Synthesis of azecino[5,4-b]indoles and indolo[3,2-e][2]benzazonines via tandem transformation of hydrogenated indoloquinolizines and indolizines

Article abstract of DOI:10.1007/s11172-012-0167-6

The reactions of partially hydrogenated indole-fused quinolizines and indolizines with activated alkynes in methanol, acetonitrile, and dichloromethane were studied. The reactions were shown to be accompanied by the cleavage of the bridging C-N bond. Azec

Full text of DOI:10.1007/s11172-012-0167-6

Russian Chemical Bulletin, International Edition, Vol. 61, No. 6, pp. 1231—1241, June, 2012
1231
Synthesis of azecino[5,4ꢀb]indoles and indolo[3,2ꢀe][2]benzazonines
via tandem transformation of hydrogenated indoloquinolizines and indolizines
L. G. Voskressensky,a T. N. Borisova,a A. A. Titov,a A. V. Listratova,a
L. N. Kulikova,a A. V. Varlamov,a V. N. Khrustalev,b and G. G. Aleksandrovc
aPeoples´ Friendship University of Russia,
6 ul. MiklukhoꢀMaklaya, 117198 Moscow, Russian Federation.
Fax: +7 (495) 955 0779. Eꢀmail: lvoskressensky@sci.pfu.edu.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Eꢀmail: vkh@xray.ineos.ac.ru
cN. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
31 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: aleks@igic.ras.ru
The reactions of partially hydrogenated indoleꢀfused quinolizines and indolizines with
activated alkynes in methanol, acetonitrile, and dichloromethane were studied. The reactions
were shown to be accompanied by the cleavage of the bridging C—N bond. Azecino[5,4ꢀb]ꢀ
indole and indolo[3,2ꢀe][2]benzazonine derivatives were synthesized.
Key words: azecino[5,4ꢀb]indoles, indolo[3,2ꢀe][2]benzazonines, domino reactions, alkynes,
hydrogenated indolizines and quinolizines, eburnamenine.
Mediumꢀsized nitrogenꢀcontaining heterocyclic comꢀ
pounds are contained in some alkaloids exhibiting high
and diverse biological activity. Some of these alkaloids are
used in the medical practice. In the first place, let us menꢀ
tion the alkaloids Vincamine and Vinblastine used in the
cancer treatment. Although mediumꢀsized heterocycles
are of considerable interest to pharmacologists, these comꢀ
pounds are poorly studied. This is primarily associated
with the fact that their synthesis from acyclic precursors
is, in most cases, a difficult problem. An approach involvꢀ
ing transformations of nitrogenꢀbridged bicyclic systems
is tempting and interesting. This approach is based on the
quaternization of the nitrogen atom in this class of comꢀ
pounds followed by the cleavage of quaternary salts with
bases. Sodium amide in liquid ammonia is very often used
for this purpose. Relatively drastic conditions of the cleavꢀ
age limit the synthetic potential of these reactions. Previꢀ
ously, we have discovered1 the tandem transformations of
(hetero)annulated tetrahydropyridines by the action of
electronꢀdeficient alkynes. This is an example of anionic
domino reactions involving the Michaelis addition as the
first step.2 In recent years, domino reactions grew in popꢀ
ularity primarily because they do not necessitate the isolaꢀ
tion of intermediates that are formed in multistep reactions
accompanied by the formation of new chemical bonds.
The tandem transformations of tetrahydropyridines and
tetrahydroazepines fused to an aromatic or heteroaromatꢀ
ic moiety, which we performed by the action of activatꢀ
ed alkynes, is an efficient and fairly versatile method
for the construction of fused azocines bearing the enamine
moiety in the azocine ring.3 The reaction of tetrahydroꢀ
ꢀcarbolines substituted at position 1 with ethyl propiꢀ
olate in acetonitrile resulted in the formation of azoꢀ
cino[5,4ꢀb]indoles via the tetrahydropyridine ring expanꢀ
sion. In methanol, the reaction affords not only azoꢀ
cinoindoles but also products of the tetrahydropyridine
ring cleavage, viz., 2ꢀmethoxyalkylꢀ3ꢀ(ethoxycarbonylꢀ
vinylꢀRꢀamino)ethylindoles.4 The reactions of alkynes
with hexahydroazepino[4,3ꢀb]ꢀ and hexahydroazepinoꢀ
[3,4ꢀb]indoles both in methanol and acetonitrile proꢀ
duce hexahydroazonino[5,6ꢀb]indoles isomeric with
respect to the position of the enamine moiety in high
yields.5 Nitrogenꢀbridged heterocyclic systems, such as
fused quinolizines and indolizines, have been not studied
in tandem transformation reactions. Heterocycles of
this type are contained in a series of alkaloids.6,7 Hydroꢀ
genated quinolizines and indolizines are used to syntheꢀ
size azonines and azecines fused to aromatic and hetꢀ
eroaromatic rings.8—10 For this purpose, quinolizines
and indolizines are transformed into quaternary ammoniꢀ
um salts followed by the reductive cleavage of the bridgꢀ
ing C—N bond by the action of sodium in liquid ammonia
to form mediumꢀsized nineꢀ and tenꢀmembered azahetꢀ
erocycles.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1218—1227, June, 2012.
1066ꢀ5285/12/6106ꢀ1231 © 2012 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Voskressensky et al.
In the present work, we report the results of the study
of the reaction of alkynes with tetrahydrobenzo[1,2]ꢀ
indolizino[8,7ꢀb]indole 1 and its Nꢀtosyl derivative 2, as
well as with alkaloids 14ꢀhydroxyꢀ14,15ꢀdihydroeburnaꢀ
menine (Vincamine) 3 and eburnamenine (Vinpocetine) 4
and their derivatives 5 and 6, respectively. Thus, tandem
transformations of tetrahydropyridines by the action of
alkynes start with the quaternization of the sp3ꢀhybridized
nitrogen atom, whereas the reactions of compounds 1—5
a priori would be expected to result in the tetrahydropyriꢀ
dine ring expansion to form the azocine moiety and the
cleavage of the bridging C—N bond to give fused azonines
and azecines.9
Fused indolizine 1 was synthesized according to a known
procedure9 starting from tryptamine and 2ꢀformylbenzoic
acid. Compound 1 was transformed into Nꢀtosyl derivaꢀ
tive 2 by the successive action of sodium hydride and tosyl
chloride (Scheme 1).
Alkaloids 3 and 4 are commercial products. The reꢀ
duction of the ester group in eburnamenine 4 afforded
hydroxymethyl derivative 5, and its acetylation gave aceꢀ
tate 6 (Scheme 2).
Indolizinoindole 1 reacts with methyl propiolate in
acetonitrile to form a multicomponent mixture, from
which Stevens rearrangement product 7 was isolated by
column chromatography in ~4% yield (Scheme 3).
Scheme 1
Scheme 2
R = H (5), Ac (6)
Scheme 3
X = H, Y = CO2Me (8, 50%); X = H, Y = COMe (9, 28%); X = Y = CO2Me (10, 24%)

