Syntheses based on anabasine : 222. Synthesis of piperidyl-substituted indolizines

Article abstract of DOI:10.1007/s11172-008-0021-z

N-Phenacyl salts of acetyl-, benzoyl-, and methylanabasine were synthesized for the first time. Their reactions with unsaturated carbonyl compounds of the ethylene and acetylene series and acrylonitrile were studied. Methods for the synthesis of 6- and 8-

Full text of DOI:10.1007/s11172-008-0021-z

Russian Chemical Bulletin, International Edition, Vol. 57, No. 1, pp. 140—150, January, 2008
140
Syntheses based on anabasine
2.* Synthesis of piperidylꢀsubstituted indolizines
L. A. Musina,a E. E. Shults,a I. Yu. Bagryanskaya,a Yu. V. Gatilov,a M. M. Shakirov,a

G. A. Tolstikov,a and S. M. Adekenovb
aN. 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
bInstitute of Phytochemistry, Ministry of Education and Science of the Republic of Kazakhstan,
4 ul. M. Gazalieva, 100009 Karaganda, Republic of Kazakhstan.
Fax: (321 2) 43 3773
NꢀPhenacyl salts of acetylꢀ, benzoylꢀ, and methylanabasine were synthesized for the first time.
Their reactions with unsaturated carbonyl compounds of the ethylene and acetylene series and
acrylonitrile were studied. Methods for the synthesis of 6ꢀ and 8ꢀ(2ꢀpiperidyl)indolizines were
developed.
Key words: anabasine, 1,3ꢀdipolar cycloaddition, piperidinylindolizines, Nꢀphenacylꢀ
pyridinium bromides, Xꢀray diffraction.
Scheme 1
Indolizine and its derivatives have various pharmacoꢀ
logical properties due to which they have attracted attenꢀ
tion of synthetic chemists. For example, 1ꢀαꢀcarboxyꢀ
ethylꢀ3ꢀbenzoylindolizines were covered by patents as
painꢀrelieving and antiꢀinflammatory drugs,2 and also as
cardiovascular3 and antiviral4 agents. Certain indolizine
derivatives serve as testosterone 5αꢀreductase inhibitors.5
1ꢀ(Carbamoylmethyl)indolizines are powerful inhibitors
of secretory phospholipase.6 In addition, indolizines are
used in the synthesis of biologically important dimeric
alkaloids.7 We focused our attention on developing a proꢀ
cedure for the synthesis of functionalized indolizines startꢀ
ing from the available plant alkaloid anabasine (1).
The aim of the present study
was to synthesize pyridinium salts
of anabasine derivatives and examꢀ
ine their behavior in reactions with
unsaturated carbonyl compounds
of the ethylene and acetylene series
and acrylonitrile.
We found that stirring of Nꢀacetylanabasine (2),
Nꢀbenzoylanabasine (3), or Nꢀmethylanabasine (4) with
phenacyl bromide or 4ꢀmethoxyphenacyl bromide in diꢀ
ethyl ether for a short period of time affords phenacylꢀ
pyridinium salts in 59—97% yields (Scheme 1). The strucꢀ
tures of compounds 5—9 were determined by spectroꢀ
scopy and elemental analysis. The 1H NMR spectra of the
pyridinium salts are characterized by downfield shifts of
i. A — EtOH, K2CO3; B — 1,2ꢀC2H4Cl2, Et3N.
R = COMe (2, 5, 8), COPh (3, 6, 9), Me (4, 7); Ar = Ph (5, 6, 7),
4ꢀOMeC H (8, 9).
* For Part 1, see Ref. 1.
6
4
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 135—145, January, 2008.
1066ꢀ5285/08/5701ꢀ0140 © 2008 Springer Science+Business Media, Inc.

Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
141
Syntheses based on anabasine
Scheme 2
the signals for the H(2) and H(6) protons of the pyridine
ring (for example, δ 9.15 and 9.07 for compound 5) and of
the CH2 group of the phenacyl substituent (δ 7.00 for
compound 5).
Attempts to synthesize ylides by treating 3ꢀ(1ꢀacetylꢀ
piperidinꢀ2ꢀyl)ꢀ1ꢀphenacylpyridinium bromide (5) with
potassium carbonate in ethanol (method A) or with triꢀ
ethylamine in dichloroethane (method B) failed. In both
cases, the reactions produced 3ꢀ(1ꢀacetylpiperidinꢀ2ꢀyl)ꢀ
1ꢀmethylpyridinium bromide (10) in 42% (method A) or
23% yield (method B) and acetylanabasine (2) (see
1
Scheme 1). In the H NMR spectrum of salt 10, the
signals for the H(2) and H(6) protons (δ 9.19 and 9.14)
and for the Me group (δ 4.64) are shifted downfield.
The treatment of 3ꢀ(1ꢀacetylpiperidinꢀ2ꢀyl)ꢀ1ꢀphenꢀ
acylpyridinium bromide (5) with an equimolar amount of
triethylamine in dichloromethane in the presence of
1.1 equiv. of ethyl propiolate at 25 °C leads to the
1,3ꢀdipolar cycloaddition giving rise to a mixture of
6ꢀ and 8ꢀpiperidylꢀsubstituted indolizines 11 and 12 in
a ratio of 1 : 1 in 75% yield (Scheme 2).
Compounds 11 and 12 were isolated in the individual
state by alumina column chromatography. The structures
of compounds 11 and 12 were determined by spectrosꢀ
1
copy. The H NMR spectrum of indolizine 11 shows
signals for the H(7) and H(8) protons as doublets at δ 7.30
and 8.31 with the spinꢀspin coupling constant of 9.3 Hz
characteristic of the 1,3ꢀdiene fragment. The H(5) proton
is observed as a singlet at δ 9.87. In the spectrum of
indolizine 12, the signals for the protons of the pyridine
ring are observed at δ 7.07 (t, H(6), J = 7.1 Hz, J =
6.8 Hz), δ 7.21 (d, H(7), J = 6.8 Hz), and δ 9.96 (d, H(5),
J = 7.1 Hz). The abnormal downfield shift of the signal for
the H(5) proton, as well as a downfield shift for the H(2´)
proton (δ 6.06 for 11 and δ 6.69 for 12) suggest that in
solution, compounds 11 and 12 exist predominantly in
the bipolar form II (Scheme 2). An analogous downfield
shift of the signal for the H(5) proton was observed for
3ꢀbenzoylindolizines8,9 (R1 = R2 = H). The structure II
(R1 = H, R2 is piperidinꢀ2ꢀyl; R1 is piperidinꢀ2ꢀyl, R2 =
H) is confirmed by the IR spectra of compounds 11 and
12, in which the stretching bands of the carbonyl group of
the benzoyl substituent (at the C(3) atom of the indolizine
system) are shifted to 1600—1630 cm–1 due to the presꢀ
i. R1OCC—C≡C—X, Et3N, CH2Cl2
Comꢀ
X
Ar
R
R´
pound
11, 12
13,14
15,16
17,18
19, 20
H
Ph
Ph
Ph
Ac
Ac
COPh
Ac
Et
CO Me
Me
Me
Me
Me
2
CO Me
2
CO Me
4ꢀMeOꢀC H
4ꢀMeOC H
2
6
4
CO Me
2
COPh
6
4
atom of the piperidine ring. The introduction of the bulky
benzoyl substituent into the piperidine fragment favors the
formation of 6ꢀsubstituted indolizines. For example, the
reaction of compounds containing the acetyl substituent
at the nitrogen atom affords 8ꢀpiperidylꢀsubstituted
indolizines as the major products (13 : 14 = 0.4 : 1, 17 : 18
= 0.5 : 1). The presence of the bulky benzoyl substituent
at the nitrogen atom of the piperidine ring changes the
direction of 1,3ꢀdipolar cyclization, and the major prodꢀ
uct (indolizine) is formed through the cyclization at posiꢀ
tion 6 of the pyridine ring (15 : 16 = 1 : 0.7, 19 : 20 =
ence of the conjugated system
.
Under the aboveꢀdescribed conditions, the reactions
of salts 5, 6, 8, and 9 with dimethyl acetylenedicarboxylate
in the presence of triethylamine afford 1,2,3,6ꢀ and
1,2,3,8ꢀtetrasubstituted indolizines 13—20 in 77—85%
yields (see Scheme 2). Compounds 13, 14, 15, and 18
were isolated in the individual state. The predominant
formation of either substituted 6ꢀpiperidylꢀ (13, 15, 17,
and 19) or 8ꢀpiperidylindolizines (14, 16, 18, and 20)
depends on the nature of the substituent at the nitrogen

142
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Musina et al.
C(16)
O(6)
C(6)
C(5)
C(7)
C(15)
N(1´)
C(8)
O(1)
C(9)
N(4)
C(3)
C(6´)
C(5´)
C(14)
C(1″)
C(2´)
O(3)
C(3´)
O(5)
C(6″)
C(1)
O(2)
C(2)
C(11)
O(4)
C(10)
C(12)
C(4´)
C(5″)
C(4″)
C(2″)
C(3″)
C(13)
Fig. 1. Threeꢀdimensional structure of one of the two independent molecules of compound 14.
position 1, we performed the detailed study of the reacꢀ
tion of pyridinium salts 5, 6, 8, and 9 with acrylonitrile.
The reaction carried out under standard conditions (salt :
acrylonitrile : Et3N = 1.0 : 1.0 : 1.1, 6—8 h) afforded
a mixture of tetrahydroindolizines, dihydroindolizines,
and indolizines 25—32. Mixtures of indolizines 25, 26
and 27, 28 were isolated in 70 and 84% yields, respecꢀ
tively, by alumina column chromatography. We failed to
precisely determine the ratio of isomeric indolizines beꢀ
cause of the complexity of the spectra of the reaction
mixture. Variations of the reaction conditions (an inꢀ
crease in the excess of acrylonitrile, the use of acetonitrile
as the solvent, a decrease in the ratio of the solvent to the
reagents by a factor of 2 and 4, the performance of the
reaction under argon) did not lead to an increase in the
yield of indolizines. Compounds 25 and 27 were isolated
by repeated column chromatography in the individual
state (in 39% and 46% yields, respectively). To determine
the ratio of isomeric indolizines, the reaction mixture,
which was prepared by the reaction of salt 9 with acryꢀ
lonitrile, was dehydrogenated with TPCD under the aboveꢀ
described conditions. As a result, we obtained a mixture
of indolizines 31 and 32 in a ratio of 2.5 : 1 (in 67% yield,
31 : 32 = 2.5 : 1). Compounds 29, 31, and 32 were isoꢀ
lated in the individual state. The reaction of salt 9 with
acrylonitrile in the presence of TPCD in DMF produced
6ꢀ and 8ꢀpiperidylꢀsubstituted indolizines 31 and 32 in
a total yield of 38% in a ratio of 1.3 : 1.0. The structures of
the resulting compounds were determined by spectroꢀ
scopy. The structure of 6ꢀsubstituted indolizine 31 was
established by Xꢀray diffraction (Fig. 2).
1 : 0.6). The ratio of the isomers was determined from the
1H NMR spectroscopic data for the reaction mixture.
8ꢀSubstituted indolizine 14 was characterized by Xꢀray
diffraction (Fig. 1). The substituent (phenyl or 4ꢀmethoxyꢀ
phenyl) in the acyl fragment of salts 5, 6 and 8, 9 has only
a slight effect on the composition and the yield of the
reaction products. Hence, the nature of the substituent at
the C(3) atom of the pyridine ring influences the cyclizaꢀ
tion pathway. The fact that it is important to take into
account the steric factor of the substituent at the C(3)
atom of the pyridine ring was mentioned in the studꢀ
ies,10,11 where the 1,3ꢀdipolar cycloaddition of
3ꢀmethylpyridinium dicyanomethylide and 3ꢀsubstituted
pyridinium Nꢀylides was discussed.
Under the aboveꢀdescribed conditions, the reactions
of pyridinium salts 5 or 6 with methyl acrylate are more
complex. These reactions produce mixtures of substituted
tetrahydroindolizines A and B and dihydroindolizines C
and D, which are transformed into completely dehydroꢀ
genated derivatives 21—24 (Scheme 3). The use of variꢀ
ous dehydrogenation reagents was documented.12—14 We
found that the treatment of the reaction mixtures with an
equimolar amount of tetrakisꢀpyridinecobalt(II) dichroꢀ
mate (TPCD) in DMF (90 °C, 2 h) with heating under the
conditions described in the study14 afforded a mixture of
isomeric indolizines 21, 22 (in 71% yield, in a ratio of
1 : 0.3) and 23, 24 (in 56% yield, in a ratio of 1 : 0.2), with
the cyclization products at the position of the pyridine
ring predominating. Compounds 21 and 23 were isolated
in the individual state. The compositions of the reaction
1
products were determined from the H NMR spectroꢀ
According to the Xꢀray diffraction data, the indolizine
fragment in molecules 14 and 31 is planar (the rms deviaꢀ
tions from the plane are 0.033 and 0.029 Å in two indeꢀ
scopic data for the reaction mixture.
With the aim of developing a procedure for the synꢀ
thesis of indolizines containing the nitrile substituents at

Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
143
Syntheses based on anabasine
Scheme 3
R = Ac (21, 22); COPh (23, 24); Ar = Ph, R = Ac (25, 26), COPh (27, 28); Ar = 4ꢀMeOC6H4, R = Ac (29, 30), COPh (31, 32)
indolizine fragment in molecules 14 and 31 are virtually
equalized, which is also observed in the closest analogs,
such as dimethyl 3ꢀbenzoylꢀ7ꢀ(N,Nꢀdimethylamino)indoꢀ
lizineꢀ1,2ꢀdicarboxylate,15 3ꢀacetylꢀ6ꢀnitroꢀ2ꢀphenylꢀ
indolizine,16 and 3ꢀ(4ꢀchlorobenzoyl)ꢀ7ꢀ(N,Nꢀdimethylꢀ
amino)ꢀ1ꢀphenylindolizine,17 found in the Cambridge
Structural Database. The geometric parameters for the
other fragments of compounds 14 and 31 are consistent
with the average parameters within 3σ.18 In the crystals,
molecules 14 and 31 form complex 3D architectures
through normal and slightly shortened intermolecular
O...H and N...H interactions. However, the stacks along
the a axis that are formed through πꢀstacking interactions
between the indolizine fragments of the adjacent molecuꢀ
les can be distinguished in the crystal packing of comꢀ
pound 31. The interplanar distance is 3.58 Å (the distance
between the centers of the fiveꢀ and sixꢀmembered rings is
3.94 Å; the corresponding angle is 0.5°). It should be
pendent molecules of 14 and 0.003 Å in 31). The angle
between the plane passing through the atoms of the carboꢀ
nyl group at the O(1) atom and the plane of the indolizine
fragment is 24.1(3) and 23.1(3)° in two independent molꢀ
ecules of compound 14 and 21.5 (3)° in molecule 31. The
dihedral angles between the carbonyl group and the pheꢀ
nyl ring are 48.8(3) and 48.3(3)° in 14 and 38.0(3)° in 31.
The piperidine ring in one of the two independent molꢀ
ecules of 14 and in molecule 31 adopts a chair conformaꢀ
tion. In another independent molecule of compound 14,
this ring partially (~35%) adopts a boat conformation (the
C(4´) atom is disordered over two positions in a ratio of
~0.35 : 0.65 for the C(4´) and C(4´B) atoms, respectively).
The angles between the planes of the carboxy groups at the
C(10) and C(11) atoms in the independent molecules of
compounds 14 and the plane of the indolizine fragment
are 33.7(3), 43.6(3)° and 77.9(3), 63.6(3)°, respectively.
The bond lengths in the fiveꢀmembered ring of the

144
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Musina et al.
C(15)
C(14)
C(13)
C(29)
N(10)
O(2)
C(12)
C(11)
C(6)
C(7)
C(5)
N(4)
O(1)
C(8)
C(28)
C(3)
C(17)
C(9)
C(1)
C(16)
C(2)
C(18)
C(19)
O(3)
C(30)
C(21)
N(31)
C(20)
C(32)
Fig. 2. Molecular structure of compound 31. The phenyl ring is disordered over two positions (C(21A)—C(26A) and C(21B)—C(26B) atoms)
13C) and Bruker DRXꢀ500 (500.13 MHz for 1H and 125.76 MHz
for 13C) spectrometers in CDCl3 and (CD3)2SO (for compound 7).
The assignment of the NMR signals was made based on the data
from protonꢀproton and carbonꢀproton chemical shift correlation
spectroscopy (COSY and COLOC). The mass spectra were obꢀ
tained on a Finnigan MATꢀ8200 highꢀresolution mass spectroꢀ
meter; the ionizing voltage was 70 eV. The Xꢀray diffraction studies
were carried out on a Bruker P4 diffractometer (graphiteꢀmonoꢀ
chromated MoꢀKα radiation, 2θ/θꢀscanning technique in the range
2θ < 52°). The melting points were determined on a Boetius hotꢀ
stage apparatus. The optical rotation was measured on
a Polamat A polarimeter at a wavelength of 578 nm at 20—23 °C.
The progress of the reactions was monitored by TLC on Silufol
UVꢀ254 plates; the compounds were visualized under UV light or
with iodine vapor. The reaction products were isolated by column
chromatography on silica gel (35—70 µm, AcrosꢀOrganics) or aluꢀ
minum oxide (50—150 µm, TU 6ꢀ09ꢀ3916ꢀ75, Russia; Brockmann
activity II).
noted that weak nonbonded interactions have attracted
considerable interest due to their important role in conꢀ
trolling the packing of organic molecules giving rise to
crystalline solids.
To summarize, the reactions of phenacylpyridinium
salts of Nꢀacylanabasines with unsaturated carbonyl comꢀ
pounds of the ethylene and acetylene series and acryloniꢀ
trile were studied for the first time. A procedure was
developed for the synthesis of piperidylꢀsubstituted
indolizines. It was found that the nature of the substituent
at the nitrogen atom of the piperidine ring influences the
cyclization pathway of phenacylpyridinium salts of anaꢀ
basine derivatives. For example, in the reaction of anaꢀ
basine derivatives with dimethyl acetylenedicarboxylate,
the presence of a bulky substituent favors an increase in
the yield of the cyclization product at the C(6) atom of
the pyridine ring. It was shown that tetrakisꢀ
pyridinecobalt(II) dichromate is a convenient reagent for
the dehydrogenation of 3ꢀ(piperidinꢀ2ꢀyl)dihydroꢀ and
tetrahydroindolizines.
Anabasine (1) was isolated from the plant Anabasis (Anabasis
Aphylla L.) according to a known procedure,19 [α]578 –72.3
23
(c 5.2, CHCl3). Freshly distilled solvents and reagents of highꢀ
purity grade were used. Commercial phenacyl bromide, ethyl
propiolate, dimethyl acetylenedicarboxylate, methyl acrylate (all
from Aldrich), acrylonitrile (Acros), and 2ꢀbromoꢀ4´ꢀmethoxyꢀ
acetophenone (Lancaster) were used. NꢀAcetylanabasine (2),
Nꢀbenzoylanabasine (3), and Nꢀmethylanabasine (4) were synꢀ
thesized according to known procedures.20—22
3ꢀ(1ꢀAcetylpiperidinꢀ2ꢀyl)ꢀ1ꢀphenacylpyridinium bromide
(5). A solution of phenacyl bromide (1.04 g, 5 mmol) in Et2O
(6.5 mL) was added with stirring to a solution of acetylanabasine 2
Experimental
The IR spectra were recorded on a VECTORꢀ22 instrument in
KBr pellets. The UV absorption spectra were measured on an HP
8453 UV Vis spectrometer in ethanol. The NMR spectra were reꢀ
corded on Bruker ACꢀ200 (200.13 MHz for 1H and 50.32 MHz for

Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
145
Syntheses based on anabasine
(1.05 g, 5 mmol) in Et2O (6.5 mL). The reaction mixture was stirred
at ~20 °C for 8.5 h. The precipitate was filtered off and washed with
Et2O. Compound 5 was obtained in a yield of 2.00 g (97%), m.p.
78–81 °C (diethyl ether (DEE)). 1H NMR (CDCl3), δ: 1.32—1.42
(m, 2 H, H(5´), H(5´)); 1.54—1.58 (m, 2H, H(4´), H(4´)); 1.73—
2 H, 2 H(5´)); 1.58—1.76 (m, 2 H, 2 H(4´)); 1.80—1.98 (m, 1 H,
H(3´)); 2.20 (s, 3 H, Me); 2.39 (d, 1 H, H(3´), Jgem = 13.7 Hz); 3.05
(t, 1 H, H(6´), Jgem = 13.2 Hz); 3.71 (d, 1 H, H(6´), Jgem = 13.2 Hz);
3.78 (s, 3 H, Me); 5.94 (s, 1 H, H(2´)); 6.86 (d, 2 H, H(3″), H(5″),
J = 8.9 Hz); 7.10 (q, 2 H, CH2, Jgem = 13.9 Hz); 7.96 (t, 1 H, H(5),
J1 = 6.7 Hz, J2 = 7.6 Hz); 8.03 (d, 2 H, H(2″), H(6″), J = 8.9 Hz);
8.24 (d, 1 H, H(4), J = 7.6 Hz); 9.12 (d, 1 H, H(6), J = 6.7 Hz); 9.22
(s, 1 H, H(2)). 13C NMR (CDCl3), δ: 19.06 (C(4´)); 21.89 (Me);
25.06 (C(5´)); 26.76 (C(3´)); 43.23 (C(6´)); 49.03 (C(2´)); 55.58
(Me); 66.24 (CH2); 114.26 (C(3″)); 114.26 (C(5″)); 126.08 (C(1″));
126.99 (C(5)); 131.19 (C(6″)); 131.26 (C(2″)); 141.42 (C(3)); 144.11
(C(4)); 144.74 (C(6)); 145.03 (C(2)); 164.65 (C(4″)); 170.71 (C=O);
188.22 (C=O). Found (%): C, 49.14; H, 5.46; N, 5.60; Br, 31.48.
C21H25N2O3Br•HBr. Calculated (%): C, 49.03; H, 5.06; N, 5.45;
Br, 31.13.
3ꢀ(1ꢀBenzoylpiperidinꢀ2ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenacyl)pyridiꢀ
nium bromide hemihydrate (9•0.5 H2O) (96% yield) was synthꢀ
esized from benzoylanabasine 3 according to the aboveꢀdescribed
procedure. M.p. 209—210 °C (DEE). 1H NMR (CDCl3), δ:
1.40—1.64 (m, 3 H, H(4´), 2 H(5´)); 1.65—1.82 (m, 1 H, H(4´));
1.89—2.09 (m, 1 H, H(3´)); 2.58 (d, 1 H, H(3´), Jgem = 13.8 Hz);
2.88 (br.t, 1 H, H(6´)); 3.78 (m, 4 H, Me, H(6´)); 5.92 (br.s, 1 H,
H(2´)); 6.87 (d, 2 H, H(3″), H(5″), J = 8.9 Hz); 7.15 (s, 2 H, CH2);
7.31—7.51 (m, 5 H, H(2″´), H(3″´), H(4″´), H(5″´), H(6″´)); 7.98
(t, 1 H, H(5), J1 = 6.1 Hz, J2 = 6.1 Hz); 8.05 (d, 2 H, H(2″), H(6″),
J = 8.9 Hz); 8.34 (d, 1 H, H(4), J = 6.1 Hz); 9.23 (d, 1 H, H(6), J =
6.1 Hz); 9.34 (s, 1 H, H(2)). 13C NMR (CDCl3), δ: 19.32 (C(4´));
25.18 (C(5´)); 26.87 (C(3´)); 42.56 (C(6´)); 50.61 (C(2´)); 55.54
(Me); 66.27 (CH2); 114.28 (C(3″)); 114.28 (C(5″)); 126.16 (C(1″));
126.64 (C(5)); 127.09 (C(4″´)); 128.45 (C(3″´)); 128.55 (C(5″´));
129.96 (C(6″´)); 130.03 (C(4″)); 131.19 (C(6″)); 131.26 (C(2″));
134.87 (C(1″´)); 140.85 (C(3)); 144.19 (C(4)); 144.89 (C(6)); 145.37
(C(2)); 164.70 (C(4″)); 171.77 (C=O); 188.22 (C=O). Found (%):
C, 61.56; H, 5.58; N, 5.37; Br, 15.61. C26H27N2O3Br•0.5H2O.
Calculated (%): C, 61.90; H, 5.55; N, 5.55; Br, 15.87.
1.87 (m, 1 H, H(3´)); 2.10 (s, 3 H, Me); 2.30 (d, 1 H, H(3´), Jgem
=
12.4 Hz); 2.98 (t, 1 H, H(6´), Jgem = 12.4 Hz); 3.68 (d, 1 H, H(6´),
Jgem = 12.4 Hz); 5.81 (s, 1 H, H(2´)); 7.00 (q, 2 H, CH2, Jgem = 14.8
Hz); 7.33 (t, 2 H, Ph, H(3″), H(5″), J = 7.6 Hz); 7.47 (t, 1 H, Ph,
H(4″), J = 7.6 Hz); 7.92 (dd, 1 H, H(5), J1 = 5.2 Hz, J2 = 8.0 Hz);
7.96 (d, 2 H, Ph, H(2″), H(6″), J = 7.6 Hz); 8.22 (d, 1 H, H(4), J =
8.0 Hz); 9.07 (d, 1 H, H(6), J = 5.2 Hz); 9.15 (s, 1 H, H(2)).
13C NMR (CDCl3), δ: 18.82 (C(4´)); 21.75 (Me); 24.79 (C(5´));
26.75 (C(3´)); 43.04 (C(6´)); 48.95 (C(2´)); 66.44 (CH2); 127.20
(C(5)); 128.51 (C(3″), C(5″)); 128.76 (C(2″), C(6″)); 133.08 (C(1″));
134.44 (C(4″)); 141.14 (C(3)); 144.11 (C(4)); 144.57 (C(2)); 144.63
(C(6)); 170.66 (C=O); 190.06 (C=O). IR (KBr), ν/cm–1: 1696.8
(C=O), 1632.9 (N—(C=O)). Found (%): C, 59.85; H, 5.80; N,
6.66; Br, 19.40. C20H23N2O2Br. Calculated (%): C, 59.54; H,
5.70; N, 6.94; Br, 19.85.
3ꢀ(1ꢀBenzoylpiperidinꢀ2ꢀyl)ꢀ1ꢀphenacylpyridinium bromide
(6) (79% yield) was synthesized from benzoylanabasine 3 accordꢀ
ing to the aboveꢀdescribed procedure. M.p. 108–110 °C (DEE).
1H NMR (CDCl3), δ: 1.30—1.72 (m, 4 H, 2 H(4´), 2 H(5´)); 1.76—
1.95 (m, 1 H, H(3´)); 2.39—2.55 (m, 1 H, H(3´)); 2.65—2.91 (m,
1 H, H(6´)); 3.53—3.87 (m, 1 H, H(6´)); 5.78 (br.s, 1 H, H(2´));
7.04 (s, 2 H, CH2); 7.25—7.52 (m, 8 H, Ph); 7.91—8.02 (m, 3 H,
Ph, H(5)); 8.29 (d, 1 H, H(4), J = 8.0 Hz); 9.21 (d, 1 H, H(6), J =
5.4 Hz); 9.34 (s, 1 H, H(2)). 13C NMR (CDCl3), δ: 19.14 (C(4´));
25.08 (C(5´)); 26.66 (C(3´)); 44.10 (C(6´)); 49.79 (C(2´)); 66.45
(CH2); 126.57 (C(5)); 127.24 (C(4″´)); 128.45 (C(3″´), C(5″´));
128.55 (C(3″), C(5″)); 128.78 (C(2″), C(6″)); 129.93 (C(2″´), C(6″´));
133.08 (C(1″)); 134.48 (C(4″)); 134.64 (C(1″´)); 140.53 (C(3));
144.10 (C(4)); 144.76 (C(6)); 145.06 (C(2)); 171.59 (C=O); 190.04
(C=O). IR (KBr), ν/cm–1: 1696.5 (C=O), 1626.4 (N—(C=O)).
Found (%): C, 64.32; H, 5.43; N, 6.05; Br, 17.19. C25H25N2O2Br.
Calculated (%): C, 64.50; H, 5.37; N, 6.02; Br, 17.20.
3ꢀ(1ꢀMethylpiperidinꢀ2ꢀyl)ꢀNꢀphenacylpyridinium bromide
(7) (59% yield) was synthesized from methylanabasine 4 according
to the aboveꢀdescribed procedure. M.p. 197—197.5 °C (ethanol).
1H NMR ((CD)3SO), δ: 1.24—1.52 (m, 2 H, H(5´), H(5´)); 1.53—
1.72 (m, 2 H, H(4´), H(4´)); 1.79—1.92 (m, 1 H, H(3´)); 2.40 (d,
1 H, H(3´), Jgem = 14 Hz); 3.06 (t, 1 H, H(6´), Jgem = 14 Hz); 3.29 (s,
3 H, Me); 3.68 (d, 1 H, H(6´), Jgem = 14 Hz); 5.68 (br.s, 1 H, H(2´));
6.51 (s, 2 H, CH2); 7.63 (t, 2 H, Ph, H(3″), H(5″), J = 7.7 Hz); 7.77
(t, 1 H, Ph, H(4″), J = 7.4 Hz); 8.05 (d, 2 H, Ph, H(2″), H(6″), J =
7.4 Hz); 8.25 (dd, 1 H, H(5), J1 = 8.2 Hz, J2 = 7.9 Hz); 8.59 (d, 1 H,
H(4), J = 8.2 Hz); 8.92 (d, 1 H, H(6), J = 7.9 Hz); 8.94 (s, 1 H,
H(2)). 13C NMR ((CD)3SO), δ: 19.79 (C(4´)); 24.92 (C(5´)); 27.41
(C(3´)); 42.94 (C(6´)); 47.96 (Me); 54.21 (C(2´)); 66.92 (CH2);
128.15 (C(5)); 128.76 (C(3″), C(5″)); 129.56 (C(2″), C(6″)); 134.16
(C(1″)); 135.17 (C(4″)); 140.36 (C(3)); 145.25 (C(4)); 163.09 (C(6));
163.58 (C(2)); 191.03 (C=O). IR (KBr), ν/cm–1: 1691.6 (C=O),
1660.0 (N—(C=O)). Found (%): C, 61.03; H, 6.27; N, 7.25; Br,
21.17. C19H23N2OBr. Calculated (%): C, 60.80; H, 6.13; N, 7.46;
Br, 21.33.
3ꢀ(1ꢀAcetylpiperidinꢀ2ꢀyl)ꢀ1ꢀmethylpyridinium bromide
(10). A. Potassium carbonate (0.4 g) was added with stirring to a
solution of salt 5 (0.70 g, 1.7 mmol) in ethanol (8 mL). The reaction
mixture was stirred at ~20 °C for 6 h. Then the precipitate was
filtered off, and the mother liquor was concentrated. Benzaldehyde
(0.04 g) (chloroform as the eluent), acetylanabasine (0.18 g, 52%)
(chloroform—ethanol, 100 : 5, as the eluent), and 3ꢀ(1ꢀacetylpiꢀ
peridinꢀ2ꢀyl)ꢀ1ꢀmethylpyridinium bromide (10) (0.22 g, 42%)
(chloroform—ethanol, 10 : 1, as the eluent) were successively isoꢀ
lated from the residue by column chromatography.
B. Triethylamine (2.09 g, 20.7 mmol) was added with stirring to
a solution of salt 5 (0.70 g, 1.7 mmol) in 1,2ꢀdichloroethane
(15 mL), and the reaction mixture was allowed to stand overnight
for 16 h. The precipitate was filtered off, and the mother liquor was
concentrated. Benzaldehyde (0.18 g), acetylanabasine (0.20 g, 57%),
and 3ꢀ(1ꢀacetylpiperidinꢀ2ꢀyl)ꢀ1ꢀmethylpyridinium bromide (10)
(0.12 g, 23% yield) were successively isolated from the residue by
1
column chromatography. H NMR (CDCl3), δ: 1.36—1.52 (m,
2 H, H(5´), H(5´)); 1.69 (d, 2 H, H(4´), H(4´), J = 8 Hz); 1.79—
1.91 (m, 1 H, H(3´)); 2.14 (s, 3 H, Me); 2.36 (d, 1 H, H(3´), Jgem
=
12.4 Hz); 3.11 (t, 1 H, H(6´), Jgem = 11.2 Hz); 3.68 (d, 1 H, H(6´),
Jgem = 11.2 Hz); 4.64 (s, 3 H, Me); 5.79 (s, 1 H, H(2´)); 7.96—8.03
(m, 1 H, H(5)); 8.20 (d, 1 H, H(4), J = 6.8 Hz); 9.14 (s, 1 H, H(6),
J = 5.4 Hz); 9.19 (s, 1 H, H(2)). 13C NMR (CDCl3), δ: 18.84
(C(4´)); 21.75 (Me); 24.60 (C(5´)); 26.82 (C(3´)); 43.13 (C(6´));
48.85 (C(2´)); 49.13 (Me); 127.73 (C(5)); 141.90 (C(3)); 143.18
3ꢀ(1ꢀAcetylpiperidinꢀ2ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenacyl)pyridiꢀ
nium bromide hydrobromide (8•HBr) (91% yield) was synthesized
according to the aboveꢀdescribed procedure by the reaction of
acetylanabasine 2 with 4ꢀmethoxyphenacylpyridinium bromide.
M.p. 105—109 °C (DEE). 1H NMR (CDCl3), δ: 1.36—1.55 (m,

146
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Musina et al.
(C(4)); 143.71 (C(6)); 143.79 (C(2)); 170.57 (C=O). Found (%):
C, 52.46; H, 6.42; N, 9.08; Br, 27.30. C13H19N2OBr. Calculated
(%): C, 52.17; H, 6.35; N, 9.36; Br, 26.75.
(COOC2H5), 1617.6 (
), 1706.4 (C=O). MS, m/z
(Irel (%)): 418.2 [M]+ (15.96), 375.1 (69.59), 345.2 (2.04), 329.1
(100.0), 274.2 (1.71), 105.1 (45.19), 77.1 (15.47). Found: m/z
418.18807 [M]+. C25H26N2O4. Calculated: M = 418.18924.
Under the aboveꢀdescribed conditions, the reaction of comꢀ
pound 5 (0.60 g, 1.5 mmol) with dimethyl acetylenedicarboxylate
afforded a mixture of dimethyl 6ꢀ(1ꢀacetylpiperidinꢀ2ꢀyl)ꢀ3ꢀ
benzoylindolizineꢀ1,2ꢀdicarboxylate (13) and dimethyl 8ꢀ(1ꢀ
acetylpiperidinꢀ2ꢀyl)ꢀ3ꢀbenzoylindolizineꢀ1,2ꢀdicarboxylate
(14) in a yield of 0.56 g (82%) (13 : 14 = 0.4 : 1). Indolizines 13 and
14 were successively isolated in the individual state by alumina
column chromatography.
Reaction of 3ꢀ(1ꢀacylpyridinꢀ2ꢀyl)ꢀ1ꢀphenacylpyridinium
bromides (5, 6, 8, and 9) with acetylenecarboxylates (general
procedure). Ethyl propiolate (0.23 g, 0.24 mL, 2.4 mmol) and a
solution of triethylamine (0.22 g, 0.30 mL, 2.2 mmol) in CH2Cl2
(7 mL) were added with stirring to a solution of salt 5 (0.87 g,
2.2 mmol) in CH2Cl2 (14 mL) for 30 min. The reaction mixture
was stirred at room temperature for 9 h. After completion of the
reaction, the mixture was treated with water (50 mL), and aqueous
ammonia was added with stirring to pH 11. After 5 min, a 0.34 M
aqueous H2SO4 solution was added to pH 2. Then an ammonia
solution was added to pH 12, the organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (5Ѕ15 mL). The
organic layers were combined, dried over MgSO4, and concenꢀ
trated. A mixture of compounds 11 and 12 (in a ratio of 1 : 1) was
isolated from the residue by alumina column chromatography (chloꢀ
roform—ethanol, 50 : 1, as the eluent) in a yield of 0.55 g (75%).
Ethyl 3ꢀbenzoylꢀ6ꢀ(1ꢀbenzoylpiperidinꢀ2ꢀyl)ꢀindolizineꢀ1ꢀcarꢀ
boxylate (11) (hexane—chloroform, 1 : 1, as the eluent) and ethyl
3ꢀbenzoylꢀ8ꢀ(1ꢀbenzoylpiperidinꢀ2ꢀyl)indolizineꢀ1ꢀcarboxylate
(12) (hexane—chloroform, 10 : 1, as the eluent) were isolated in the
individual state by repeated column chromatography.
Compound 11, m.p. 73—75 °C (DEE). 1H NMR (CDCl3), δ:
1.36 (t, 3 H, Me); 1.46—1.80 (m, 4 H, 2 H(4´), 2 H(5´)); 1.95 (br.t,
1 H, H(3´), Jgem = 13.6 Hz); 2.34 (s, 3 H, Me); 2.39 (br.d, 1 H,
H(3´), Jgem = 13.6 Hz); 3.14 (br.t, 1 H, H(6´), Jgem = 12.2 Hz); 3.74
(br.d, 1 H, H(6´), Jgem = 12.2 Hz); 4.34 (q, 2 H, CH2); 6.06 (br.s,
1 H, H(2´)); 7.30 (d, 1 H, H(7), J = 9.3 Hz); 7.45—7.59 (m, 3 H,
H(3″), H(4″), H(5″)); 7.78 (d, 2 H, H(2″), H (6″), J = 7.7 Hz); 7.77
(s, 1 H, H(2)); 8.31 (d, 1 H, H(8), J = 9.3 Hz); 9.87 (s, 1 H, H(5)).
13C NMR (CDCl3), δ: 14.40 (Me); 19.24 (C(4´)); 21.73 (Me);
25.81 (C(5´)); 26.79 (C(3´)); 42.90 (C(6´)); 48.66 (C(2´)); 60.04
(CH2); 106.27 (C(1)); 119.48 (C(8)); 122.46 (C(6)); 126.72 (C(5));
127.51 (C(3)); 128.06 (C(7)); 128.32 (C(3″), (C(5″)); 128.84 (C(2″),
(C(6″)); 129.04 (C(4″)); 131.45 (C(2)); 138.61 (C(9)); 139.72
(C(1″)); 163.89 (C=O); 170.04 (C=O); 185.67 (C=O). UV (ЕtOH),
Compound 13, m.p. 69—71 °C (hexane). 1H NMR (CDCl3),
δ: 1.47—1.83 (m, 4 H, 2 H(4´), 2 H(5´)); 1.94 (br.t, 1 H, H(3´), Jgem
= 13.4 Hz); 2.23 (s, 3 H, Me); 2.34 (br.d, 1 H, H(3´), Jgem
=
13.4 Hz); 3.13 (br.t, 1 H, H(6´), Jgem = 13.1 Hz); 3.28 (s, 3 H, Me);
3.75 (br.d, 1 H, H(6´), Jgem = 13.1 Hz); 3.85 (s, 3 H, Me); 6.06 (br.s,
1 H, H(2´)); 7.32 (d, 1 H, H(7), J = 9.3 Hz); 7.43 (t, 2 H, H(3″),
H(5″), J = 7.3 Hz); 7.53 (t, 1 H, H(4″), J = 7.3 Hz); 7.67 (d, 2 H,
H(2″), H (6″), J = 7.3 Hz); 8.31 (d, 1 H, H(8), J = 9.3 Hz); 9.50
(s, 1 H, H(5)). 13C NMR (CDCl3), δ: 19.15 (C(4´)); 21.63 (Me);
26.68 (C(5´)); 29.52 (C(3´)); 42.84 (C(6´)); 48.59 (C(2´)); 51.49
(Me); 52.03 (Me); 103.95 (C(1)); 119.93 (C(8)); 120.75 (C(6));
126.04 (C(5)); 128.00 (C(3″), C(5″)); 128.14 (C(3)); 128.26 (C(7));
128.36 (C(2)); 128.51 (C(2″), C(6″)); 131.76 (C(4″)); 137.02 (C(9));
139.44 (C(1″)); 163.16 (C=O); 164.97 (C=O); 170.03 (C=O);
186.85 (C=O). UV (ЕtOH), λmax/nm (ε): 240 (24728), 281 (179186),
367 (134058). IR (KBr), ν/cm–1: 1221.8 (CO2Me), 1639.2
(
), 1707.1, 1740.8 (C=O). MS, m/z (Irel (%)): 462.2
[M]+ (8.72), 444.3 (5.61), 419.2 (10.76), 387.2 (100.0), 312.1 (1.38),
274.1 (5.01), 105.1 (12.74), 77.0 (12.16). Found: m/z 462.17690
[M]+. C26H26N2O6. Calculated: M = 462.17505.
Compound 14, m.p. 164—165 °C (DEE). 1H NMR (CDCl3),
δ: 1.41—1.60 (m, 2 H, 2H(4´)); 1.62—1.93 (m, 4 H, 2 H(3´),
2 H(5´)); 2.09 (s, 3 H, Me); 3.04 (br.t, 1 H, H(6´), Jgem = 12.2 Hz);
3.20 (s, 3 H, Me); 3.82 (s, 3 H, Me); 4.71 (br.d, 1 H, H(6´), Jgem
=
12.2 Hz); 6.21 (br.s, 1 H, H(2´)); 6.99 (t, 1 H, H(6), J = 6.9 Hz,
6.9 Hz); 7.15 (d, 1 H, H(7), J = 6.9 Hz); 7.43 (t, 2 H, H(3″), H(5″),
J = 7.2 Hz); 7.53 (t, 1 H, H(4″), J = 7.2 Hz); 7.68 (d, 2 H, H(2″), H
(6″), J = 7.2 Hz); 9.38 (d, 1 H, H(5), J = 6.9 Hz). 13C NMR
(CDCl3), δ: 19.55 (C(4´)); 22.56 (Me); 24.94 (C(5´)); 29.88 (C(3´));
40.50 (C(6´)); 52.74 (Me); 53.35 (Me); 53.91 (C(2´)); 108.06 (C(1));
115.62 (C(5)); 121.73 (C(8)); 124.80 (C(6)); 127.33 (C(7)); 129.04
(C(3″)); 129.04 (C(5″)); 129.49 (C(2″)); 129.49 (C(6″)); 130.84
(C(2)); 133.03 (C(4″)); 133.56 (C(3)); 135.07 (C(9)); 140.58 (C(1″));
165.54 (C=O); 165.59 (C=O); 173.06 (C=O); 187.49 (C=O).
UV (ЕtOH), λmax/nm (ε): 238 (27144), 371 (11906). IR (KBr),
λmax/nm (ε): 241 (25589), 284 (21580), 333 (10892), 368 (16491).
IR (KBr), ν/cm–1: 1219.2 (COOC2H5), 1612.7 (
),
1697.9 (C=O). MS, m/z (Irel (%)): 418.3 [M]+ (19.71), 400.2
(15.78), 375.2 (100.0), 274.2 (1.96), 105.1 (27.94), 77.1 (9.39).
Found: m/z 418.18890 [M]+. C25H26N2O4. Calculated: M =
418.18924.
Compound 12, m.p. 129—130 °C (DEE). 1H NMR (CDCl3),
δ: 1.34 (t, 3 H, Me); 1.44—1.80 (m, 4 H, 2 H(4″), 2 H(5″)); 1.81—
1.97 (m, 2 H, 2 H(3″)); 2.09 (s, 3 H, Me); 3.06 (br.t, 1 H, H(6´),
Jgem = 13.5 Hz); 4.22—4.28 (m, 2 H, CH2); 4.72 (br.d, 1 H, H(6´),
Jgem = 13.5 Hz); 6.69 (br.s, 1 H, H(2´)); 7.07 (t, 1 H, H(6), J1 =
6.8 Hz, J2 = 7.1 Hz); 7.21 (d, 1 H, H(7), J = 6.8 Hz); 7.51 (d, 2 H,
H(3″), H(5″), J = 7.2 Hz); 7.59 (t, 1 H, H(4″), J = 7.2 Hz); 7.80 (d,
2 H, H(2″), H(6″), J = 7.2 Hz); 7.81 (s, 1 H, H(2)); 9.96 (d, 1 H,
H(5), J = 7.1 Hz). 13C NMR (CDCl3), δ: 14.30 (Me); 18.51 (C(4´));
21.79 (Me); 24.00 (C(5´)); 29.49 (C(3´)); 39.51 (C(6´)); 53.56
(C(2´)); 60.63 (CH2); 108.01 (C(1)); 114.48 (C(5)); 122.07 (C(8));
124.78 (C(6)); 127.87 (C(7)); 128.27 (C(3″), C(5″)); 128.89 (C(2″)),
C(6″)); 130.83 (C(4″)); 131.49 (C(2)); 132.24 (C(3)); 135.88
(C(1″)); 139.74 (C(9)); 163.88 (C=O); 172.25 (C=O); 185.24
(C=O). UV (ЕtOH), λmax/nm (ε): 236 (222778), 260 (190821), 282
(156347), 332 (92249), 368 (153305). IR (KBr), ν/cm–1: 1192.3
ν/cm–1: 1226.6 (CO2Me); 1630.3 (
); 1711.1,
1739.8 (C=O). MS, m/z (Irel (%)): 462.2 [M]+ (8.72), 419.2 (17.87),
387.1 (100.0), 274.2 (2.60), 105.1 (17.49), 77.1 (13.34). Found:
m/z 462.18150 [M]+. C26H26N2O6. Calculated: M = 462.17907.
Under the aboveꢀdescribed conditions, the reaction of comꢀ
pound 6 (0.60 g, 1.3 mmol) with dimethyl acetylenedicarboxylate
afforded a mixture of dimethyl 3ꢀbenzoylꢀ6ꢀ(1ꢀbenzoylpiperidinꢀ
2ꢀyl)indolizineꢀ1,2ꢀdicarboxylate (15) and dimethyl 3ꢀbenzoylꢀ
8ꢀ(1ꢀbenzoylpiperidinꢀ2ꢀyl)indolizineꢀ1,2ꢀdicarboxylate (16) in
a yield of 0.52 g (77%) (15 : 16 = 1 : 0.7). Compound 15 was
isolated by alumina column chromatography, m.p. 145—148 °C
(DEE). 1H NMR (CDCl3), δ: 1.53—1.76 (m, 3 H, H(4´), 2 H(5´));

Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
147
Syntheses based on anabasine
3 H, Me); 3.84 (s, 3 H, Me); 6.02 (br.s, 1 H, H(2´)); 6.82—6.98 (m,
2 H, H(3″), H(5″)); 7.26 (d, 1 H, H(7), J = 8.9 Hz); 7.67 (d, 2 H,
H(2″), H(6″), J = 7.7 Hz); 8.27 (d, 1 H, H(8), J = 8.9 Hz); 9.29
(s, 1 H, H(5)).
1.77—1.85 (m, 1 H, H(4´)); 2.07 (br.t, 1 H, H(3´), Jgem = 13.3 Hz);
2.43 (br.d, 1 H, H(3´), Jgem = 13.3 Hz); 3.00 (br.t, 1 H, H(6´),
Jgem = 11.7 Hz); 3.29 (s, 3 H, Me); 3.86 (m, 4 H, H(6´), Me); 6.08
(br.s, 1 H, H(2´)); 7.38—7.56 (m, 9 H, H(7), H(3″), H(4″), H(5″),
H(2″´), H(3″´), H(4″´), H(5″´), H(6″´)); 7.67 (d, 2 H, H(2″), H(6″),
J = 7.1 Hz); 8.32 (d, 1 H, H(8), J = 9.3 Hz); 9.66 (s, 1 H, H(5)).
13C NMR (CDCl3), δ: 19.39 (C(4´)); 25.83 (C(5´)); 27.34 (C(3´));
43.21 (C(6´)); 49.15 (C(2´)); 51.59 (Me); 52.12 (Me); 104.03 (C(1));
120.11 (C(8)); 120.82 (C(6)); 126.23 (C(7)); 126.74 (C(5)); 127.97
(C(2)); 128.03 (C(3″), C(5″)); 128.56 (C(2″), C(6″), C(3″´), C(4″´),
C(5″´)); 129.66 (C(4″)); 131.81 (C(2″´), C(6″´)); 132.76 (C(3));
135.79 (C(1″)); 137.01 (C(9)); 139.44 (C(1″´)); 163.19 (C=O);
164.99 (C=O); 171.49 (C=O); 186.83 (C=O). UV (ЕtOH),
Under the aboveꢀdescribed conditions, the reaction of salt 9
(0.61 g, 1.5 mmol) with dimethyl acetylenedicarboxylate afforded a
mixture of dimethyl 6ꢀ(1ꢀbenzoylpiperidinꢀ2ꢀyl)ꢀ3ꢀ(4ꢀmethoxyꢀ
benzoyl)indolizineꢀ1,2ꢀdicarboxylate (19) and dimethyl 8ꢀ(1ꢀ
benzoylpiperidinꢀ2ꢀyl)ꢀ3ꢀ(4ꢀmethoxybenzoyl)indolizineꢀ1,2ꢀ
dicarboxylate (20) in a yield of 0.54 g (79%) (19 : 20 = 1 : 0.6).
1H NMR of a mixture of indolizines (CDCl3), δ: 6.15 (br.s, 1 H,
H(2´) (19)); 6.21 (br.s, 1 H, H(2´) (20)); 6.91—6.99 (m, 4 H,
H(4″), H(5″) (19)), H(4″), H(5″) (20)); 7.03 (t, 1 H, H(6), J =
7.06 Hz, (20)); 7.30—7.56 (m, 12 H, H(2″´), H(3″´), H(4″´),
H(5″´), H(6″´), H(7) (19 and 20)); 7.70—7.78 (m, 4 H, H(2″),
H(6″) (19 and 20)); 8.38 (d, 1 H, H(8), J = 9.4 Hz (19)); 9.22 (d,
1 H, H(5), J = 7.06 Hz (20)); 9.49 (s, 1 H, H(5) (19)).
Methyl 6ꢀ(1ꢀacetylpiperidinꢀ2ꢀyl)ꢀ3ꢀbenzoylindolizineꢀ1ꢀ
carboxylate (21). Under the aboveꢀdescribed conditions, the reacꢀ
tion of pyridinium salt 5 (0.62 g, 1.54 mmol) with methyl acrylate
afforded a mixture of indolizines (1H NMR) in a yield of 0.55 g
(87%). Tetrakisꢀpyridinecobalt(II) dichromate (0.31 g) was added
to this mixture (0.37 g) in DMF (2.5 mL). The reaction mixture
was stirred at 90 °C for 2 h, cooled, and treated with a 5% HCl
solution (14 mL). The product was extracted with chloroform. The
extract was dried over MgSO4 and concentrated. The residue
(0.26 g) was chromatographed on alumina, and a mixture of 8ꢀ and
6ꢀsubstituted derivatives of indolizine was isolated in a yield of 71%
in a ratio of 1 : 0.3, respectively. Compound 21 was isolated from
the mixture by additional alumina column chromatography,
m.p. 110—112 °C (diethyl ether). 1H NMR (CDCl3), δ: 1.53—1.81
(m, 4 H, 2 H(4´), 2 H(5´)); 1.84—2.06 (m, 1 H, H(3´)); 2.25 (s, 3 H,
Me); 2.38 (d, 1 H, H(3´), Jgem = 12.5 Hz); 3.15 (t, 1 H, H(6´),
Jgem = 12.5 Hz); 3.75 (d, 1 H, H(6´), Jgem = 12.5 Hz); 3.87 (s, 3 H,
Me); 6.08 (s, 1 H, H(2´)); 7.31 (d, 1 H, H(7), J = 9 Hz); 7.44—7.52
(m, 2 H, H(3″), H(5″)); 7.52—7.59 (m, 1 H, H(4″)); 7.77 (s, H,
H(2)); 7.78 (d, 2 H, H(2″), H(6″), J = 6.7 Hz); 8.31 (d, 1 H, H(8),
J = 9 Hz); 9.87 (s, 1 H, H(5)). 13C NMR (CDCl3), δ: 19.26 (C(4´));
21.65 (Me); 25.81 (C(5´)); 26.83 (C(3´)); 42.89 (C(6´)); 48.69
(C(2´)); 51.15 (Me); 105.86 (C(1)); 119.41 (C(8)); 122.53 (C(6));
126.74 (C(5)); 127.68 (C(3)); 128.11 (C(7)); 128.31 (C(3″)); 128.31
(C(5″)); 128.82 (C(6″)); 128.89 (C(2″)); 128.98 (C(4″)); 131.44
(C(2)); 138.65 (C(9)); 139.73 (C(1″)),; 164.22 (C=O); 169.98
(C=O); 185.66 (C=O). IR (KBr), ν/cm–1: 1223.0 (CO2Me), 1615.0
λmax/nm (ε): 245 (30216), 281 (15637), 333 (10049), 366 (11592).
IR (KBr), ν/cm–1: 1224.2 (COOMe), 1627.8 (
),
1706.6, 1741.2 (C=O). MS, m/z (Irel (%)): 524.9 [M]+ (3.73),
506.8 (4.42), 419.9 (6.62), 386.7 (100.0), 104.8 (51.30), 76.9 (33.44).
Found: m/z 524.19839 [M]+. C31H28N2O6. Calculated:
M = 524.19472. The 1H NMR spectrum of compound 16 (data
were obtained from the spectrum of a mixture of compounds 15 : 16
= 0.4 : 1) (CDCl3), δ: 1.50—2.00 (m, 6 H, 2 H(3´), 2 H(4´),
2 H(5´)); 3.17 (s, 3 H, Me); 3.33 (m, 1 H, H(6´)); 3.64 (br.s, 3 H,
Me); 4.78 (m, 1 H, H(6´)); 6.15 (br.s, 1 H, H(2´)); 7.05 (t, 1 H,
H(6), J = 7.0 Hz); 7.28—7.56 (m, 9 H, H(7), H(3″), H(4″), H(5″),
H(2″´), H(3″´), H(4″´), H(5″´), H(6″´)); 7.66 (d, 2 H, H(2″),
H (6″), J = 7.2 Hz); 9.42 (d, 1 H, H(5), J = 7.0 Hz).
Under the aboveꢀdescribed conditions, the reaction of 3ꢀ(1ꢀ
acetylpiperidinꢀ2ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenacyl)pyridinium bromide
(8) (0.64 g, 1.5 mmol) with dimethyl acetylenedicarboxylate afꢀ
forded a mixture of dimethyl 6ꢀ(1ꢀacetylpiperidinꢀ2ꢀyl)ꢀ3ꢀ(4ꢀ
methoxybenzoyl)indolizineꢀ1,2ꢀdicarboxylate (17) and dimethyl
8ꢀ(1ꢀacetylpiperidinꢀ2ꢀyl)ꢀ3ꢀ(4ꢀmethoxybenzoyl)indolizineꢀ
1,2ꢀdicarboxylate (18) in a yield of 0.62 g (85%) (17 : 18 = 0.5 : 1).
Compound 18 was isolated from the mixture of the products by
alumina column chromatography, m.p. 87—90 °C (hexane). 1H
NMR (CDCl3), δ: 1.42—1.58 (m, 2 H, 2 H(4´)); 1.68—1.90 (m, 4
H, 2 H(3´), 2 H(5´)); 2.08 (s, 3 H, Me); 3.03 (br.t, 1 H, H(6´),
Jgem = 12.5 Hz); 3.30 (s, 3 H, Me); 3.82 (s, 3 H, Me); 3.84 (s, 3 H,
Me); 4.69 (br.d, 1 H, H(6´), Jgem = 12.5 Hz); 6.18 (br.s, 1 H, H(2´));
6.92 (t, 1 H, H(6), J = 6.9 Hz); 6.90 (d, 2 H, H(3″), H(5″), J = 8.6
Hz); 7.07 (d, 1 H, H(7), J = 6.9 Hz); 7.70 (d, 2 H, H(2″), H (6″), J
= 8.6 Hz); 9.12 (d, 1 H, H(5), J = 6.9 Hz). 13C NMR (CDCl3),
δ: 18.64 (C(4´)); 21.73 (Me); 24.06 (C(5´)); 29.98 (C(3´)); 39.71
(C(6´)); 52.06 (Me); 52.53 (Me); 53.08 (C(2´)); 55.41 (Me); 106.82
(C(1)); 113.53 (C(3″), C(5″)); 114.34 (C(5)); 121.67 (C(8)); 123.32
(C(6)); 126.14 (C(7)); 128.62 (C(2)); 131.12 (C(2″), C(6″)); 132.25
(C(1″)); 133.02 (C(3)); 134.14 (C(9)); 163.23 (C(4″)); 164.89
(C=O); 165.01 (C=O); 172.23 (C=O); 185.46 (C=O). UV (ЕtOH),
(
), 1701.9 (C=O). UV (ЕtOH), λmax/nm (ε): 241
(10552), 284 (8900), 332 (4391), 367 (6809). MS, m/z (Irel (%)):
404.1 [M]+ (20.18), 386.2 (19.94), 361.1 (100.0), 105.0 (35.91),
77.0 (11.68). Found: m/z 404.17415 [M]+. C24H24N2O4. Calcuꢀ
lated: M = 404.17359.
λ
max/nm (ε): 236 (25728), 285 (15148), 369 (12029). IR (KBr),
Methyl 3ꢀbenzoylꢀ6ꢀ(1ꢀbenzoylpiperidinꢀ2ꢀyl)indolizineꢀ1ꢀ
carboxylate (23). Under the aboveꢀdescribed conditions, the reacꢀ
tion of salt 6 (0.65 g, 1.39 mmol) with methyl acrylate in the
presence of triethylamine (0.16 g, 0.22 mL, 1.54 mmol) afforded a
mixture of products in a yield of 0.64 g (98%). Tetrakisꢀpyriꢀ
dinecobalt(II) dichromate (0.60 g) was added to this mixture
(0.64 g) in DMF (4.8 mL). The reaction mixture was stirred at
90 °C for 2 h, cooled, and treated with a 5% HCl solution (40 mL).
The precipitate was filtered off. A mixture of 8ꢀ and 6ꢀsubstituted
derivatives of indolizine was isolated by alumina column chromaꢀ
ν/cm–1: 1224.2 (COOMe), 1626.3 (
), 1599.6,
1732.7 (C=O). MS, m/z (Irel (%)): 492.2 [M]+ (15.81), 461.1 (1.11),
449.1 (18.89), 417.1 (100), 135.1 (20.64), 77.1 (4.35). Found:
m/z 492.18950 [M]+. C27H28N2O7. Calculated: M = 492.18964.
The 1H NMR spectrum of compound 17 (data were obtained from
the spectrum of a mixture of compounds 17 : 18 = 1 : 2) (CDCl3),
δ: 1.40—1.92 (m, 5 H, H(3´), 2 H(4´), 2 H(5´)); 2.19 (s, 3 H, Me);
2.31 (d, 1 H, H(3´), Jgem = 12.9 Hz); 3.08 (br.t, 1 H, H(6´),
Jgem = 14.6 Hz); 3.37 (s, 3 H, Me); 3.72 (m, 1 H, H(6´)); 3.81 (s,

