀEthenotetrahydroꢀ and dihydromorphiꢀ
nanes synthesized by modification of thebaine adducts
with various dienophiles constitute an important group of
pharmacologically valuable agents and drugs. For inꢀ
stance, some of them (buprenorphine, diprenorphine, and
etorphine) are efficient analgesics or opioid antagonists
against drug overdose; others are of interest as selective
ligands of opiate receptors for research purposes.1—3
6,14ꢀendoꢀEthenodihydrothebaineꢀhydroquinones preꢀ
pared from thebaine and various benzoquinones have been
used to obtain very promising analgesics deprived of side
effects of morphine (lowered toxicity, no effect on respiꢀ
ration).4—6 Transformations of morphine and codeine
via modifications of substituents in aromatic ring A7—10
gave two groups of pharmacologically promising agents,
namely, 4ꢀalkoxymorphinanes (cyprodime and analogs),
which are specific antagonists to µꢀreceptors,3,9 and
3ꢀdeoxyꢀ3ꢀcarbamoylmorphinanes, which show an affinꢀ
ity for µꢀopiate receptors.10 Introduction of substituents
into the C(1) and C(2) positions of ring A of morphinanes
is restricted to the syntheses of 1ꢀhydroxyꢀ, 1ꢀchloroꢀ,
and 2ꢀdimethylamino derivatives of morphine, codeine,
and 7ꢀacetylꢀendoꢀethenotetrahydrothebaine. It has been
demonstrated that even such slight structural modificaꢀ
tions substantially change the analgesic properties of comꢀ
pounds.7 In connection with this, a pressing problem is
to obtain new 6,14ꢀendoꢀethenodihydrothebaineꢀhydroꢀ
quinone derivatives containing various substituents in ring
A and study their specific pharmacological activities.
The goal of the present work was to develop methods
for the synthesis of new 6,14ꢀendoꢀethenodihydroꢀ
thebaineꢀhydroquinone derivatives containing functionalꢀ
ized olefin substituents in aromatic ring A. The most conꢀ
venient way of introducing such fragments is the Heck
reaction of appropriate halo derivatives of endoꢀethenoꢀ
dihydrothebaineꢀhydroquinone.
Results and Discussion
Treatment of dihydrothebaineꢀhydroquinone derivaꢀ
tive 1 with bromine (1 equiv.) in formic acid at 0 °C gave
1ꢀbromo derivative 2 in 25% yield (Scheme 1); the startꢀ
ing compound 1 was partially recovered. With an increase
in the amount of bromine (1.1—1.5 equiv.), dibromide 3
was obtained along with bromide 2. The optimal amount
of bromine was 1.3 equiv. (total yield 85%; 2 : 3 = 1 : 1).
At higher amounts of bromine, the yields of compounds 2
and 3 were 32 and 48% (1.4 equiv. Br2) or 17 and 33%
(1.5 equiv. Br2), respectively.
Iodine was introduced into compound 1 through ioꢀ
dine chloride11 (method A) or iodine in the presence of
ammonium cerium nitrate12 (method B). Heating of comꢀ
pound 1 with an excess of iodine chloride in formic acid
proceeded slowly to give a mixture of three compounds
(TLC data). The reaction products were 1ꢀiodoꢀ6,14ꢀ
endoꢀethenoꢀ7,8ꢀ(1ꢀacetoxyꢀ4ꢀhydroxybenzo)dihydroꢀ
thebaine (4) (yield 57%), 1ꢀiodoꢀ6,14ꢀendoꢀethenoꢀ7,8ꢀ
(1,4ꢀhydroquinono)dihydrothebaine (5) (yield 13%), and
5´ꢀchloroꢀ1ꢀiodoꢀ6,14ꢀendoꢀethenoꢀ7,8ꢀ(1,4ꢀhydroquiꢀ
nono)dihydrothebaine (6) (yield 11%). Iodide 5 was the
major product in the iodination of compound 1 or 7 with
iodine in the presence of ammonium cerium nitrate. The
yields were 62 and 52%, respectively (see Scheme 1,
method B). The reaction was accompanied by hydrolysis
of the acetoxy group.
The halogenation products were identified from 1H and
1
13C NMR, 2D COSY, and H—13C correlation spectra
* Dedicated to the memory of Academician N. N. Vorozhtsov
on the 100th anniversary of his birth.
(COSY, COLOC). In the 1H NMR spectra of comꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1206—1214, June, 2007.
1066ꢀ5285/07/5606ꢀ1252 © 2007 Springer Science+Business Media, Inc.

The Heck olefination of alkaloids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1253
Scheme 1
X = Ac (1), H (7)
R = H, X = Ac (4); R = X = H (5); R = Cl, X = H (6)
pounds 2—6, a singlet for the proton of aromatic ring A
appears at δ 6.84 (2, 3) and 7.06—7.08 (4—6). The
13C NMR spectra of compounds 2 and 3 show signals for
the C(1) (δ 112—113, s) and C(2) atoms (δ 116, d). The
1H—13C COLOC spectra contain cross peaks between
the signals of the above proton of the aromatic ring and
the C(4) atom and between the signals for the C(1) atom
(singlet in the 13C JMod spectrum) and the H(14) proton
(δ 3.03 and 2.25—2.44 in the spectrum of compound 2).
These couplings indicate introduction of the halogen atom
into the C(1) position of ring A.* The location of the
OH group at the C(11) atom and of the Br atom at the
C(10) atom in compound 3 was confirmed by NOESY
data for compounds 3 and 1. Irradiation of the signal for
the OH proton in compound 1 revealed NOE on the
H(10) and H(13) protons; irradiation of the signal of
the OH proton in compound 3 revealed NOE on the
H(13) proton. In addition, the 1H—13C COLOC specꢀ
trum of compound 3 shows a cross peak between the
signals for the H(9) and C(7) atoms.
while the signals for the C(2) (doublet in the 13C NMR
spectrum) and C(15) atoms are shifted downfield
(∆δ ~4—6) (Table 1).