Synthesis of annulated azecines and azonines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1233
Scheme 4
The reaction of compound 1 with dimethyl acetyleneꢀ
dicarboxylate (DMAD), methyl propiolate, and acetylꢀ
acetylene in methanol easily and rapidly (for not longer
than 1 h) proceeds at 40 C to give indolobenzazonines
8—10 in moderate yields (see Scheme 3).
In the reaction with DMAD in dichloromethane, toꢀ
sylꢀsubstituted benzoindolizinoindole 2 is transformed into
pentacyclic derivative 11, whereas the reaction of comꢀ
pound 2 with acetylacetylene gives Stevens rearrangement
product 12 (Scheme 4).
Our results are in good agreement with the data11 on
the reactions of 2ꢀvinyltetrahydroꢀꢀcarboline and vinylꢀ
substituted indolizinoindole with activated alkynes.
Since 14ꢀhydroxyꢀ14,15ꢀdihydroeburnamenine 3 is
poorly soluble in methanol, it reacts much more slowly with
activated alkynes compared to indolizinoindole 1. In this
case, the reactions produce azecines 13—15 in high yields via
the cleavage of the bridging C—N bond (Scheme 5). These
compounds are highꢀmeltingꢀpoint colorless crystalline
substances. Apparently, the transformation of compound 3
into products 13—15 proceeds through the transition state A.
Eburnamenine (Vinpocetine) 4 and its derivatives 5
and 6 react with alkynes much more actively than diꢀ
hydroeburnamenine, which is apparently associated with
the stabilization of the transition state В (Scheme 6)
through the conjugation in the enamine moiety (of the
indole group with the double bond of the cyclohexene
group).
The methanolꢀmediated cleavage of the bridging C—N
bond of the quinolizine moiety in the transition state В
affords azecinoindoles 16—21. Acetoxymethylꢀsubstitutꢀ
ed compound 6 reacts with methyl propiolate as easily as
hydroxymethyl derivative 5. However, the chromatoꢀ
graphic separation on alumina results in the acetyl deproꢀ
tection and the formation of azecine 19 in 43% yield.
The structures of all the synthesized compounds were
confirmed by spectroscopic data. The structure of azonine
10 was studied by Xꢀray diffraction. Compound 10 is polyꢀ
cyclic and contains four (one fiveꢀmembered (pyrrole),
two sixