Alkaloids of siberia and altai flora: XVIII.* alkyl 2-acetylamino-5-[2-(pyridin-3-yl)vinyl]benzoates in the synthesis of indolizines containing an anthranilic acid ester moiety

Article abstract of DOI:10.1134/S1070428011040191

Methyl 2-acetylamino-5-[2-(6-methylpyridin-3-yl)vinyl]benzoate reacted with phenacyl bromide to produce quaternary 1-(2-aryl-2-oxoethyl)-2-methyl-5-(4- acetylamino-3-methoxycarbonyl)pyridinium bromides. 1,3-Dipolar cycloaddition of the latter to methyl pr

Full text of DOI:10.1134/S1070428011040191

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 4, pp. 581–588. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.E. Romanov, E.E. Shul’ts, M.M. Shakirov, G.A. Tolstikov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 4,
pp. 578–585.
Alkaloids of Siberia and Altai Flora: XVIII.* Alkyl
2-Acetylamino-5-[2-(pyridin-3-yl)vinyl]benzoates in the Synthesis
of Indolizines Containing an Anthranilic Acid Ester Moiety
V. E. Romanov, E. E. Shul’ts, M. M. Shakirov, and G. A. Tolstikov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: schultz@nioch.nsc.ru
Received June 1, 2010
Abstract—Methyl 2-acetylamino-5-[2-(6-methylpyridin-3-yl)vinyl]benzoate reacted with phenacyl bromide to
produce quaternary 1-(2-aryl-2-oxoethyl)-2-methyl-5-(4-acetylamino-3-methoxycarbonyl)pyridinium
bromides. 1,3-Dipolar cycloaddition of the latter to methyl propynoate and dimethyl but-2-ynedioate gave the
corresponding indolizine derivatives containing an anthranilic acid ester moiety. Reactions of acetylenes with
N-phenacylpyridinium salts obtained from a diterpene alkaloid derivative, 2-(pyridin-3-yl)vinyl-substituted
lappaconitine afforded analogous compounds in which the indolizine fragment is conjugated to the aromatic
ring of the alkaloid. 1,3-Dipolar cycloaddition of 1-(2-aryl-2-oxoethyl)-2-methyl-5-(4-acetylamino-3-methoxy-
carbonyl)pyridinium bromides with methyl propynoate was regioselective.
DOI: 10.1134/S1070428011040191
Heterocyclic indolizine system is a structural frag-
ment of a number of alkaloids exhibiting valuable
biological activity [2]. In the recent years, synthetic ap-
proaches to substituted indolizines possessing a signif-
icant therapeutic potential have been extensively de-
veloped. 1-α-Ethoxycarbonyl-3-benzoylindolizines
were found to act as efficient cardiovascular [3] and
antiviral agents [4]. 1-Carbamoylmethylindolizines
and 1-oxamoylindolizines were reported to inhibit
secretory phospholipase A2 [5]. Functionalized indoli-
zine derivatives are inhibitors of MPtpA/MPtpB phos-
phatases [6], testosterone 5α-reductase [7], and
15-lipoxygenase [8], and they possess antioxidant [9]
and antibacterial activity [10]. Taking into account the
above stated, we believed that development of methods
for the synthesis of compounds possessing indolizine
fragments and exhibiting selective biological activity is
an important problem.
peutic agents for the treatment of cardiovascular dis-
orders [11]. Among natural anthranilic acid deriva-
tives, some diterpene alkaloids have found application
as efficient medical agents [12].
The goal of the present work was to synthesize pyr-
idinium salts having a 2-(4-amino-3-R-oxycarbonyl-
O
OMe
Ac
1
6'
Me
5
3'
2
N1'
N
H
I
OMe
16
13
12
MeO
1
HO
OMe
17
14
9
Me
15
8
N
5
3
OH
We were interested in synthesizing indolizines con-
taining a 2-(4-amino-3-R-oxycarbonylphenyl)vinyl
substituent (i.e., anthranilic acid ester residue), for het-
erocyclic derivatives of anthranilic acid are promising
as niacin receptor agonists which can be used as thera-
7
Me
6''
O
N1''
3''
5'
1'
O
2'
Ac
N
H
* For communication XVII, see [1].
II
581

ROMANOV et al.
582
Scheme 1.
3
Me
2
4
5
O
OMe
O
O
HA
α
R2
R1
Br
R2
R1
N1
5'
1'
2'
1''
3''
4''
Et2O
β
I
+
Br–
HB
Ac
N
H
IIIa–IIIc
IVa–IVc
6
MeO
O
Me
5
7
8
HA
α
OMe
O
N4
O
OMe
1'
3'
4'
3
O
9
1
Et3N, CH2Cl2
β
1''
R2
3''
HB
Ac
2
N
OMe
O
H
4''
O
R1
OMe
Va–Vc
R1 = R2 = H (a); R1 = MeO, R2 = H (b); R1 = R2 = Cl (c).
phenyl)vinyl substituent and examine their behavior
in reactions with carbonyl compounds of the acetylene
series. As starting compounds we used methyl 2-ace-
tylamino-5-[(6-methylpyridin-3-yl)vinyl]benzoate (I)
and its structural analog containing a diterpene moiety
in the ester fragment, lappaconitine derivative II.