It follows from the data obtained that the halogenaꢀ
tion of 6,14ꢀendoꢀethenodihydrothebaineꢀhydroquinone
derivatives occurs at the C(1) atom of the morphinane
framework. Apparently, the attack of the reagent is diꢀ
rected by the O atom of the dihydrofuran ring. A similar
substitution into the metaꢀposition relative to the methoxy
group has taken place in the chlorination and brominaꢀ
tion of the aromatic ring of some morphinanes.14—16
Halodihydrothebaines 2—6 were used in the Heck reꢀ
actions with ethyl acrylate, 2ꢀmethylꢀ5ꢀvinylpyridine, styꢀ
rene, and ethyl vinyl ether. A reaction of 1ꢀiodoꢀendoꢀ
ethenodihydrothebaine 4 with ethyl acrylate in DMF in
the presence of the catalytic system Pd(OAc)2—tris(oꢀ
tolyl)phosphine and triethylamine as a base16—18 gave
1ꢀ[2ꢀ(ethoxycarbonyl)ethenyl]ꢀ6,14ꢀendoꢀethenoꢀ7,8ꢀ
(1ꢀacetoxyꢀ4ꢀhydroxybenzo)dihydrothebaine (8) in
80% yield (Scheme 2). The yield of compound 8 from
bromide 2 was 30%. The Heck reaction of dibromide 3
with ethyl acrylate under the above conditions gave prodꢀ
ucts 9 and 10 in 13 and 6% yields, respectively. Analogous
reactions of 1ꢀiodoꢀendoꢀethenodihydrothebaineꢀhydroꢀ
quinones 5 and 6 with ethyl acrylate afforded the correꢀ
sponding 1ꢀ[2ꢀ(ethoxycarbonyl)ethenyl]dihydrothebaineꢀ
hydroquinone derivatives 11 and 12 in 96 and 95% yields,
respectively.
The formation of 1ꢀiodo derivatives 4—6 was unamꢀ
biguously proved by 13C NMR spectroscopy with conꢀ
sideration of increments of the substituent iodine
atom.13 The signal for the C(1) atom is shifted upfield
to δ 85—87 (singlet in the 13C NMR JMod spectrum),
* The atomic numbering used in this paper for the morphinane
framework is shown in Scheme 1.

1254
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Bauman et al.
Table 1. 13C NMR spectra of dihydrothebaine 1 and halodihydrothebaines 2—6 (75.47 MHz,
CDCl3)
Atom
δ
1
2
3
4
5
6
C(1)
С(2)
С(3)
С(4)
С(5)
С(6)
C(7)
С(8)
119.28
113.96
142.34
149.20
93.66
112.59
116.75
143.48
148.79
94.11
112.63*
116.72
143.50
148.65
93.71
85.75
122.97
143.68
149.89
94.10
87.12
122.88
143.49
149.14
97.27
86.14
121.76
146.36
119.47
116.82
147.42
129.24
58.23
28.56
125.99
132.88
50.48
50.10
33.70
44.79
42.01
137.32
129.18
55.68
56.70
—
86.96
122.98
143.03
149.06
96.98
86.24
123.69
143.01
127.30
116.96
146.73
121.14
58.08
28.58
128.96
132.44
50.54
50.41
33.63
44.64
41.97
137.14
129.36
55.75
56.66
—
85.52
85.53
85.39
85.53
128.31
138.70
122.06
118.79
151.55
131.71
57.69
127.96
138.89
122.34
119.10
151.77
131.72
57.87
131.67
138.09
112.71*
125.56
149.39
128.51
57.73
127.92
138.95
122.36
119.10
151.79
131.81
58.42
C(9)
С(10)
С(11)
С(12)
С(13)
C(14)
С(15)
С(16)
С(17)
С(18)
C(19)
С(20)
N(21)Me
С(22)
С(23)
СН3ОС(6)
СН3ОС(3)
CH3CO
CH3CO
22.43
24.30
24.32
28.71
125.69
131.86
50.11
50.07
33.67
44.87
41.76
136.40
129.26
55.09
125.18
133.04
50.53
50.00
33.73
44.85
41.93
136.44
129.76
55.23
124.82
132.55
50.43
50.40
33.62
44.69
41.90
136.20
129.85
55.30
128.89
132.85
50.70
50.15
33.81
44.90
41.98
136.49
129.85
55.22
56.37
170.52
20.62
56.58
170.56
20.69
56.50
170.29
20.56
56.67
170.49
20.68
—
—
* The signals may be interchanged.
Condensation of 1ꢀiododihydrothebaine derivatives 4
and 5 with 2ꢀmethylꢀ5ꢀvinylpyridine or styrene under the
above conditions gave the corresponding 1ꢀ[aryl(hetꢀ
aryl)ethenyl]dihydrothebaineꢀhydroquinones 13—15 in
63—71% yields (Scheme 3).
work well as agonists of neuronal acetylcholine receptors
(NꢀAChRs) and are very promising as regards a search for
therapeutic means against the Alzheimer and Parkinson
diseases and other problems of ageꢀassociated neuroꢀ
degeneration.20,21 To obtain indolizinomorphinane, we
entered pyridinium salt 18 (prepared from compound 14
and phenacyl bromide) into a 1,3ꢀdipolar cycloaddition
reaction with ethyl propiolate in the presence of triethylꢀ
amine. The reaction gave individual adduct 19 in 65% yield
(Scheme 5). Its structure was proven by spectroscopic
(including 2DꢀNMR) data. The 1H NMR spectrum of
compound 19 shows signals for the H(4´) and H(5´) proꢀ
tons of the indolizine fragment at δ 6.98 (dd, H(5´), J =
8.4 Hz, J = 1.6 Hz due to couplings with the H(4´) proton
and the methyl protons at the C(6´) atom) and 8.09
(H(4´), J = 8.4 Hz). A singlet for the H(8´) proton apꢀ
A reaction of 1ꢀiododihydrothebaine 5 with ethyl viꢀ
nyl ether gave 1ꢀacetylꢀ6,14ꢀendoꢀethenoꢀ7,8ꢀ(1ꢀacetoxyꢀ
4ꢀhydroxybenzo)dihydrothebaine (16) in 50% yield
(Scheme 4). We did not isolate a product of arylation at
the βꢀposition of ethyl vinyl ether (compound 17), alꢀ
though its formation (~3%) was detected by 1H NMR
spectroscopy (the presence of the H(1a) and H(1b) proꢀ
tons at the double bond). The ratio 16 : 17 was deterꢀ
mined from the integral intensity ratio of the signal for the
H(5) proton (δ 4.74 for 16 and δ 4.69 for 17). Earlier,18,19
analogous addition of aryl halides to vinyl ethers has been
observed for aryl halides containing electronꢀdonating
substituents.
1
pears at δ 7.80 (the H—13C COLOC spectrum exhibits
a cross peak between the signals for the H(8´) and
Because alkenyldihydrothebaineꢀhydroquinones 13
and 14 are accessible, we studied their transformations, in
particular, for the synthesis of indolizinomorphinane deꢀ
rivatives. It should be noted that substituted indolizines
C(7´) atoms (δ 124.96)).
The structures of crossꢀcoupling products 8—17 were
identified from spectroscopic data (Table 2). The Eꢀconꢀ
figuration of the double bond in compounds 8—15 and

The Heck olefination of alkaloids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1255
Scheme 2
R = H (11), Cl (12)
1
17—19 is evident from the H NMR spectra. The H(1a)
To sum up, we synthesized a number of bromoꢀ and
iododihydrothebaineꢀhydroquinones. By the Heck crossꢀ
coupling of these halides with ethyl acrylate, styrene, or
2ꢀmethylꢀ5ꢀvinylpyridine, we obtained for the first time
and H(1b) protons at the newly introduced double bond
are manifested as doublets with coupling constants of
16—17 Hz, which corresponds to their transꢀarrangement.