148
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Musina et al.
tography in a yield of 0.37 g (56%) in a ratio of 1 : 0.2, respectively.
Compound 23 was isolated from the mixture by additional alumina
column chromatography, m.p. 76—79 °C (diethyl ether). 1H NMR
(CDCl3), δ: 1.46—1.68 (m, 2 H, H(5´), H(5´)); 1.68—1.77 (m,
1 H, H(4´)); 1.77—1.88 (m, 1 H, H(4´)); 1.98—2.16 (m, 1 H,
H(3´)); 2.47 (d, 1 H, H(3´), Jgem = 13.7 Hz); 3.04 (br.t, 1 H, H(6´),
Jgem = 14.1 Hz); 3.69 (m, 1 H, H(6´)); 3.89 (s, 3 H, Me); 6.14 (br.s,
1 H, H(2´)); 7.38—7.47 (m, 4 H, H(7), H(3″´), H(4″´), H(5″´));
7.47—7.57 (m, 5 H, H(2″´), H(6″´), H(3″), H(4″), H(5″)); 7.79 (s,
1 H, H(2)); 7.80 (d, 2 H, H(2″), H(6″), J = 8.3 Hz); 8.37 (d, 1 H,
H(8), J = 9.3 Hz); 10.02 (s, 1 H, H(5)). 13C NMR (CDCl3),
δ: 19.44 (C(4´)); 24.70 (C(5´)); 25.86 (C(3´)); 43.88 (C(6´)); 49.19
(C(2´)); 51.16 (Me); 105.89 (C(1)); 119.53 (C(8)); 122.56 (C(6));
126.57 (C(4″´)); 126.88 (C(5)); 127.31 (C(3)); 128.21 (C(7)); 128.38
(C(3″)); 128.38 (C(5″)); 128.55 (C(3″´)); 128.55 (C(5″´)); 128.82
(C(6″)); 128.82 (C(2″)); 128.98 (C(4″)); 129.56 (C(6″´)); 129.56
(C(2″´)); 131.42 (C(2)); 135.98 (C(1″´)); 138.59 (C(9)); 139.72
(C(1″)); 164.21 (C=O); 171.44 (C=O); 185.60 (C=O). IR (KBr),
by additional silica gel chromatography in a yield of 0.18 g (20%).
D. Acrylonitrile (0.25 g, 0.32 mL, 4.8 mmol) and triethylamine
(0.13 g, 0.18 mL, 1.3 mmol) were added with stirring to a solution of
salt 5 (0.97 g, 2.4 mmol) in CH2Cl2 (14 mL). After 1 h, an addiꢀ
tional amount of triethylamine (0.13 g, 0.18 mL, 1.3 mmol) was
added. The reaction mixture was stirred at ~20 °C for 6 h. After
completion of the reaction, the mixture was diluted with water
(50 mL) (pH 7), and an aqueous ammonia solution (pH 11—12)
was added with stirring. After 5 min, a 0.34 M aqueous H2SO4
solution (pH 2) was added. Then pH was brought to 10—11 with an
ammonia solution. The organic layer was separated, and the aqueꢀ
ous layer was extracted with CH2Cl2 (5×15 mL). The organic
layers were combined, dried over MgSO4, and concentrated.
A mixture of reaction products was isolated by alumina column
chromatography in a yield of 0.54 g (53%). Compound 25 was
isolated from the mixture by additional alumina chromatography
in a yield of 0.35 g (39%).
E. Acrylonitrile (0.11 g, 0.14 mL, 2.1 mmol) was added with
stirring to a solution of salt 5 (0.77 g, 1.9 mmol) in CH2Cl2 (14 mL).
Then a solution of triethylamine (0.19 g, 0.27 mL, 1.9 mmol) in
CH2Cl2 (7 mL) was added for 1 h. The reaction mixture was stirred
at ~20 °C for 4 h. After completion of the reaction, the mixture was
diluted with water (50 mL) (pH 7), and an aqueous ammonia
solution (pH 11) was added with stirring. After 5 min, a 0.34 M
aqueous H2SO4 solution (pH 2) and an ammonia solution (to
pH 11) were successively added. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (5×15 mL). The
organic layers were combined, dried over MgSO4, and concenꢀ
trated. Compound 25 was isolated by alumina column chromatoꢀ
graphy in a yield of 0.22 g (32%), [α]578 –119.8° (c 1.2, CHCl3).
1H NMR (CDCl3), δ: 1.51—1.78 (m, 4 H, 2 H(4´), 2 H(5´)); 1.80—
2.00 (m, 1 H, H(3´)); 2.23 (s, 3 H, Me); 2.35 (d, 1 H, H(3´),
Jgem = 15 Hz); 3.13 (t, 1 H, H(6´), Jgem = 12.7 Hz); 3.75 (d, 1 H,
H(6´), Jgem = 12.7 Hz); 6.04 (s, 1 H, H(2´)); 7.34 (d, 1 H, H(7), J =
8.9 Hz); 7.48 (t, 2 H, H(3″), H(5″), J1 = 7.7 Hz, J2 = 7.4 Hz); 7.53—
7.58 (m, 1 H, H(4″)); 7.56 (s, 1 H, H(2)); 7.73 (d, 3 H, H(8), H(2″),
H(6″), J = 7.4 Hz); 9.81 (s, 1 H, H(5)). 13C NMR (CDCl3), δ: 19.08
(C(4´)); 21.96 (Me),; 25.57 (C(5´)); 26.61 (C(3´)); 43.08 (C(6´));
53.11 (C(2´)); 84.48 (C(1)); 114.92 (C≡N); 117.59 (C(8)); 122.61
(C(6)); 127.11 (C(5)); 128.25 (C(7)); 128.38 (C(3″)); 128.38 (C(5″));
128.42 (C(3)); 128.65 (C(6″)); 128.75 (C(2″)); 129.28 (C(4″)); 132.12
(C(2)); 138.89 (C(1″)); 139.81 (C(9)); 170.03 (C=O); 185.09 (C=O).
ν/cm–1: 1220.8 (CO2Me), 1629.7 (
), 1705.3
(C=O). UV (ЕtOH), λmax/nm (ε): 240 (24728), 284 (16960), 333
(84986), 367 (12782). MS, m/z (Irel (%)): 466.2 [M]+ (13.00),
448.2 (14.27), 361.2 (100.0), 274.2 (1.67), 105.1 (55.89), 77.1
(25.34). Found: m/z 466.18932 [M]+. C29H26N2O4. Calculated:
M = 466.18924.
6ꢀ(1ꢀAcetylpiperidinꢀ2ꢀyl)ꢀ3ꢀbenzoylꢀ1ꢀcyanoindolizine
(25). A. Acrylonitrile (0.09 g, 0.12 mL, 1.7 mmol) and triethyꢀ
lamine (0.19 g, 0.27 mL, 1.9 mmol) were successively added with
stirring to a solution of salt 5 (0.70 g, 1.7 mmol) in acetonitrile
(2 mL). The reaction mixture was stirred at room temperature for
5 h. After completion of the reaction, the mixture was diluted with
water (25 mL) and extracted with chloroform (5×10 mL). The
extract was dried over MgSO4 and concentrated. A mixture of
indolizines (0.23 g, 33%) was isolated by silica gel column chromaꢀ
tography using a chloroform—petroleum ether mixture (10 : 6) as
the eluent. Compound 25 (0.13 g, 18%) was isolated from the
mixture by repeated silica gel column chromatography, m.p.
80—82 °C (diethyl ether).
B. Acrylonitrile (0.25 g, 0.32 mL, 4.8 mmol) and triethylamine
(0.26 g, 0.37 mL, 2.6 mmol) were successively added with stirring to
a solution of salt 5 (0.97 g, 2.4 mmol) in CH2Cl2 (7 mL).
The reaction mixture was stirred at ~20 °C for 3.3 h. After compleꢀ
tion of the reaction, the mixture was diluted with water (50 mL), the
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (4×10 mL). The extracts were combined, dried over
MgSO4, and concentrated. A mixture of reaction products was
isolated by silica gel column chromatography in a yield of 0.28 g
(31%). Compound 25 was isolated from the mixture by additional
alumina chromatography in a yield of 0.15 g (17%).
C. Acrylonitrile (0.25 g, 0.32 mL, 4.8 mmol) and triethylamine
(0.13 g, 0.18 mL, 1.3 mmol) were successively added with stirring to
a solution of salt 5 (0.97 g, 2.4 mmol) in CH2Cl2 (14 mL). After 1 h,
an additional amount of triethylamine (0.13 g, 0.18 mL, 1.3 mmol)
was added. The reaction mixture was stirred at room temperature
for 6 h. After completion of the reaction, the mixture was diluted
with water (50 mL), the organic layer was separated, and the aqueꢀ
ous layer was extracted with CH2Cl2 (5×15 mL). The extracts were
combined, dried over MgSO4, and concentrated. A mixture of reacꢀ
tion products was isolated by silica gel column chromatography in
a yield of 0.64 g (70%). Compound 25 was isolated from the mixture
IR (KBr), ν/cm–1: 2206.9 (C≡N); 1630.0 (
). MS,
m/z (Irel (%)): 371.4 [M]+ (3.66), 415.1 (14.50), 328.1 (100), 298.2
(0.57), 271.2 (2.27), 245.0 (1.4), 105.1 (58.43), 77.1 (37.57). Found:
m/z 371.16217 [M]+. C23H21N3O2. Calculated: M = 371.16337.
3ꢀBenzoylꢀ6ꢀ(1ꢀbenzoylpiperidinꢀ2ꢀyl)ꢀ1ꢀcyanoindolizine
(27). Acrylonitrile (0.19 g, 0.23 mL, 3.4 mmol) and triethylamine
(0.09 g, 0.12 mL, 0.85 mmol) were successively added with stirring
to a solution of salt 6 (0.81 g, 1.7 mmol) in CH2Cl2 (14 mL). After
1 h, an additional amount of triethylamine (0.09 g, 0.12 mL,
0.85 mmol) was added. The reaction mixture was stirred at ~20 °C
for 8 h. After completion of the reaction, the mixture was diluted
with water (50 mL), the organic layer was separated, and the aqueꢀ
ous layer was extracted with CH2Cl2 (5Ѕ15 mL). The organic
layers were combined, dried with MgSO4, and concentrated.
A mixture of reaction products was isolated in a yield of 0.63 g
(84%) by alumina column chromatography. Compound 27 was
isolated from the mixture by additional alumina column chromaꢀ

Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
149
Syntheses based on anabasine
358.0 (100), 105.0 (3.90), 77.0 (9.84). Found: m/z 401.17371 [M]+.
C24H23N3O3. Calculated: M = 401.17393.
tography in a yield of 0.37 g (49%), m.p. 95—98 °C (hexane), [α]578
–202.4° (c 0.4, CHCl3). 1H NMR (CDCl3), δ: 1.57—1.78 (m, 3 H,
H(4´), 2 H(5´)); 1.79—1.86 (m, 1 H, H(4´)); 2.01—2.18 (m, 1 H,
H(3´)); 2.46 (d, 1 H, H(3´), J = 13.2 Hz); 3.05 (br.t, 1 H, H(6´),
Jgem = 14 Hz); 3.78 (m, 1 H, H(6´)); 6.18 (br.s, 1 H, H(2´)); 7.41—
7.45 (m, 3 H, H(7), H(3″), H(5″)); 7.46—7.57 (m, 5 H, H(2″´),
H(3″´), H(4″´), H(5″´), H(6″´)); 7.57—7.62 (m, 1 H, H(4″)); 7.61
(s, 1 H, H(2)); 7.78 (d, 2 H, H(2″), H(6″), J = 7.1 Hz); 7.83 (d, 1 H,
H(8), J = 9.2 Hz); 9.99 (s, 1 H, H(5)). 13C NMR (CDCl3), δ: 19.38
(C(4´)); 25.72 (C(5´)); 26.24 (C(3´)); 43.97 (C(6´)); 49.13 (C(2´));
84.69 (C(1)); 115.00 (C≡N); 117.21 (C(8)); 122.80 (C(6)); 126.57
(C(4″´)); 127.11 (C(5)); 128.16 (C(3)); 128.41 (C(7)); 128.47
(C(3″)); 128.47 (C(5″)); 128.61 (C(3″´)); 128.61 (C(5″´)); 128.79
(C(6″)); 128.79 (C(2″)); 129.40 (C(4″)); 129.71 (C(6″´)); 129.71
(C(2″´)); 131.97 (C(2)); 135.69 (C(1″´)); 139.01 (C(1″)); 139.91
(C(9)); 171.54 (C=O); 185.21 (C=O). IR (KBr), ν/cm–1: 2208.2
6ꢀ(1ꢀBenzoylpiperidinꢀ2ꢀyl)ꢀ1ꢀcyanoꢀ3ꢀ(4ꢀmethoxybenꢀ
zoyl)indolizine (31). Acrylonitrile (0.28 g, 0.35 mL, 5.25 mmol),
TPCD (0.52 g, 0.85 mmol), and pyridine (0.47 mL) were succesꢀ
sively added with stirring to a solution of salt 9 (0.65 g, 1.31 mmol)
in DMF (9.4 mL). The reaction mixture was stirred at 90 °C for
1.5 h, cooled, and treated with a 5% HCl solution (23 mL). The
precipitate was filtered off. A mixture of 8ꢀ and 6ꢀsubstituted derivaꢀ
tives of indolizine (0.23 g, 38%) was isolated in a ratio of 1 : 1.3 by
alumina column chromatography. Compound 31 was isolated from
the mixture by crystallization from ethyl acetate, m.p. 218—
219 °C. 1H NMR (CDCl3), δ: 1.55—1.67 (m, 2 H, H(5´), H(5´));
1.68—1.78 (m, 1 H, H(4´)); 1.79—1.86 (m, 1 H, H(4´)); 2.02—
2.12 (m, 1 H, H(3´)); 2.44 (d, 1 H, H(3´), Jgem = 15.7 Hz); 2.94
(br.t, 1 H, H(6´), Jgem = 13.7 Hz); 3.89 (m, 4 H, Me, H(6´)); 6.04
(br.s, 1 H, H(2´)); 7.01 (d, 2 H, H(3″), H(5″), J = 8.8 Hz); 7.39—
7.48 (m, 4 H, H(7), H(3″´), H(4″´), H(5″´)); 7.49—7.54 (m, 2 H,
H(2″), H(6″)); 7.60 (s, 1 H, H(2)); 7.81 (d, 3 H, H(8), H(2″),
H(6″), J = 8.8 Hz); 9.92 (s, 1 H, H(5)). IR (KBr), ν/cm–1: 2219.7
(C≡N); 1622.8 (
). UV (ЕtOH), λmax/nm (ε): 237
(19550), 367 (6227). MS, m/z (Irel (%)): 433.1 [M]+ (14.35), 415.1
(14.50), 328.1 (100), 298.2 (0.57), 271.2 (2.27), 245.0 (1.4), 105.1
(58.43), 77.1 (37.57). Found: m/z 433.17571 [M]+. C28H23N3O2.
Calculated: M = 433.17902.
(C≡N); 1623.3 (
); 1599.6 (C=O). UV (ЕtOH),
λ
max/nm (ε): 236 (34786), 273 (20047), 368 (18095). MS, m/z
6ꢀ(1ꢀAcetylpiperidinꢀ2ꢀyl)ꢀ1ꢀcyanoꢀ3ꢀ(4ꢀmethoxybenzoꢀ
yl)indolizine (29). Acrylonitrile (0.15 g, 2.82 mmol) and triethyꢀ
lamine (0.16 g, 0.22 mL, 1.55 mmol) were successively added with
stirring to a solution of salt 8 (0.61 g, 1.41 mmol) in CH2Cl2 (7 mL)
for 1 h. The reaction mixture was stirred at ~20 °C for 5 h. After
completion of the reaction, the mixture was diluted with water, and
aqueous ammonia was added with stirring (to pH 11). After 5 min,
a 0.34 M aqueous H2SO4 solution (pH 2) was added. Then an
ammonium solution was added to pH 12, the organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
(5×15 mL). The organic layers were combined, dried over MgSO4,
and concentrated. A mixture of reaction products was obtained in a
yield of 0.56 g (98%). Then 0.14 g of this mixture was added to DMF
and TPCD in a ratio of 1 : 40 : 0.65. The reaction mixture was
stirred at 90 °C for 2 h, cooled, and treated with a 5% HCl solution
(10 mL). The aqueous layer was extracted with chloroform. The
extract was dried over MgSO4 and concentrated. A mixture of 8ꢀ
and 6ꢀsubstituted derivatives of indolizine (0.07 g, 52%) was isolated
from the residue by alumina column chromatography in a ratio of
1 : 5, respectively. Compound 29 was additionally isolated from the
mixture by alumina column chromatography, m.p. 84—86 °C
(DEE). 1H NMR (CDCl3), δ: 1.52—1.91 (m, 2 H, H(5´), H(5´));
1.92—2.09 (m, 2 H, H(4´), H(4´)); 2.10—2.18 (m, 1 H, H(3´));
2.24 (s, 3 H, Me); 2.37 (d, 1 H, H(3´), Jgem = 15 Hz); 3.12 (t, 1 H,
H(6´), Jgem = 12.6 Hz); 3.75 (d, 1 H, H(6´), Jgem = 12.6 Hz); 3.89 (s,
3 H, Me); 6.07 (s, 1 H, H(2´)); 6.99 (d, 2 H, H(3″), H(5″), J =
8.7 Hz); 7.33 (d, 1 H, H(7), J = 8.9 Hz); 7.58 (s, H, H(2)); 7.79 (d,
3 H, H(8), H(2″), H(6″), J = 8.7 Hz); 9.76 (s, 1 H, H(5)). 13C NMR
(CDCl3), δ: 19.05 (C(4´)); 21.73 (Me); 25.98 (C(5´)); 26.48 (C(3´));
45.58 (C(6´)); 48.13 (C(2´)); 55.87 (Me); 84.38 (C(1)); 113.80
(C(3″)); 113.80 (C(5″)); 115.03 (C≡N); 117.42 (C(8)); 122.94
(C(6)); 126.85 (C(5)); 128.17 (C(3)); 128.32 (C(7)); 128.57 (C(2));
131.11 (C(6″)); 131.22 (C(2″)); 131.47 (C(1″)); 139.80 (C(9));
(Irel (%)): 463.1 [M]+ (11.13), 445.0 (17.93), 358.0 (100), 275.1
(0.75), 105.0 (32.71), 77.1 (22.80). Found: m/z 463.18736 [M]+.
C29H25N3O3. Calculated: M = 463.18958.
8ꢀ(1ꢀBenzoylpiperidinꢀ2ꢀyl)ꢀ1ꢀcyanoꢀ3ꢀ(4ꢀmethoxybenꢀ
zoyl)indolizine (32). Acrylonitrile (0.08 g, 0.1 mL, 1.5 mmol) and a
solution of triethylamine (0.14 g, 0.19 mL, 1.35 mmol) in CH2Cl2
(7 mL) were successively added with stirring to a solution of salt 9
(0.67 g, 1.35 mmol) in CH2Cl2 (14 mL). The reaction mixture was
stirred at ~20 °C for 7 h. After completion of the reaction, the
mixture was diluted with water (50 mL). Then aqueous ammonia
(pH 11) was added with stirring. After 5 min, a 0.34 M aqueous
H2SO4 solution (pH 2) was added. Then pH was brought to 12 with
an ammonia solution, the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (5Ѕ15 mL). The organic
layers were combined, dried over MgSO4, and concentrated.
A mixture of reaction products was obtained in a yield of 0.62 g
(98%). This mixture (0.62 g, 1.35 mmol) was mixed with DMF and
TPCD in a ratio of 1 : 40 : 0.65. The resulting mixture was stirred at
90 °C for 1.5 h, cooled, and treated with a 5% HCl solution (40 mL).
The precipitate was filtered off. A mixture of 8ꢀ and 6ꢀ(piperidylꢀ2ꢀ
ylꢀ)indolizines (0.42 g, 67%) in a ratio of 1 : 2.5 was isolated from
the precipitate by alumina column chromatography. Compound
32 was isolated from the mixture by crystallization from ethyl acꢀ
etate, m.p. 240—242 °C. 1H NMR (CDCl3), δ: 1.51—1.88 (m, 4 H,
2 H(4´), 2 H(5´)); 2.07—2.38 (m, 2 H, H(3´), H(3´)); 3.51—3.72
(m, 1 H, H(6´)); 3.88 (m, 4 H, H(6´), Me); 5.89 (br.s, 1 H, H(2´),
J = 1.4 Hz); 6.98 (d, 2 H, H(3″), H(5″), J = 8.6 Hz); 7.09 (t, 1 H,
H(6), J = 6.9 Hz); 7.25—7.44 (m, 5 H, H(2″´), H(3″´), H(4″´),
H(5″´), H(6″´)); 7.37 (d, 1 H, H(7), J = 6.9 Hz); 7.57 (s, 1 H, H(2));
7.77 (d, 2 H, H(2″´), H(6″´), J = 8.6 Hz); 9.77 (d, 1 H, H(5), J =
6.9 Hz). 13C NMR, (CDCl3), δ: 20.04 (C(4´)); 24.73 (C(5´)); 29.83
(C(3´)); 53.33 (C(6´)); 55.56 (Me); 60.40 (C(2´)); 83.26 (C(1));
113.86 (C(3″)); 113.86 (C(5″)); 115.05 (C(5)); 115.15 (C≡N); 117.57
(C(6)); 123.03 (C(8)); 123.85 (C(7)); 126.63 (C(4″´)); 127.79
(C(2)); 128.51 (C(3″´)); 128.51 (C(5″´)); 129.67 (C(6″´)); 130.08
(C(2″´)); 131.26 (C(2″)); 131.31 (C(6″)); 131.56 (C(3)); 133.78
(C(1″)); 136.09 (C(1″´)); 139.75 (C(9)); 162.83 (C(4″)); 171.48
162.89 (C(4″)); 170.07 (C=O); 184.52 (C=O). IR (KBr), ν/cm–1
:
2216.9 (C≡N); 1729.7, 1706.2 (OMe); 1643.6 ( );
1600.3 (C=O). UV (ЕtOH), λmax/nm (ε): 234 (10415), 274 (7095),
367 (6252). MS, m/z (Irel (%)): 401.1 [M]+ (14.50), 383.1 (12.10),