Compounds I and II were synthesized according to
Heck from the corresponding iodo-substituted anthra-
nilic acid esters and 5-vinyl-2-methylpyridine, follow-
ing the procedure described in [13]. The antiarrhyth-
mic activity of compounds I and II was reported
previously [14].
of diterpene derivative II with phenacyl bromides
IIIa–IIIc in acetone (yield 70–73%; Scheme 2). Pyri-
dinium bromides VIa–VIc reacted with dimethyl ace-
tylenedicarboxylate in the presence of triethylamine to
produce indolizines VIIa–VIIc in 50–55% yield.
We found that 1,3-dipolar cycloaddition of unsym-
metrical dipolarophile, methyl propynoate, to pyridi-
nium salts IVc and VIb is regioselective. The reactions
carried out according to the standard procedure led to
the formation of methyl indolizine-1-carboxylates VIII
and IX which were isolated in 54 and 49% yield,
respectively (Scheme 3).
Treatment of compound I with phenacyl bromides
IIIa–IIIc in diethyl ether gave the corresponding pyri-
dinium salts IVa–IVc in 68–71% yield (Scheme 1).
1-Phenacylpyridinium bromides thus obtained were
brought into 1,3-dipolar cycloaddition reaction with di-
methyl acetylenedicarboxylate in methylene chloride
in the presence of triethylamine. As a result, we iso-
lated 51–54% of substituted indolizines Va–Vc
(Scheme 1). By varying conditions (reaction time after
mixing the reactants from 10 min to 3 h and order of
mixing of the reactants) of the reaction of pyridinium
salt IVa with dimethyl acetylenedicarboxylate we
found that the best results were obtained when a solu-
tion of triethylamine and dipolarophile in methylene
chloride was gradually added to a solution of pyridi-
nium salt IVa in the same solvent at room temperature,
followed by keeping the reaction mixture for 1 h.
We can conclude that 1,3-dipolar cycloaddition of
1-phenacylpyridinium salts to acetylenic compounds
may be regarded as a synthetic route to “hybrid” struc-
tures containing a diterpene alkaloid and indolizine
fragments. Such indolizine–lappaconitine conjugates
attract interest from the viewpoint of search for phar-
macologically important metabolites of plant and
marine origin, whose molecules contain different struc-
tural fragments, including alkaloid dimers [15].
The structure of the isolated compounds was deter-
mined on the basis of their spectral parameters and
elemental compositions. Pyridinium bromides IVa–
IVc and VIa–VIc were characterized by sharp melting
1
points. In the H NMR spectra of IVa–IVc and VIa–
VIc, the 6-H proton in the pyridine ring appeared in
a weaker field relative to that of initial compound I
(δ 8.84 ppm for IVb against δ 8.53 ppm for I [13]), and
protons in the phenacyl methylene group resonated as
two doublets at δ 6.17 and 6.22 ppm (IVb). Indolizines
Va–Vc and VIIa–VIIc displayed specific UV spectra.
Compounds containing lappaconitine and indoli-
zine fragments were synthesized by 1,3-dipolar cyclo-
addition of dimethyl acetylenedicarboxylate to pyridi-
nium salts VIa–VIc which were obtained by alkylation
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ALKALOIDS OF SIBERIA AND ALTAI FLORA: XVIII.
583
Scheme 2.
OMe
MeO
HO
OMe
Me
N
OH
Me 2''
O
O
HA
O
R2
R1
N1''
Br–
5''
α
R2
R1
Br
3'
4'
Me2CO
O
β
1'
II
+
HB
Ac
N
H
IIIa–IIIc
VIa–VIc
OMe
16
13
12
MeO
HO
OMe
17
14
22
Me
1
9
15
8
N
21
5
OH
3
6''
MeO
O
O
7
Me
5''
7''
8''
HA
α
O
19
O
N4''
OMe
1'
3'
4'
3''
O
9''
Et3N, CH2Cl2
β
1'''
1''
R2
3'''
HB
Ac
2''
N
OMe
O
H
4'''
O
R1
OMe
VIIa–VIIc
R1 = R2 = H (a); R1 = MeO, R2 = H (b); R1 = R2 = Cl (c).
For example, the electronic absorption spectrum of
VIIb contained strong absorption bands with their
maxima at λ 228 (logε 4.52), 262 (4.49), 302 (4.25),
and 382 nm (4.03). The 1H and 13C NMR spectra of V
and VII were fully consistent with their structure: we
observed only one set of signals from the indolizine
fragment and the corresponding substituents. In the
1H NMR spectra of VIIa–VIIc, the 6-H and 7-H
protons in the indolizine fragment resonated as dou-
blets at δ 6.64–6.97 (6-H) and 7.21–7.67 ppm (7-H)
with a coupling constant J of 8.0–8.2 Hz, which is
typical of 1,3-dienes. The E configuration of the ethyl-
ene bridge in pyridinium salts IVa–IVc and VIa–VIc,
as well as in indolizines Va–Vc and VIIa–VIIc, unam-
1
biguously followed from the H NMR data. Protons at
the double bond (HA and HB) gave rise to doublets with
a coupling constant 3J of 16.0–16.8 Hz, which indicat-
ed their trans orientation with respect to each other.
The structure of compounds VIII and IX was deter-
1
mined by analysis of their H and 13C NMR spectra,
1
including two-dimensional 2D COSY and H–13C cor-
relation spectra (COSY, COLOC). The 2-H and 2″-H
Scheme 3.