Scheme 3
R = H (13), Ac (14)

1256
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Bauman et al.
Scheme 4
Scheme 5
matography on silica gel (Acros, 0.035—0.070 mm, pore diamꢀ
eter 6 nm) with benzene—ethyl acetate and chloroform—ethaꢀ
nol as eluents.
ethenylꢀsubstituted dihydrothebaineꢀhydroquinones in
30—96% yields. A reaction of 1ꢀiododihydrothebaineꢀ
hydroquinone with ethyl vinyl ether gave the correspondꢀ
ing 1ꢀacetyldihydrothebaineꢀhydroquinone. We demonꢀ
strated that 1ꢀ[(E)ꢀpyridinylethenyl]dihydrothebaineꢀ
hydroquinone can be used in the synthesis of hybrid strucꢀ
tures containing indolizine and isoquinoline fragments of
alkaloids.
Freshly distilled solvents and highꢀpurity reagents were used.
Ethyl acrylate, phenacyl bromide, ethyl propiolate, ethyl vinyl
ether, and styrene were purchased from Aldrich; highꢀpurity
benzoquinone (TUꢀ6ꢀ09ꢀ07ꢀ1638ꢀ87) was additionally purified
by sublimation. Thebaine produced at the Chimkent chemical
and pharmaceutical plant (Kazakhstan) was employed. Pallaꢀ
dium diacetate was synthesized according to a known proceꢀ
dure;22 ICl was prepared as described earlier.23
Experimental
3,6ꢀDimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenoꢀ
benzo[i]isomorphinaneꢀ8,11ꢀdiol (7) was obtained from an adꢀ
duct of thebaine and benzoquinone (see Ref. 24). 1H NMR
(CDCl3), δ: 1.62, 1.85 (both m, 1 H each, H(19)); 2.46—2.69
(m, 3 H, H(14), H(20)); 2.58 (s, 3 H, MeN(21)); 3.36 (d, 1 H,
H(14), J = 19 Hz); 3.83 (s, 3 H, MeC(6)); 3.93 (s, 3 H, MeC(3));
3.99 (d, 1 H, H(13), J = 7 Hz); 4.66 (m, 1 H, H(5)); 5.71 (d,
1 H, H(22), J = 8 Hz); 6.39 (m, 1 H, H(23)); 6.50—6.71 (m,
4 H, H(1), H(2), H(9), H(10)); 9.00 (s, 1 H, OH); 12.10
(br.s, 1 H, OH).
8ꢀAcetoxyꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ6α,18αꢀ
endoꢀethenobenzo[i]isomorphinanꢀ11ꢀol (1). Thebaineꢀhydroꢀ
quinone 7 (3.78 g, 9 mol) was added to a mixture of acetic
anhydride (7.56 mL) and pyridine (37.8 mL). The reaction mixꢀ
ture was kept at ~20 °C for 24 h and poured onto ice. The
product was extracted with CH2Cl2. The extract was dried over
MgSO4, the solvent was removed, and the residue was recrystalꢀ
lized from ether to give compound 1 (3.167 g, 94%), m.p.
NMR spectra were recorded in CDCl3 on Bruker ACꢀ200
(200.13 (1H) and 50.32 MHz (13C)), Bruker AVꢀ300 (300.13 (1H)
and 75.47 MHz (13C)), Bruker AMꢀ400 (400.13 (1H) and
100.78 MHz (13C)), and Bruker DRXꢀ500 spectrometers
(500.13 (1H) and 125.76 MHz (13C)). For signal assignments in
the NMR spectra, various types of protonꢀproton and carbonꢀ
proton correlation spectroscopy (COSY, COLOC, CORRD)
and 1H NMR 2D NOESY spectroscopy were used. Mass spectra
were recorded on a Finnigan MATꢀ8200 highꢀresolution mass
spectrometer (EI, 70 eV, injector temperature 270—300 °C);
molecular masses and elemental compositions were deterꢀ
mined. IR spectra were recorded on a VECTORꢀ22 instrument
(KBr pellets). Electronic absorption spectra were recorded on
an HP 8453 UV Vis spectrometer in ethanol.
The course of the reactions was monitored by TLC on Silufol
UVꢀ254 plates. Reaction products were isolated by column chroꢀ

The Heck olefination of alkaloids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1257
Table 2. 13C NMR spectra of dihydrothebaineꢀhydroquinone derivatives 8 and 11—16 (75.47 MHz, CDCl3)
Atom
δ
8
11
12
13
14
15
16
С(2)
С(3)
С(4)
С(5)
С(6)
С(7)
С(8)
С(9)
111.59
143.05
151.62
94.55
85.55
—
138.88
119.14
122.34
151.74
—
111.80
142.95
150.88
97.83
87.21
121.64
146.38
116.86
119.55
147.45
—
111.91
143.02
150.78
97.53
87.04
123.79
143.04
116.82
127.49
149.80
121.02
57.49
21.58
—
132.13
49.94
50.25
33.62
44.68
42.06
137.30
129.35
56.45
55.77
117.01
139.97
—
110.31
142.91
148.97
97.51
87.22
126.34
146.32
116.73
119.39
147.38
121.86
57.71
21.49
124.21
130.33
49.86
50.06
33.70
44.91
42.09
137.45
129.00
56.59
55.71
125.51
127.08
—
110.31
143.03
149.72
94.21
85.59
—
138.85
118.99
122.27
151.76
—
110.39
143.08
151.83
94.28
85.70
—
138.93
119.07
122.35
149.51
—
118.21
141.34
147.33
98.13
87.22
124.52
146.52
116.88
119.60
152.44
—
С(10)
С(11)
С(12)
С(13)
C(14)
С(15)
С(16)
С(17)
С(18)
C(19)
С(20)
N(21)Me
С(22)
С(23)
СН3ОС(3)
СН3ОС(6)
С(1a)
С(1b)
CH3COO
CH3COO
57.72
21.64
—
57.62
21.54
—
57.85
21.66
124.06
—
58.00
21.74
—
57.46
28.42
—
—
132.54
49.81
50.01
33.68
44.82
42.10
137.48
129.16
56.47
55.71
116.60
140.16
—
—
—
49.75
50.18
33.70
44.86
42.04
136.63
129.69
56.31
55.26
116.26
140.27
170.58
20.71
49.85
50.21
33.77
44.98
42.05
136.61
129.64
56.50
55.22
124.07
125.66
170.59
20.71
49.98
50.33
33.91
45.11
42.13
136.74
129.72
56.61
55.33
123.82
124.59
170.69
20.81
49.43
49.84
33.83
44.55
42.06
137.92
129.78
56.95
55.72
—
—
—
—
—
—
—
Note. The other signals appear at δ 14.26 (CH3CH2COO), 60.38 (CH=CHCOOCH2CH3), 125.28, 126.27,
128.10, 131.60, 132.36 (C(1), C(7), C(12), C(15), C(16)), 167.23 (CH=CH—COOEt) (compound 8); 14.25
(CH3CH2COO), 60.41 (CH=CHCOOCH2CH3), 125.59, 126.19, 126.59 (C(1), C(12), C(15)), 167.15
(CH=CH—COOEt) (11); 14.24 (CH3CH2COO), 60.42 (CH=CHCOOCH2CH3), 125.74, 126.23 (C(1),
C(15)), 167.05 (CH=CH—COOEt) (12); 23.95 (CH3C(6´)), 123.19 (C(5´)), 128.25 (C(1)), 129.29 (C(3´)),
132.22 (C(4´)), 147.37 (C(2´)), 157.08 (C(6´)) (13); 23.91 (CH3C(6´)), 123.19 (C(5´)), 127.97, 128.21,
130.40, 131.83, 132.97 (C(1), C(3´), C(7), C(12), C(16)), 132.97 (C(4´)), 147.28 (C(2´)), 156.96 (C(6´)) (14);
126.31 (C(2´), C(6´)), 127.50, 128.20, 128.37, 128.60, 131.99, 132.11, 137.54 (C(1), C(7), C(12), C(15),
C(16), C(1´), C(4´)), 128.70 (C(3´), C(5´)) (15); 24.19 (CH3CO), 198.19 (CH3CO), 126.22, 128.26, 128.99,
133.22 (C(1), C(12), C(15), C(16)) (16).
245—250 °C. 1H NMR (CDCl3), δ: 1.56, 1.85 (both m, 1 H each,
H(19)); 2.24 (s, 3 H, MeCOO); 2.55 (s, 3 H, MeN); 2.58—2.67
(m, 3 H, H(14), H(20)); 3.36 (d, 1 H, H(14), J = 17 Hz); 3.63
(s, 3 H, MeC(6)); 3.79 (s, 3 H, MeC(3)); 4.01 (m, 1 H, H(13));
4.58 (d, 1 H, H(5), J = 1 Hz); 5.65 (d, 1 H, H(22), J = 7.8 Hz);
6.30 (m, 1 H, H(23)); 6.55 (d, 1 H, H(1), J = 8.8 Hz); 6.65 (m,
2 H, H(2), H(10)); 6.74 (d, 1 H, H(9), J = 8 Hz). MS,
m/z (Irel (%)): 461 [M]+ (31), 417 (54), 375 (19), 242 (98), 202
(19), 201 (57), 200 (100), 44 (92). Highꢀresolution MS, found:
m/z 461.18497 [M]+. C27H27NO6. Calculated: M = 461.18382.
8ꢀAcetoxyꢀ1ꢀbromoꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ
6α,18αꢀendoꢀethenobenzo[i]isomorphinanꢀ11ꢀol (2) and
8ꢀacetoxyꢀ1,10ꢀdibromoꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ
6α,18αꢀendoꢀethenobenzo[i]isomorphinanꢀ11ꢀol (3). A 1 M soꢀ
lution of bromine (2.6 mL) in formic acid was added at 0 °C to a
stirred solution of compound 1 (0.776 g, 1.7 mmol) in formic
acid (11 mL). The reaction mixture was stirred at 0—5 °C for 2 h
and poured into a Petri dish for free evaporation. The residue
was treated with a saturated solution of NaHCO3 (20 mL). The
products were extracted with CH2Cl2 and the extract was washed
with brine, dried over MgSO4, and concentrated. The residue
was recrystallized from ethanol. A 1 : 1 mixture of bromides 2
and 3 was filtered off (the total yield was 0.795 g (85%)). These
compounds were separated in boiling benzene. Dibromide 3
(0.177 g, 17%) was filtered off hot. To isolate the individual
monobromide, the mother liquor was concentrated to 5 mL and
chromatographed on silica gel in benzene—ethyl acetate (10 : 3).
The yield of compound 2 was 0.360 g (39%).
Compound 2, m.p. 260—264 °C (from ether). 1H NMR
(CDCl3), δ: 1.60, 1.85 (both m, 1 H each, H(19)); 2.24 (s, 3 H,

1258
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Bauman et al.
MeCOO); 2.30—2.80 (m, 3 H, H(14), H(20)); 2.59 (s, 3 H,
MeN); 3.20 (d, 1 H, H(14), J = 19.2 Hz); 3.63 (s, 3 H, MeC(6));
3.79 (s, 3 H, MeC(3)); 4.07 (d, 1 H, H(13), J = 6 Hz); 4.60 (m,
1 H, H(5)); 5.66 (d, 1 H, H(22), J = 8.4 Hz); 6.35 (m, 1 H,
H(23)); 6.67 (d, 1 H, H(10), J = 8.8 Hz); 6.75 (d, 1 H, H(9), J =
8.8 Hz); 6.84 (s, 1 H, H(2)); 12.85 (br.s, 1 H, OH). MS,
m/z (Irel (%)): 539 [M]+ (39), 498 (17), 286 (10), 244 (16), 243
(76), 202 (58), 201 (95), 115 (10), 44 (100). Highꢀresolution
MS, found: m/z 539.09469 [M]+. C27H26BrNO6. Calculated:
M = 539.09439.
Compound 3, m.p. 275—280 °C. Found (%): C, 52.00;
H, 4.00; Br, 25.80; N, 2.26. C27H25Br2NO6. Calculated (%):
C, 51.53; H, 4.04; Br, 25.00; N, 2.26. 1H NMR (CDCl3), δ:
1.58, 1.88 (both m, 1 H each, H(19)); 2.23 (s, 3 H, MeCOO);
2.54—2.63 (m, 2 H, H(14), H(20)); 2.69 (s, 3 H, MeN); 2.70
(m, 1 H, H(20)); 3.20 (d, 1 H, H(14), J = 19.5 Hz); 3.61 (s, 3 H,
MeC(6)); 3.79 (s, 3 H, MeC(3)); 4.06 (d, 1 H, H(13), J =
6.5 Hz); 4.59 (d, 1 H, H(5), J = 1 Hz); 5.64 (d, 1 H, H(22), J =
8.5 Hz); 6.35 (m, 1 H, H(23)); 6.84 (s, 1 H, H(2)); 7.01 (s, 1 H,
H(9)); 14.02 (s, 1 H, OH).
Iodination of endoꢀethenobenzo[i]isomorphinane 1. A. A soꢀ
lution of ICl (1.11 g, 6.8 mmol) in formic acid (0.9 mL) was
added dropwise to a stirred solution of compound 1 (4.6 mmol,
2.1 g) in formic acid (6 mL). The reaction mixture was heated
with stirring for 9 h and poured into a Petri dish for free evaporaꢀ
tion. The residue was treated with a saturated solution of
NaHCO3 and the product was extracted with chloroform. The
extract was dried over MgSO4 and concentrated in vacuo. The
residue was triturated with ether. The resulting amorphous preꢀ
cipitate (2.68 g) was dissolved in a minimum amount of chloroꢀ
form and chromatographed on silica gel with CHCl3—EtOH as
an eluent (gradient from 100 : 0 to 10 : 1). Elution successively
gave 8ꢀacetoxyꢀ1ꢀiodoꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ
6α,18αꢀendoꢀethenobenzo[i]isomorphinanꢀ11ꢀol (4) (with
CHCl3 as the eluent), 1ꢀiodoꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀ
epoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isomorphinaneꢀ8,11ꢀdiol (5)
(CHCl3—EtOH, 100 : 0.5), and 10ꢀchloroꢀ1ꢀiodoꢀ3,6ꢀdiꢀ
methoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isoꢀ
morphinaneꢀ8,11ꢀdiol (6) (CHCl3—EtOH, 100 : 1 → 10 : 1). The
collected fractions were concentrated and the residues were trituꢀ
rated with ether.
H(10), J = 8.4 Hz); 6.65 (d, 1 H, H(9), J = 8.4 Hz); 7.08
(s, 1 H, H(2)); 8.93 (s, 1 H, C(8)OH); 12.01 (br.s, 1 H,
C(11)OH).
Compound 6. The yield was 0.30 g (11%), m.p. 243—245 °C.
1H NMR (CDCl3), δ: 1.61, 1.86 (both m, 1 H each, H(19));
2.43 (m, 1 H, H(14)); 2.50—2.60 (m, 1 H, H(20)); 2.61 (s, 3 H,
MeN); 2.69 (m, 1 H, H(20)); 3.11 (d, 1 H, H(14), J = 19 Hz);
3.81 (s, 3 H, MeC(6)); 3.91 (s, 3 H, MeC(3)); 4.02 (d, 1 H,
H(13), J = 6.2 Hz); 4.65 (d, 1 H, H(5), J = 0.9 Hz); 5.67 (d,
1 H, H(22), J = 8.4 Hz); 6.43 (m, 1 H, H(23)); 6.71 (s, 1 H,
H(9)); 7.08 (s, 1 H, H(2)); 8.94 (s, 1 H, C(8)OH); 13.10
(br.s, 1 H, C(11)OH). MS, m/z (Irel (%)): 579 [M]+ (77), 344
(22), 238 (19), 237 (55), 235 (100), 74 (16), 59 (25), 44 (84),
31 (53). Highꢀresolution MS, found: m/z 579.03035 [M]+.
C25H23ClINO5. Calculated: M = 579.03112.
B. Ammonium cerium(IV) nitrate (0.559 g, 1.02 mmol) and
iodine (0.26 g, 1.02 mmol) were successively added to a stirred
solution of compound 7 (0.7 g, 1.7 mmol) in acetonitrile (42 mL).
The reaction mixture was stirred at 20 °C for 5 h and then at
30—35 °C for 9 h and concentrated in a Petri dish. The residue
was treated with water and the product was extracted with chloꢀ
roform. The extract was washed with Na2S2O3, dried over
MgSO4, and concentrated in vacuo. The residue was triturated
with ether. The yield of 1ꢀiodoꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀ
epoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isomorphinaneꢀ8,11ꢀdiol (5)
was 0.46 g (52%). Compound 5 was also obtained by iodination
of compound 1 (0.63 g) under analogous conditions. The yield
was 0.5 g (62%).
The Heck reaction (general procedure). A twoꢀneck flask
fitted with a magnetic stirring bar was evacuated and filled
with argon. This manipulation was repeated three times. The
flask was successively charged under argon with bromoꢀ or
iododihydrothebaine (1 mmol), palladium diacetate (2 mol.%),
tri(oꢀtolyl)phosphine (8 mol.%), and DMF (6 mL). Triethylꢀ
amine (1.4 mmol) and ethyl acrylate (or 2ꢀmethylꢀ5ꢀvinylꢀ
pyridine, or styrene, or ethyl vinyl ether) (4 mmol) was added to
the stirred resulting suspension. The reaction mixture was stirred
at 150 °C for 9—10 h and poured into a Petri dish. The solid
residue was dissolved in a minimum amount of chloroform
and chromatographed on silica gel in CHCl3—EtOH (gradient
from 100 : 0 to 10 : 1). The successively eluted products were
tri(oꢀtolyl)phosphine, the starting halide, and the reaction prodꢀ
uct (100 : 1 → 50 : 3). The product was rechromatographed and
recrystallized.
Compound 4. The yield was 1.52 g (57%), m.p. 253—255 °C.
Found (%): C, 55.19; H, 4.42; I, 21.63; N, 2.38. C27H26INO6.
1
Calculated (%): C, 54.01; H, 4.41; I, 22.44; N, 2.03. H NMR
(CDCl3), δ: 1.57, 1.85 (both m, 1 H each, H(19)); 2.24 (s, 3 H,
MeCOO); 2.45 (m, 1 H, H(14)); 2.55 (m, 1 H, H(20)); 2.60 (s,
3 H, MeN); 2.66 (m, 1 H, H(20)); 3.12 (d, 1 H, H(14), J =
19.4 Hz); 3.64 (s, 3 H, MeC(6)); 3.80 (s, 3 H, MeC(3)); 4.06 (d,
1 H, H(13), J = 6.2 Hz); 4.60 (d, 1 H, H(5), J = 1.2 Hz); 5.67
(d, 1 H, H(22), J = 8.4 Hz); 6.36 (m, 1 H, H(23)); 6.67 (d, 1 H,
H(10), J = 8.7 Hz); 6.76 (d, 1 H, H(9), J = 8.7 Hz); 7.06 (s, 1 H,
H(2)); 12.75 (br.s, 1 H, OH).
8ꢀAcetoxyꢀ1ꢀ[(E)ꢀ2ꢀ(ethoxycarbonyl)ethenyl]ꢀ3,6ꢀdiꢀ
methoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isoꢀ
morphinanꢀ11ꢀol (8). After repeated chromatography and reꢀ
crystallization from ether, the yield of compound 8 was 80 (from
iodide 4) or 30% (from bromide 2), m.p. 255—257 °C. 1H NMR
(CDCl3), δ: 1.32 (m, 3 H, COOCH2CH3); 1.55—1.65, 1.85
(both m, 1 H each, H(19)); 2.25 (s, 3 H, MeCOO); 2.56 (m,
1 H, H(20)); 2.61 (s, 3 H, MeN); 2.67 (m, 1 H, H(14)); 2.73 (m,
1 H, H(20)); 3.45 (m, 1 H, H(14), J = 19 Hz); 3.64 (s, 3 H,
MeC(6)); 3.83 (s, 3 H, MeC(3)); 4.09 (m, 1 H, H(13)); 4.25 (q,
2 H, COOCH2CH3, J = 7 Hz); 4.65 (d, 1 H, H(5), J = 1.2 Hz);
5.69 (d, 1 H, H(22), J = 8.3 Hz); 6.24 (d, 1 H, H(1b), J =
15.6 Hz); 6.37 (m, 1 H, H(23)); 6.67 (d, 1 H, H(9), J = 8.7 Hz);
6.76 (d, 1 H, H(10), J = 8.7 Hz); 6.97 (s, 1 H, H(2)); 7.77
(d, 1 H, H(1a), J = 15.6 Hz); 12.78 (br.s, 1 H, OH). MS,
m/z (Irel (%)): 559 [M]+ (78), 517 (15), 516 (31), 327 (14), 316
(19), 244 (20), 243 (91), 202 (54), 201 (92), 44 (100). Highꢀ
Compound 5. The yield was 0.36 g (13%), m.p. 232—235 °C.
Found (%): C, 55.04; H, 4.40; I, 23.30; N, 2.56. C25H24INO5.
1
Calculated (%): C, 49.83; H, 4.50; I, 21.63; N, 2.34. H NMR
(CDCl3), δ: 1.61, 1.83 (both m, 1 H each, H(19)); 2.42 (m, 1 H,
H(14)); 2.49—2.62 (m, 1 H, H(20)); 2.58 (s, 3 H, MeN);
2.66 (m, 1 H, H(20)); 3.11 (d, 1 H, H(14), J = 19.2 Hz);
3.82 (s, 3 H, MeC(6)); 3.91 (s, 3 H, MeC(3)); 4.03 (d, 1 H,
H(13), J = 6.2 Hz); 4.66 (m, 1 H, H(5)); 5.71 (d, 1 H,
H(22), J = 8.4 Hz); 6.43 (m, 1 H, H(23)); 6.55 (d, 1 H,

The Heck olefination of alkaloids
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1259
resolution MS, found: m/z 559.21958 [M]+. C32H33NO8. Calꢀ
culated: M = 559.22060.
1H NMR (CDCl3), δ: 1.63, 1.85 (both m, 1 H each, H(19));
2.50—2.75 (m, 3 H, H(14), H(20)); 2.56 (s, 3 H, MeC(6´));
2.61 (s, 3 H, MeN(21)); 3.41 (d, 1 H, H(14), J = 18.8 Hz); 3.90
(s, 3 H, MeC(6)); 3.93 (s, 3 H, MeC(3)); 4.07 (m, 1 H, H(13));
4.70 (m, 1 H, H(5), J = 0.8 Hz); 5.75 (d, 1 H, H(22), J =
8.7 Hz); 6.44 (m, 1 H, H(23)); 6.56 (d, 1 H, H(9), J = 8.7 Hz);
6.65 (d, 1 H, H(10), J = 8.7 Hz); 6.85 (d, 1 H, H(1b), J =
16.2 Hz); 7.00 (s, 1 H, H(2)); 7.15 (m, 2 H, H(1a), H(5´)); 7.74
(m, 1 H, H(4´)); 8.56 (m, 1 H, H(2´)); 12.11 (br.s, 1 H,
C(11)OH). MS, m/z (Irel (%)): 536 [M]+ (100), 493 (21), 346
(35), 345 (41), 292 (18), 202 (28), 201 (87), 83 (13), 44 (23).
Highꢀresolution MS, found: m/z 536.23134 [M]+. C33H32N2O5.
Calculated: M = 536.23111. IR, ν/cm–1: 706, 732, 817, 841, 861,
926, 1103, 1120, 1558, 1597, 1615, 3348. UV, λmax/nm (logε):
256 (2.45), 343 (3.09).
8ꢀAcetoxyꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ1ꢀ[(E)ꢀ2ꢀ(6ꢀmethylꢀ
pyridinꢀ3ꢀyl)ethenyl]ꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenꢀ
zo[i]isomorphinanꢀ11ꢀol (14). The yield was 71%, m.p. 214 °C.
1H NMR (CDCl3), δ: 1.53—1.67, 1.76—1.94 (both m, 1 H each,
H(19)); 2.25 (s, 3 H, MeCOO); 2.51—2.80 (m, 3 H, H(14),
H(20)); 2.56 (s, 3 H, MeC(6´)); 2.63 (s, 3 H, MeN); 3.43 (m,
1 H, H(14), J = 18.8 Hz); 3.65 (s, 3 H, MeC(6)); 3.88 (s, 3 H,
MeC(3)); 4.11 (m, 1 H, H(13)); 4.63 (m, 1 H, H(5), J = 0.8 Hz);
5.71 (d, 1 H, H(22), J = 8.1 Hz); 6.36 (m, 1 H, H(23)); 6.67 (d,
1 H, H(9), J = 8.4 Hz); 6.76 (d, 1 H, H(10), J = 8.4 Hz); 6.84
(d, 1 H, H(1a), J = 16.2 Hz); 6.98 (s, 1 H, H(2)); 7.11—7.19 (m,
2 H, H(1b), H(5´)); 7.73 (m, 1 H, H(4´)); 8,57 (m, 1 H, H(2´));
12.90 (br.s, 1 H, C(11)OH). MS, m/z (Irel (%)): 578 [M]+ (100),
535 (16), 492 (10), 345 (46), 344 (52), 291 (29), 243 (86), 202
(43), 201 (89), 83 (26), 44 (75). Highꢀresolution MS, found:
m/z 578.24738 [M]+. C35H34N2O6. Calculated: M = 578.24167.
8ꢀAcetoxyꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ1ꢀ[(E)ꢀ2ꢀphenylꢀ
ethenyl]ꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isomorphinanꢀ
11ꢀol (15). The yield was 63%, m.p. 155—161 °C. 1H NMR
(CDCl3), δ: 1.53—1.66, 1.89 (both m, 1 H each, H(19)); 1.26 (s,
3 H, MeCOO); 2.58—2.78 (m, 3 H, H(14), H(20)); 2.63 (s, 3 H,
MeN); 3.43 (m, 1 H, H(14), J = 19 Hz); 3.65 (s, 3 H, MeC(6));
3.88 (s, 3 H, MeC(3)); 4.10 (m, 1 H, H(13)); 4.63 (m, 1 H,
H(5), J = 0.8 Hz); 5.72 (d, 1 H, H(22), J = 8.4 Hz); 6.37 (m,
1 H, H(23)); 6.68 (d, 1 H, H(9), J = 8.4 Hz); 6.77 (d, 1 H,
H(10), J = 8.4 Hz); 6.91 (d, 1 H, H(1b), J = 16 Hz); 7.00 (s,
1 H, H(2)); 7.14 (m, 1 H, H(5´), J = 16 Hz); 7.35 (m, 3 H,
H(3´)—H(5´)); 7.49 (m, 2 H, H(2´), H(6´)); 12.94 (br.s, 1 H,
C(11)OH). MS, m/z (Irel (%)): 563 [M]+ (49), 520 (14), 495
(20), 331 (20), 330 (23), 243 (67), 202 (36), 201 (60), 91 (11),
44 (100). Highꢀresolution MS, found: m/z 563.23222 [M]+.
8ꢀAcetoxyꢀ10ꢀbromoꢀ1ꢀ[(E)ꢀ2ꢀ(ethoxycarbonyl)ethenyl]ꢀ
3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenꢀ
zo[i]isomorphinanꢀ11ꢀol (9) and 8ꢀacetoxyꢀ1ꢀbromoꢀ10ꢀ[(E)ꢀ2ꢀ
(ethoxycarbonyl)ethenyl]ꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ
6α,18αꢀendoꢀethenobenzo[i]isomorphinanꢀ11ꢀol (10). 1H NMR
data for compounds 9 and 10 were obtained from the spectrum
of a mixture of compounds 3, 9, and 10 (6 : 1 : 0.5).
Compound 9, selected signals, δ: 1.32 (m,
3 H,
COOCH2CH3); 1.54—1.64, 1.89 (both m, 1 H each, H(19));
2.23 (s, 3 H, MeCOO); 2.53—2.66 (m, 2 H, H(14), H(20)); 2.62
(s, 3 H, MeN); 2.71 (m, 1 H, H(20)); 3.45 (m, 1 H, H(14)); 3.63
(s, 3 H, MeC(6)); 3.79 (s, 3 H, MeC(3)); 4.07 (m, 1 H, H(13));
4.25 (q, 2 H, COOCH2CH3, J = 7 Hz); 4.60 (m, 1 H, H(5));
5.65 (m, 1 H, H(22)); 6.24 (d, 1 H, H(1b), J = 16 Hz); 6.36 (m,
1 H, H(23)); 6.97 (s, 1 H, H(2)); 7.01 (s, 1 H, H(9)); 7.76 (d,
1 H, H(1a), J = 16 Hz); 14.01 (s, 1 H, OH).
Compound 10, selected signals, δ: 1.32 (m,
3 H,
COOCH2CH3); 1.54—1.64, 1.89 (both m, 1 H each, H(19));
2.23 (s, 3 H, MeCOO); 2.53—2.66 (m, 2 H, H(14), H(20)); 2.62
(s, 3 H, MeN); 2.71 (m, 1 H, H(20)); 3.45 (m, 1 H, H(14)); 3.63
(s, 3 H, MeC(6)); 3.79 (s, 3 H, MeC(3)); 4.07 (m, 1 H, H(13));
4.22 (q, 2 H, COOCH2CH3, J = 7 Hz); 4.60 (m, 1 H, H(5));
5.65 (m, 1 H, H(22)); 6.36 (m, 1 H, H(23)); 6.52 (d, 1 H, H(1a),
J = 16 Hz); 6.85 (s, 1 H, H(2)); 7.06 (s, 1 H, H(9)); 7.95 (d, 1 H,
H(1b), J = 16 Hz); 14.01 (s, 1 H, OH).
1ꢀ[(E)ꢀ2ꢀ(Ethoxycarbonyl)ethenyl]ꢀ3,6ꢀdimethoxyꢀNꢀ
methylꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isomorphinaneꢀ
1
8,11ꢀdiol (11). The yield was 95%, m.p. 254—257 °C. H NMR
(CDCl3), δ: 1.33 (m, 3 H, COOCH2CH3); 1.55—1.70, 1.84
(both m, 1 H each, H(19)); 2.46—2.76 (m, 3 H, H(14), H(20));
2.59 (s, 3 H, Me); 3.44 (d, 1 H, H(14), J = 19 Hz); 3.85 (s, 3 H,
MeC(6)); 3.92 (s, 3 H, MeC(3)); 4.06 (m, 1 H, H(13)); 4.26 (q,
2 H, COOCH2CH3, J = 6.9 Hz); 4.72 (d, 1 H, H(5), J =
0.8 Hz); 5.73 (d, 1 H, H(22), J = 8.4 Hz); 6.25 (d, 1 H, H(1b),
J = 15.8 Hz); 6.44 (m, 1 H, H(23)); 6.55 (d, 1 H, H(9), J =
8.8 Hz); 6.65 (d, 1 H, H(10), J = 8.8 Hz); 6.98 (s, 1 H, H(2));
7.77 (d, 1 H, H(1a), J = 15.8 Hz); 8.92 (s, 1 H, C(8)OH); 12.00
(br.s, 1 H, C(11)OH). MS, m/z (Irel (%)): 517 [M]+ (53), 474
(9), 316 (10), 202 (14), 201 (35), 200 (100), 44 (35). Highꢀ
resolution MS, found: m/z 517.20640 [M]+. C30H31NO7. Calꢀ
culated: M = 517.21004.
10ꢀChloroꢀ1ꢀ[(E)ꢀ2ꢀ(ethoxycarbonyl)ethenyl]ꢀ3,6ꢀdiꢀ
methoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isoꢀ
morphinaneꢀ8,11ꢀdiol (12). The yield was 96%, m.p. 188—192 °C.
1H NMR (CDCl3), δ: 1.32 (m, 3 H, COOCH2CH3); 1.54—1.69,
1.86 (both m, 1 H each, H(19)); 2.48—2.77 (m, 3 H, H(14),
H(20)); 2.62 (s, 3 H, MeN); 3.44 (d, 1 H, H(14), J = 19.2 Hz);
3.85 (s, 3 H, MeC(6)); 3.91 (s, 3 H, MeC(3)); 4.05 (m, 1 H,
H(13)); 4.25 (q, 2 H, COOCH2CH3, J = 7 Hz); 4.70 (d, 1 H,
H(5), J = 1.2 Hz); 5.70 (d, 1 H, H(22), J = 8.4 Hz); 6.24 (d,
1 H, H(1b), J = 15.7 Hz); 6.43 (m, 1 H, H(23)); 6.71 (s, 1 H,
H(9)); 6.98 (s, 1 H, H(2)); 7.76 (d, 1 H, H(1a), J = 15.7 Hz);
8.94 (s, 1 H, C(8)OH); 13.08 (br.s, 1 H, C(11)OH). MS,
m/z (Irel (%)): 551 [M]+ (75), 508 (15), 327 (45), 238 (24),
237 (54), 235 (96), 44 (100). Highꢀresolution MS, found:
m/z 551.17040 [M]+. C30H30ClNO7. Calculated: M = 551.17106.