150
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Musina et al.
Table 1. Crystallographic characteristics and the Xꢀray data colꢀ
lection and refinement statistics for compounds 14 and 31*
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
32365).
Parameter
14
31
References
Molecular formula
Molecular weight/at. units
Crystal system
Space group
Diffractometer
Radiation
θꢀScan range/deg
Unit cell parameters
a/Å
C26H26N2O6
462.49
Monoclinic
P21
Bruker P4
MoꢀKα
C29H25N3О3
463.52
Orthorhombic
P212121
Bruker P4
MoꢀKα
1. L. A. Musina, E. E. Shults, L. A. Krichevskii, S. M. Adekenov,
M. M. Shakirov, G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim.,
2006, 322 [Russ. Chem. Bull., Int. Ed., 2006, 55, 331].
2. Pat. Germany 2046904, 1971; Chem. Abstrs, 1971, 75, 48933.
3. Eur. Pat. Appl. EP 235111, 1987; Chem. Abstrs, 1988, 109,
6405.
1.9—25.5
1.9—26.0
16.742(3)
7.708(1)
18.615(3)
103.44(1)
2336.5(7)
4
4.911 (1)
20.972 (5)
23.617(5)
4. C. Foster, M. Ritchie, D. L. Selwood, W. Snowden, Antiviral
Chem. Chemother., 1995, 6, 289.
b/Å
c/Å
β/deg
5. Brit. UK Pat. Appl. GB 2 287706, 1995; Chem. Abstrs, 1996,
124, 175847.
6. S. Hagishita, M. Yamada, K. Shirahase, T. Okada,
Y. Murakami, Y. Ito, T. Matsuura, M. Wada, T. Kato,
M. Ueno, Y. Chikazawa, K. Yamada, T. Uno, I. Teshirogi,
M. Ohtani, J. Med. Chem., 1996, 39, 3636.
Unit cell volume/Å3
Z
2432.6 (10)
4
1.266
0.083
ρ
calc/g cm–3
1.315
0.094
0.03×0.12×1.00
4683
µ/mm–1
Crystal dimensions/mm
Number of independent
reflections
Transmission
Number of reflections
with I > 2σ(I)
Number of refinement
parameters
R1 based on reflections
with F > 4σ(F)
0.08×0.30×0.95
2787
7. H. Sonnenschein, H. Kösslick, F. Tittelbach, Synthesis, 1998,
1596.
8. J. Fröhlich, F.Kröhnke, Chem. Ber., 1971, 104, 1621.
9. E. Oeser, Chem. Ber., 1972, 105, 2351.
10. T. Sasaki, K. Kanematsu, Y. Yukimoto, S. Ochiai, J. Org.
—
2249
0.97—0.99
980
Chem., 1971, 36, 813.
624
334
11. Y. Tamura, Y. Sumida, Y. Mili, M. Ikeda, J. Chem. Soc., Perkin
Trans. 1, 1975, 406.
12. Х. Wei, Y. Hu, T. Li, H. Hu, J. Chem. Soc., Perkin Trans. 1,
1993, 2487.
0.0555
0.0659
wR2 based on all reflections
GOOF
0.1835
0.972
0.1909
1.072
13. X. Zhang, F. Liang, L. Sun, Y. Hu, H. Hu, Synthesis, 2000,
1733.
14. T. Weide, L. Arve, H. Prinz, H. Waldmann, H. Kessler, Bioorg.
Med. Chem. Lett., 2006, 16, 59.
15. R. Hema, V. Parthasarathi, K. Ravikumar, K. Sarkunam,
M. Nallu, Acta Crystallogr., Sect. E: Struct. Rep. Online, 2004,
60, 479.
*No absorption correction was applied for 14, and the empirical
absorption correction was applied for 31.
(C=O); 183.79 (C=O). IR (KBr), ν/cm–1: 2214.3 (C≡N); 1735.7
16. L. A. Aslanov, V. A. Tafeenko, K. A. Pasechnichenko,
Zh. Strukt. Khim., 1983, 24, 115 [J. Struct. Chem., 1983, 24
(Engl. Transl.)].
17. R. Hema, V. Parthasarathi, K. Sarkunam, M. Nallu, A. Linꢀ
den, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 2003,
59, 703.
(OMe); 1632.8 (
); 1600.0 (C=O). UV (ЕtOH),
λmax/nm (ε): 233 (15457), 258 (8718), 273 (9364), 366 (9419). MS,
m/z (Irel (%)): 463.1 [M]+ (28.85), 358.0 (100.0), 1350 (39.62),
105.0 (67.89), 77.0 (50.11). Found: m/z 463.19043 [M]+.
C29H25N3O3. Calculated: M = 463.18958.
Xꢀray diffraction study of compounds 14 and 31.* Crystalloꢀ
graphic characteristics and the Xꢀray data collection and refineꢀ
ment statistics are given in Table 1. The structures were solved by
direct methods with the use of the SHELXSꢀ97 program package
and refined by the fullꢀmatrix leastꢀsquares method with anisotroꢀ
pic displacement parameters using the SHELXLꢀ97 program packꢀ
age. The parameters of the H atoms were calculated in each refineꢀ
ment cycle from the coordinates of the corresponding carbon atoms
(the riding model). The phenyl ring C(22)—C(27) in molecule 31 is
disordered over two positions, A and B (with the occupancy ratio of
0.40 : 0.60 (2), respectively).
18. F. H. Allen, O. Kenard, D. G. Watson, L. Bramer,
A. G. Orpen, R. Taylor, J. Chem. Soc., Perkin Trans 2, 1987,
No. 12, Suppl. 1.
19. A. S. Sadykov, Khimiya alkaloidov Anabasis aphylla [Chemistry
of Alkaloids from Anabasis aphylla], Izdꢀvo AN Uzb. SSR,
Tashkent, 1956, 222 pp. (in Russian).
20. O. S. Otroshchenko, A. S. Sadykov, Zh. Obshch. Khim., 1954,
24, 1884 [J. Gen. Chem. USSR, 1954, 24 (Engl.Transl.)].
21. Kh. A. Aslanov, K. T. Toremuratov, A. A. Abduvakhabov,
S. Z. Mukhamedzhanov, A. S. Sadykov, Zh. Obshch. Khim.,
1972, 42, 2293 [J. Gen. Chem. USSR, 1972, 42 (Engl.Transl.)].
22. A. Orechoff, S. Norkina, Chem. Ber., 1932, 65, 724.
* The structures were deposited with the Cambridge Structural
Database (CCDC 622624 for 14 and CCDC 622623 for 31).
The Xꢀray diffraction data can be obtained, free of charge, on appliꢀ
cation to the Cambridge Crystallographic Data Centre,
http://www.ccdc.cam.ac.uk/data_request/cif deposit.
Received November 2, 2006;
in revised form April 25, 2007