6
O
Me
5
7
8
HA
α
OR
HC
Me
O
N4
OR
OMe
O
1'
3'
3
O
9
Et3N, CH2Cl2
β
Cl
Cl
N
1''
4'
1
3''
O
HB
Ac
Cl
2
N
H
OMe
Br–
Ac
N
H
4''
O
Cl
IVc, VIc
VIII, X
IVc, VIII, R = Me; VIc, IX, R = diterpene residue.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ROMANOV et al.
584
1
protons in the H NMR spectra of VIII and IX res-
onated at δ 7.76–7.78 ppm. The 13C NMR spectra of
VIII and IX contained a singlet from C1 (δC 107.51
and 107.37 ppm, respectively) and a doublet from C2
(δC 131.81 and 131.93 ppm, respectively). The pres-
ence of three cross-peaks belonging to 2-H in the
1H–13C COLOC spectrum of VIII indicated its interac-
tion with C9 (δC 137.97 ppm) and two carbonyl
carbon atoms: 1-C=O (δC 163.88 ppm) and 3-C=O
(δC 185.35 ppm). These correlations correspond to the
position of the methoxycarbonyl group on C1. Analo-
gous interactions were observed for the 2″-H proton in
13C NMR spectra were determined using standard
J-modulation technique (JMOD). The two-dimensional
1H–1H (COSY) and 13C–1H (COSY 125 Hz, COLOC
7 Hz) NMR spectra were obtained on a Bruker DRX-
1
600 instrument (600.30 MHz for H and 150.96 MHz
for 13C) using standard Bruker procedures. The IR
spectra were measured in KBr on a Vector-22 spec-
trometer. The UV spectra were recorded from solutions
in ethanol or chloroform on an HP 8453 UV-Vis spec-
trophotometer. The melting points were determined on
a Kofler hot stage. The elemental compositions were
determined on a Carlo Erba 1106 CHN analyzer.
the H–13C COLOC spectrum of IX. The position of
1
The progress of reactions was monitored, and the
purity of products was checked, by thin-layer chroma-
tography on Silufol UV-254 plates using chloroform–
ethanol (20:1) as eluent; spots were detected under UV
light. The products were isolated by preparative thin-
layer chromatography on silica gel containing 1% of
K-35 luminophore (1-mm unfixed layer, 20×20 cm;
chloroform–ethanol, 20:1).
the ester group on C1 also follows from the downfield
shift of the doublet signal of HB in the 1H NMR spectra
of VIII and IX as compared to 1,2-bis(methoxycar-
bonyl)-substituted indolizines V and VII and initial
pyridine derivatives I and II. The HB signal in the
1H NMR spectra of pyridinium salts IVa–IVc is
located at δ 7.24–7.46 ppm, in the spectra of Va–Vc, at
δ 7.53–7.57 ppm, and in the spectra of VIII and IX, at
δ 8.35–8.36 ppm.
Freshly distilled solvents and commercially avail-
able reagents of pure grade were used. 2-Acetylamino-
5-[(E)-2-(6-methylpyridin-3-yl)vinyl]benzoates I and
II were synthesized by the Heck reaction of methyl
5-iodo-2-(acetylamino)benzoate or 5′-iodolappaconitine
with 5-vinyl-2-methylpyridine according to the proce-
dure described in [13]. Compounds VIa–VIc and
VIIa–VIIc were reported previously [16].
The structure of compounds VIII and IX is consist-
ent with the reaction mechanism shown in Scheme 4.
Deprotonation of pyridinium salt IVc or VIc by the ac-
tion of triethylamine gives resonance-stabilized pyridi-
nium ylide A which reacts with methyl propynoate (as
dipolar canonical structure B), and oxidative aromati-
zation of cycloaddition product C yields final com-
pound VIII or IX.
Pyridinium salts IVa–IVc (general procedure).
A solution of 310 mg (1 mmol) of compound I and
1.1 mmol of the corresponding phenacyl bromide
IIIa–IIIc in 20 ml of anhydrous diethyl ether was
stirred for 48 h at room temperature. The precipitate
was filtered off, washed with anhydrous diethyl ether,
and dried in air until constant weight.
EXPERIMENTAL
The NMR spectra were recorded on a Bruker
1
AV-300 spectrometer at 300.13 MHz for H and
13
75.47 MHz for C. The multiplicities of signals in the
Scheme 4.
Me
Me
Me
O
NEt3
O
O
N
N
N
Ar
Ar
Ar
IVc, VIc
A
O
H
O
Me
Me
HC
C
C
O
O
OMe
OMe
N
N
B
[O]
Ar
Ar
HB
O
H
O
MeO
MeO
VIII, IX
C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ALKALOIDS OF SIBERIA AND ALTAI FLORA: XVIII.