3,6ꢀDimethoxyꢀNꢀmethylꢀ1ꢀ[(E)ꢀ2ꢀ(6ꢀmethylpyridinꢀ3ꢀ
yl)ethenyl]ꢀ4,5αꢀepoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isomorꢀ
phinaneꢀ8,11ꢀdiol (13). The yield was 67%, m.p. 200—205 °C.
C
35H33NO6. Calculated: M = 563.23077.
1ꢀAcetylꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀepoxyꢀ6α,18αꢀ
endoꢀethenobenzo[i]isomorphinaneꢀ8,11ꢀdiol (16). The yield
was 50%, m.p. 145—150 °C. 1H NMR (CDCl3), δ: 1.64, 1.82
(both m, 1 H each, H(19)); 2.44—2.70 (m, 3 H, H(14), H(20));
1.54 (s, 3 H, MeCO); 2.59 (s, 3 H, MeN); 3.80 (d, 1 H, H(14),
J = 20.5 Hz); 3.91 (s, 3 H, MeC(6)); 3.93 (s, 3 H, MeC(3)); 3.99
(m, 1 H, H(13)); 4.74 (m, 1 H, H(5), J = 1.3 Hz); 5.79 (d, 1 H,
H(22), J = 8.5 Hz); 6.44 (m, 1 H, H(23)); 6.56 (d, 1 H, H(9),
J = 8.6 Hz); 6.65 (d, 1 H, H(10), J = 8.6 Hz); 7.30 (s, 1 H,
H(2)); 8.90 (s, 1 H, C(8)OH); 12.22 (br.s, 1 H, C(11)OH).
MS, m/z (Irel (%)): 461 [M]+ (48), 260 (7), 214 (7), 203 (15),
202 (35), 201 (100), 44 (20). Highꢀresolution MS, found:
m/z 461.18277 [M]+. C27H27NO6. Calculated: M = 461.18382.
IR, ν/cm–1: 815, 843, 861, 939, 1592, 1620, 1670, 3424.

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Bauman et al.
8ꢀAcetoxyꢀ1ꢀ{2ꢀ[(E)ꢀ(7ꢀbenzoylꢀ9ꢀethoxycarbonylꢀ6ꢀ
methylindolizinꢀ3ꢀyl)]ethenyl}ꢀ3,6ꢀdimethoxyꢀNꢀmethylꢀ4,5αꢀ
epoxyꢀ6α,18αꢀendoꢀethenobenzo[i]isomorphinanꢀ11ꢀol (19).
Phenacyl bromide (0.034 g, 0.17 mmol) in ether (1 mL) was
added to a stirred solution of compound 14 (0.1 g, 0.17 mmol) in
chloroform (3 mL). The reaction mixture was stirred at 50 °C
for 8 h and concentrated in vacuo. The residue of salt 18 (0.148 g)
was dissolved in CH2Cl2 (20 mL) and ethyl propiolate (0.031 mL,
0.3 mmol) was added with stirring. Then triethylamine
(0.2 mmol) in CH2Cl2 (4 mL) was added dropwise for 10 min.
The mixture was stirred at ~20 °C for 12 h, treated with water
(20 mL), and alkalified with stirring with aqueous ammonia to
pH 12. The organic layer was separated and the product from
the aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and concentrated in vacuo.
The resulting oil was chromatographed on silica gel. Fractions
containing the product were concentrated in vacuo and the resiꢀ
due was treated with ether. The yield of compound 19 was
0.088 g (65%), m.p. 150—155 °C. Found (%): C, 72.72; H, 5.55;
N, 3.53. C48H44N2O9. Calculated (%): C, 72.30; H, 5.67;
N, 3.10. 1H NMR (CDCl3), δ: 1.27 (t, 3 H, Me, J = 6.8 Hz);
1.63, 1.94 (both m, 1 H each, H(19)); 2.30 (s, 3 H, MeCOO);
2.61 (d, 3 H, MeC(6´), J = 1.6 Hz); 2.62—2.78 (m, 2 H, H(20));
2.70 (s, 3 H, MeN(21)); 2.94 (m, 1 H, H(14)); 3.60 (d, 1 H,
H(14), J = 19 Hz); 3.71 (s, 3 H, MeC(6)); 3.95 (s, 3 H, MeC(3));
4.16 (m, 1 H, H(13)); 4.29 (q, 2 H, CH2, J = 6.8 Hz); 4.68 (d,
1 H, H(5), J = 0.8 Hz); 5.77 (d, 1 H, H(22), J = 8.6 Hz); 6.41
(m, 1 H, H(23)); 6.71 (d, 1 H, H(9), J = 8.3 Hz); 6.80 (d, 1 H,
H(10), J = 8.3 Hz); 6.98 (dd, 1 H, H(5´), J = 8.4 Hz, J =
1.6 Hz); 7.10 (d, 1 H, H(1a), J = 15.7 Hz); 7.23 (s, 1 H, H(2));
7.33—7.74 (m, 5 H, Ph); 7.80 (s, 1 H, H(8´)); 8.09 (m, 1 H,
H(4´)); 8.37 (d, 1 H, H(1b), J = 15.7 Hz). 13C NMR, δ: 14.30
(CH3CH2); 20.72 (CH3COO); 21.99 (C(14)); 23.35 (CH3C(6´));
33.92 (C(19)); 42.00 (CH3N(21)); 45.02 (C(20)); 49.93 (C(17));
50.30 (C(18)); 55.23 (CH3OC(6)); 56.18 (CH3OC(3)); 58.02
(C(13)); 60.27 (CH3CH2); 85.65 (C(6)); 94.25 (C(5)); 107.26
(C(9´)); 111.50 (C(2)); 116.96 (C(5´)); 118.96 (C(10)); 122.26
(C(9)); 123.70 (C(15)); 124.16 (C(4´)); 124.96 (C(7´)); 126.09
(C(1a)); 126.45 (C(1b)); 128.55 (2 CPh); 128.39 (C(1)); 128.74
(C(3´)); 129.64 (C(23)); 130.20 (2 CPh); 131.29 (C(8´)); 132.60
(1 CPh); 136.76 (C(22)); 138.28, 138.36, 138.86, 139.14 (C(16),
C(11), C(2´), C(6´)); 143.14 (C(3)); 149.41 (C(4)); 151.82
(C(8)); 164.23 (COOEt); 170.58 (COOCH3); 182.65 (COPh).
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ32365)
and the Council on Grants of the President of the Russian
Federation (Program for Support of Leading Scientific
Schools, Grant NSh 1588.2006.3).
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Received February 9, 2007;
in revised form May 23, 2007