585
(E)-5-[4-Acetylamino-3-(methoxycarbonyl)-
styryl]-2-methyl-1-(2-oxo-2-phenylethyl)pyridinium
bromide (IVa) was synthesized from 310 mg
(1 mmol) of compound I and 220 mg (1.1 mmol) of
ω-bromoacetophenone (IIIa). Yield 361 mg (71%),
mp 245–247°C (decomp.). IR spectrum, ν, cm–1: 3473,
3256, 3053, 3001, 2954, 1702, 1686, 1679, 1633,
1593, 1526, 1371, 1339, 1319, 1300, 1287, 1231,
1219, 1165, 1089, 1035, 998, 966, 942, 927, 849, 833,
NHCO). 13C NMR spectrum (CD3OD–CDCl3, 1:1 by
volume), δC, ppm: 20.16 q (2-CH3), 25.30 q (CH3CO),
52.99 q (CH3OCO), 56.07 q (4″-OCH3), 64.64 t (CH2),
115.01 d (C3″, C5″), 116.21 s (C3′), 120.50 d (Cβ),
121.19 d (C5′), 126.58 s (C1′), 130.22 d (C2′), 130.65 s
(C1″), 130.75 d (Cα), 131.70 d (C2″, C6″), 133.22 d (C6′),
134.98 d (C4), 136.74 s (C5), 141.93 s (C4′), 142.32 d
(C3), 144.79 d (C6), 154.21 s (C2), 165.89 s (C4″),
168.67 s (3′-COOCH3), 170.40 s (NHCO), 188.38 s
(C=O). Found, %: C 59.87; H 4.93; Br 15.38; N 6.25.
C27H27BrN2O5. Calculated, %: C 60.11; H 5.01;
Br 14.84; N 5.69.
1
795, 758, 704, 688, 572, 534. H NMR spectrum
(CD3OD–CDCl3, 1:1 by volume), δ, ppm: 2.12 s
(3H, CH3CO), 2.62 s (3H, 2-CH3), 3.93 s (3H,
3′-COOCH3), 6.38 d and 6.52 d (1H each, CH2N+, J =
14.2 Hz), 7.18 d (1H, HA, J = 16.3 Hz), 7.46 d (1H, HB,
J = 16.3 Hz), 7.58–7.64 m (2H, 3″-H, 5″-H), 7.73 m
(1H, 4″-H), 7.81 d.d (1H, 6′-H, J = 7.8, 2.0 Hz), 8.01 d
(1H, 3-H, J = 8.2 Hz), 8.03–8.08 m (2H, 2″-H, 6″-H),
8.11 d (1H, 2′-H, J = 2.0 Hz), 8.36 d (1H, 5′-H, J =
7.8 Hz), 8.66 d.d (1H, 4-H, J = 8.2, 2.2 Hz), 9.03 d
(1H, 6-H, J = 2.2 Hz), 10.75 br.s (1H, NHCO).
13C NMR spectrum (CD3OD–CDCl3, 1:1 by volume),
δC, ppm: 19.92 q (2-CH3), 25.30 q (CH3CO), 53.10 q
(OCH3), 64.33 t (CH2), 117.34 s (C3′), 121.08 d (Cβ),
121.56 d (C5′), 128.96 d (C2″, C6″), 129.66 d (C3″, C5″),
130.31 d (C2′), 130.66 s (C1′), 132.12 d (Cα), 132.56 d
(C6′), 133.68 s (C1″), 134.02 d (C4″), 135.60 d (C4),
135.84 s (C5), 141.02 s (C4′), 142.59 d (C3), 144.51 d
(C6), 154.44 s (C2), 168.06 s (3′-CO), 169.68 s
(NHCO), 190.70 s (C=O). Found, %: C 60.88; H 4.72;
Br 16.01; N 5.60. C26H25BrN2O4. Calculated, %:
C 61.30; H 4.91; Br 15.72; N 5.50.
(E)-5-[4-Acetylamino-3-(methoxycarbonyl)-
styryl]-1-[2-(3,4-dichlorophenyl)-2-oxoethyl]-2-
methylpyridinium bromide (IVc) was synthesized
from 310 mg (1 mmol) of compound I and 294 mg
(1.1 mmol) of 2-bromo-1-(3,4-dichlorophenyl)ethan-
one (IIIc). Yield 410 mg (71%), mp 238–240°C
(decomp.). IR spectrum, ν, cm–1: 3413, 3267, 3224,
3059, 2997, 2954, 1704, 1639, 1587, 1557, 1520,
1441, 1412, 1379, 1349, 1304, 1283, 1233, 1213,
1155, 1089, 1032, 1009, 993, 968, 882, 848, 821, 795,
1
781, 747, 697, 675, 605, 575, 536. H NMR spectrum
(CD3OD–CDCl3, 1:1 by volume), δ, ppm: 2.03 s (3H,
CH3CO), 2. 54 s (3H, 2-CH3), 3. 81 s (3H,
3′-COOCH3), 6.44 d and 6.52 d (1H each, CH2N+, J =
14.2 Hz), 7.00 d (1H, HA, J = 16.2 Hz), 7.30 d (1H, HB,
J = 16.2 Hz), 7.53 d (1H, 5″-H, J = 7.6 Hz), 7.60 d.d
(1H, 6′-H, J = 7.8, 1.8 Hz), 7.73 d (1H, 3-H, J =
7.6 Hz), 7.95 d.d (1H, 6″-H, J = 7.6, 2.0 Hz), 8.04 d
(1H, 2″-H, J = 2.0 Hz), 8.09 d (1H, 2′-H, J = 1.8 Hz),
8.34 d.d (1H, 4-H, J = 7.6, 2.0 Hz), 8.47 d (1H, 5′-H,
J = 7.8 Hz), 9.07 d (1H, 6-H, J = 2.0 Hz), 11.00 br.s
(1H, NHCO). 13C NMR spectrum (CD3OD–CDCl3,
1:1 by volume), δC, ppm: 20.32 q (2-CH3), 25.59 q
(CH3CO), 53.01 q (CH3OCO), 64.48 t (CH2), 116.02 s
(C3′), 120.26 d (Cβ), 121.19 d (C5′), 127.58 d (C6″),
129.07 s (C1′), 129.36 d (C2′), 129.65 d (Cα), 129.91 d
(C2″), 130.94 d (C5″), 131.20 s (C1″), 132.34 d (C6′),
133.82 s (C3″), 135.60 d (C4), 135.84 s (C5), 138.08 s
(C4″), 141.02 s (C4′), 142.28 d (C3), 143.89 d (C6),
154.04 s (C2), 168.70 s (3′-CO), 170.28 s (NHCO),
188.72 s (C=O). Found, %: Br 13.61; Cl 11.96; N 4.57.
C26H23BrCl2N2O4. Calculated, %: Br 13.84; Cl 12.28;
N 4.84.
(E)-5-[4-Acetylamino-3-(methoxycarbonyl)-
styryl]-1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-meth-
ylpyridinium bromide (IVb) was synthesized from
310 mg (1 mmol) of compound I and 252 mg
(1.1 mmol) of 2-bromo-1-(4-methoxyphenyl)ethanone
(IIIb). Yield 367 mg (68%), mp 232–235°C
(decomp.). IR spectrum, ν, cm–1: 3435, 3263, 3037,
3000, 2953, 1701, 1679, 1634, 1600, 1524, 1368,
1342, 1284, 1242, 1172, 1120, 1090, 1015, 974, 836,
1
795, 755, 695, 669, 632, 572, 530. H NMR spectrum
(CD3OD–CDCl3, 1:1 by volume), δ, ppm: 2.00 s (3H,
CH3CO), 2.45 s (3H, 2-CH3), 3.68 s (3H, 3′-COCH3),
3.73 s (3H, 4″-OCH3), 6.17 d and 6.22 d (1H each,
CH2N+, J = 14.2 Hz), 6.81 br.d (2H, 3″-H, 5″-H, J =
8.2 Hz), 6.90 d (1H, HA, J = 16.3 Hz), 7.24 d (1H, HB,
J = 16.3 Hz), 7.53 d.d (1H, 6′-H, J = 8.0, 2.2 Hz),
7.66 d (1H, 3-H, J = 8.4 Hz), 7.87 d (2H, 2″-H, 6″-H,
J = 8.2 Hz), 8.00 d (1H, 2′-H, J = 2.2 Hz), 8.32 d.d
(1H, 4-H, J = 8.4, 2.0 Hz), 8.39 d (1H, 5′-H, J =
8.0 Hz), 8.84 d (1H, 6-H, J = 2.0 Hz), 10.88 br.s (1H,
Indolizines Va–Vc (general procedure). A solution
of 1.1 equiv of dimethyl acetylenedicarboxylate and
1 equiv of triethylamine in 10 ml of anhydrous methyl-
ene chloride was added dropwise over a period of
10 min to a solution of pyridinium bromide IVa–IVc
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ROMANOV et al.
586
in 10 ml of anhydrous methylene chloride. The dark
red solution was stirred for 1 h at room temperature,
treated with aqueous ammonia to pH ~11, stirred for
10 min, treated with 10% sulfuric acid to pH ≈ 3,
stirred for 10 min, and treated again with aqueous am-
monia to pH ≈ 11. The organic phase was separated
and dried over MgSO4, the solvent was distilled off,
and the residue was subjected to chromatography on
silica gel using chloroform–ethanol as eluent. A yel-
low–orange fraction (with bright luminescence under
UV light) was separated, and the product was washed
off from the sorbent with ethanol. The solvent was dis-
tilled off, and the residue (a brown–red powder) was
dried under reduced pressure until constant weight.
(0.39 mmol) of dimethyl acetylenedicarboxylate. Yield
107 mg (51%), mp 136–138°C. IR spectrum, ν, cm–1:
3436, 3309, 2953, 2845, 1703, 1597, 1515, 1372,
1293, 1238, 1168, 1089, 1062, 1025, 955, 921, 835,
789, 758, 661, 620, 583. UV spectrum (ethanol), λmax
,
nm (logε): 228 (4.52), 262 (4.49), 302 (4.25), 382
1
(4.03). H NMR spectrum (CDCl3), δ, ppm: 2.25 s
(3H, NHCOCH3), 2.35 s (3H, 5-CH3), 3.48 s and
3.86 s (3H each, 1-COOCH3, 2-COOCH3), 3.89 s (3H,
4″-OCH3), 3.96 s (3H, 3′-COOCH3), 6.64 d (1H, 6-H,
J = 8.2 Hz), 6.93 d (2H, 3″-H, 5″-H, J = 7.6 Hz),
6.99 d (1H, HA, J = 16.2 Hz), 7.21 d (1H, 7-H, J =
8.2 Hz), 7.57 d (1H, HB, J = 16.2 Hz), 7.73 d.d (1H,
6′-H, J = 7.5, 2.0 Hz), 7.85 d (2H, 2″-H, 6″-H, J =
7.6 Hz), 8.18 d (1H, 2′-H, J = 2.0 Hz), 8.74 d (1H,
5′-H, J = 7.5 Hz), 11.06 br.s (1H, NH). 13C NMR spec-
trum (CDCl3), δC, ppm: 22.16 q (5-CH3), 25.36 q
(NHCOCH3), 51.81 q (1-COOCH3), 52.30 q
(2-COOCH3), 52.40 q (3′-COOCH3), 55.44 q
(4″-OCH3), 107.23 s (C1), 113.82 d (C3″, C5″), 114.95 s
(C3′), 115.51 d (C6), 120.30 d (C7), 120.56 d (C5′),
122.38 s (C2), 124.16 d (Cβ), 124.34 s (C1′), 128.16 s
(C8), 128.97 d (C2′), 129.91 d (Cα), 131.39 s (C3),
131.92 s (C9), 131.96 d (C6′), 132.32 d (C2″, C6″),
132.66 s (C1″), 135.18 s (C5), 140.97 s (C4′), 163.83 s
(C4″), 164.02 s and 166.47 s (1-CO, 2-CO), 168.45 s
(3′-CO), 168.85 s (NHCO), 187.20 s (3-C=O). Found,
%: C 65.88; H 5.15; N 4.46. C33H30N2O9. Calculated,
%: C 66.21; H 5.05; N 4.68.
Dimethyl 8-[(E)-4-acetylamino-3-(methoxycar-
bonyl)styryl]-3-benzoyl-5-methylindolizine-1,2-di-
carboxylate (Va) was synthesized from 200 mg
(0.39 mmol) of pyridinium salt IVa and 62 mg
(0.43 mmol) of dimethyl acetylenedicarboxylate. Yield
120 mg (54%), mp 143–146°C. IR spectrum, ν, cm–1:
3432, 3316, 3266, 2952, 1705, 1643, 1589, 1519,
1377, 1294, 1233, 1089, 1062, 1001, 957, 915, 836,
790, 751, 728, 693, 645, 584. UV spectrum (chloro-
form), λmax, nm (logε): 260 (4.37), 302 (4.19), 380
1
(3.69). H NMR spectrum (CDCl3), δ, ppm: 2.22 s
(3H, CH3CO), 2.31 s (3H, 5-CH3), 3.36 s and 3.83 s
(3H each, 1-COOCH3, 2-COOCH3), 3.92 s (3H,
3′-COOCH3), 6.65 d (1H, 6-H, J = 8.2 Hz), 6.96 d (1H,
HA, J = 16.5 Hz), 7.22 d (1H, 7-H, J = 8.2 Hz), 7.42–
7.50 m (2H, 3″-H, 5″-H), 7.53 d (1H, HB, J = 16.5 Hz),
7.52–7.58 m (1H, 4″-H), 7.69 d.d (1H, 6′-H, J = 7.4,
2.2 Hz), 7.82–7.89 m (2H, 2″-H, 6″-H), 8.15 d (1H,
2′-H, J = 2.2 Hz), 8.71 d (1H, 5′-H, J = 7.4 Hz),
11.03 br.s (1H, NH). 13C NMR spectrum (CDCl3), δC,
ppm: 22.52 q (5-CH3), 25.35 q (NHCOCH3), 51.81 q
(1-COOCH3), 52.30 q (2-COOCH3), 52.40 q
(3′-COOCH3), 107.31 s (C1), 114.90 s (C3′), 115.85 d
(C6), 120.51 d (C5′), 120.75 d (C7), 123.46 s (C2),
123.55 s (C1′), 124.07 d (Cβ), 128.13 s (C8), 128.48 d
(C3″, C5″), 128.98 d (C2′), 129.38 d (C2″, C6″), 129.95 d
(Cα), 131.32 s (C1″), 132.28 d (C6′), 133.10 s (C9),
133.30 d (C4″), 135.34 s (C5), 138.66 s (C3), 140.97 s
(C4′), 163.97 s and 166.20 s (1-CO, 2-CO), 168.40 s
(3′-CO), 168.83 s (NHCO), 188.01 s (3-C=O). Found,
%: C 67.24; H 4.71; N 4.64. C32H28N2O8. Calculated,
%: C 67.60; H 4.96; N 4.93.
(E)-Dimethyl 8-[4-acetylamino-3-(methoxycar-
bonyl)styryl]-3-(3,4-dichloroobenzoyl)-5-methylin-
dolizine-1,2-dicarboxylate (Vc) was synthesized from
230 mg (0.4 mmol) of salt IVc and 63 mg (0.44 mmol)
of dimethyl acetylenedicarboxylate. Yield 138 mg
(54%), mp 151–154°C. IR spectrum, ν, cm–1: 3430,
2953, 1724, 1699, 1590, 937, 956, 999, 1030, 1062,
1095, 1159, 1221, 1261, 1292, 1384, 1523, 832, 788,
767, 681, 587, 553. UV spectrum (chloroform), λmax
,
nm (logε): 260 (4.34), 303 (4.09), 380 (3.09). 1H NMR
spectrum (CDCl3), δ, ppm: 2.26 s (3H, NHCOCH3),
2.32 s (3H, 5-CH3), 3.52 s and 3.86 s (3H each,
1-COOCH3, 2-COOCH3), 3.97 s (3H, 3′-COOCH3),
6.73 d (1H, 6-H, J = 8.0 Hz), 6.96 d (1H, HA, J =
16.6 Hz), 7.31 d (1H, 7-H, J = 8.0 Hz), 7.53 d (1H, HB,
J = 16.6 Hz), 7.56 d (1H, 5″-H, J = 7.8 Hz), 7.72 d.d
(1H, 6″-H, J = 7.8, 2.3 Hz), 7.74 d.d (1H, 6′-H, J = 7.5,
2.0 Hz), 8.05 d (1H, 2″-H, J = 2.3 Hz), 8.18 d (1H,
2′-H, J = 2.0 Hz), 8.73 d (1H, 5′-H, J = 7.5 Hz),
11.09 br.s (1H, NH). 13C NMR spectrum (CDCl3), δC,
ppm: 22.73 q (5-CH3), 25.38 q (NHCOCH3), 52.05 q
(1-COOCH3), 52.34 q (2-COOCH3), 52.52 q
Dimethyl 8-[(E)-4-acetylamino-3-(methoxycar-
bonyl)styryl]-3-(4-methoxybenzoyl)-5-methylindoli-
zine-1,2-dicarboxylate (Vb) was synthesized from
190 mg (0.35 mmol) of pyridinium salt IVb and 55 mg
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ALKALOIDS OF SIBERIA AND ALTAI FLORA: XVIII.
587
(3′-COOCH3), 107.73 s (C1), 115.01 s (C3′), 116.35 d
(C6), 120.63 d (C5′), 121.28 d (C7), 122.78 s (C2),
123.88 d (Cβ), 123.90 s (C1′), 128.44 s (C8), 128.62 d
(C2′), 129.08 d (C6″), 130.39 d (Cα), 130.65 d (C5″),
131.13 d (C2″), 131.28 s (C3), 132.34 d (C6′), 133.32 s
(C1″), 133.57 s (C3″), 135.33 s (C5), 137.97 s (C9),
138.32 s (C4″), 141.11 s (C4′), 163.88 s and 166.08 s
(1-CO, 2-CO), 168.53 s (3′-CO), 168.94 s (NHCO),
185.35 s (3-CO). Found, %: C 59.85; H 4.20; Cl 10.88;
N 3.83. C32H26Cl2N2O8. Calculated, %: C 60.29;
H 4.11; Cl 11.12; N 4.39.
Methyl 8-{(E)-4-acetylamino-3-[(8,9-dihydroxy-
1α,14α,16β-trimethoxy-20-ethylaconitan-4β-yl)oxy-
carbonyl]styryl}-3-(3,4-dichlorobenzoyl)-5-methyl-
indolizine-1-carboxylate (IX). A solution of 20 mg
(0.23 mmol) of methyl propynoate and 22 mg
(0.21 mmol) of triethylamine in 10 ml of methylene
chloride was added dropwise over a period of 10 min
to a solution of 200 mg (0.21 mmol) of pyridinium salt
VIc (prepared as described in [16]) in 10 ml of
methylene chloride. The dark red solution was stirred
for 1 h and treated in succession with aqueous ammo-
nia, 10% sulfuric acid, and aqueous ammonia again.
The organic phase was separated and dried over mag-
nesium sulfate, and the product was purified by
chromatography. Yield 98 mg (49%), yellow powder,
mp 126–128°C. IR spectrum, ν, cm–1: 3403, 2962,
2819, 1705, 1634, 1587, 1553, 1515, 1368, 1330,
1264, 1212, 1117, 1089, 1032, 967, 915, 792, 765,
(E)-Methyl 8-[4-acetylamino-3-(methoxycarbon-
yl)styryl]-3-(3,4-dichlorobenzoyl)-5-methylindoli-
zine-1-carboxylate (VIII). A solution of 62 mg
(0.432 mmol) of methyl propynoate and 40 mg
(0.393 mmol) of triethylamine in 10 ml of methylene
chloride was added dropwise over a period of 10 min
to a solution of 509 mg (0.393 mmol) of pyridinium
salt IVc in 10 ml of methylene chloride. The dark red
solution was stirred for 1 h and treated in succession
with aqueous ammonia, 10% sulfuric acid, and aque-
ous ammonia again. The organic phase was separated
and dried over magnesium sulfate, and the product was
isolated by chromatography. Yield 120 mg (54%),
bright yellow powder. An analytical sample was
obtained by additional purification by TLC, mp 173–
175°C. IR spectrum, ν, cm–1: 3435, 2955, 1727, 1699,
1591, 1530, 1387, 1295, 1260, 1227, 1153, 1091,
1065, 1030, 1013, 958, 937, 835, 790, 761, 689, 583.
1H NMR spectrum (CDCl3), δ, ppm: 2.24 s (3H,
NHCOCH3), 2.55 s (3H, 5-CH3), 3.83 s (3H,
1-COOCH3), 3.95 s (3H, 3′-COOCH3), 6.94 d (1H, HA,
J = 16.2 Hz), 6.97 d (1H, 6-H, J = 8.0 Hz), 7.60 d (1H,
5″-H, J = 7.0 Hz), 7.67 d (1H, 7-H, J = 8.0 Hz), 7.78 s
(1H, 2-H), 7.83 d.d (1H, 6′-H, J = 7.5, 2.3 Hz),
7.87 d.d (1H, 6″-H, J = 7.0, 2.0 Hz), 8.11 d (1H, 2″-H,
J = 2.0 Hz), 8.21 d (1H, 2′-H, J = 2.3 Hz), 8.35 d (1H,
HB, J = 16.2 Hz), 8.74 d (1H, 5′-H, J = 7.5 Hz),
11.05 br.s (1H, NH). 13C NMR spectrum (CDCl3), δC,
ppm: 23.35 q (5-CH3), 25.44 q (NHCOCH3), 51.71 q
(1-COOCH3), 52.31 q (3′-COOCH3), 107.37 s (C1),
114.86 s (C3′), 117.38 d (C6), 120.60 d (C5′), 124.13 s
(C1′), 125.19 d (C7), 126.55 d (Cβ), 128.11 s (C8),
128.84 d (Cα), 129.07 d (C6″), 129.35 d (C2′), 130.47 d
(C5″), 131.78 d (C2″), 131.81 d (C2), 131.88 s (C3″),
132.33 d (C6′), 133.01 s (C4″), 137.04 s (C1″), 138.07 s
(C3), 138.77 s (C5), 139.49 s (C9), 140.85 s (C4′),
162.27 s (1-CO), 168.59 s (3′-CO), 168.86 s (NHCO),
179.58 s (3-CO). Found, %: C 61.66; H 4.24; Cl 12.25;
N 4.44. C30H24Cl2N2O6. Calculated, %: C 62.18;
H 4.14; Cl 12.24; N 4.84.
1
752, 676. H NMR spectrum (CDCl3), δ, ppm: 1.12 t
(3H, 22-H, J = 7.2 Hz), 1.52 br.s (2H, OH, w/2 =
18.0 Hz), 1.62 d.d (1H, 6-H, J = 15.0, 8.2 Hz), 1.83 m
2
(1H, 3-H, J = 13.2 Hz), 1.97–2.10 m (2H, 12-H,
15-H), 2.08 d.d (1H, 10-H, J = 11.6, 4.2 Hz), 2.13–
2.23 m (3H, 2-H, 7-H, 12-H), 2.23 s (3H, NHCOCH3),
2.29–2.41 m (2H, 13-H, 15-H), 2.46 d.d (1H, 2-H, J =
14.8, 2.6 Hz), 2.48–2.60 m (4H, 5-H, 19-H, 21-H),
2
2.55 s (3H, 5″-CH3), 2.60 m (1H, 3-H, J = 13.2 Hz),
2.72 d.d (1H, 6-H, J = 15.0, 6.2 Hz), 3.00 s (1H,
17-H), 3.18 d.d (1H, 1-H, J = 9.9, 6.4 Hz), 3.28 s (3H,
1-OCH3), 3.29 s (3H, 16-OCH3), 3.30 m (1H, 16-H),
3.39 s (3H, 14-OCH3), 3.42 d (1H, 14-H, J = 5.0 Hz),
3.60 d (1H, 19-H, J = 11.5 Hz), 3.82 s (3H,
1″-COOCH3), 6.94 d (1H, 6″-H, J = 8.0 Hz), 6.97 d
(1H, HA, J = 16.8 Hz), 7.60 d (1H, 5′′′-H, J = 7.2 Hz),
7.72 d (1H, 7″-H, J = 8.0 Hz), 7.76 br.s (1H, 2″-H),
7.86 d.d (1H, 6′′′-H, J = 7.2, 2.2 Hz), 7.89 d.d (1H,
6′-H, J = 8.0, 2.4 Hz), 7.98 (1H, 2′′′-H, J = 2.2 Hz),
8.12 d (1H, 2′-H, J = 2.4 Hz), 8.36 d (1H, HB, J =
16.8 Hz), 8.72 (1H, 5-H, J = 8.0 Hz), 11.04 br.s (1H,
2′-NH). 13C NMR spectrum (CDCl3), δC, ppm: 13.48 q
(C22), 23.34 q (5″-CH3), 24.10 t (C6), 25.50 q
(NHCOCH3), 26.17 t (C12), 26.76 t (C2), 31.82 t (C3),
36.29 d (C13), 44.79 t (C15), 47.56 d (C7), 48.51 d (C5),
48.89 t (C21), 49.85 d (C10), 50.98 s (C11), 51.82 q
(1″-COOCH3), 55.48 t (C19), 56.05 q (16-OCH3),
56.44 q (1-OCH3), 57.85 q (14-OCH3), 61.43 d (C17),
75.61 s (C8), 78.53 s (C9), 82.83 d (C16), 84.11 s (C4),
84.83 d (C1), 90.10 d (C14), 107.51 s (C1″), 115.86 s
(C3′), 117.40 d (C6″), 120.70 d (C5′), 124.10 s (C1′),
125.01 d (C7″), 126.43 d (Cβ), 128.26 s (C8″), 129.10 d
and 129.18 d (C6′′′, Cα), 130.06 d (C2′), 130.46 d (C5′′′),
131.46 d (C6′), 131.77 s (C3″), 131.86 d (C2′′′), 131.93 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ROMANOV et al.
588
(C2″), 133.88 s (C3′′′), 136.99 s (C4′′′), 138.19 s (C1′′′),
138.74 s (C5″), 139.53 s (C9″), 141.02 s (C4′), 164.26 s
(C1″-COOCH3), 167.29 s (3′-CO), 168.83 s (NHCO),
179.56 s (3″-C=O). Found, %: C 63.96; H 5.64;
Cl 7.36; N 4.04. C52H57Cl2N3O11. Calculated, %:
C 64.32; H 5.88; Cl 7.32; N 4.33.
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and Rise, F., Bioorg. Med. Chem., 2005, vol. 13,
p. 3127.
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This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 08-03-00340, 09-03-00183).
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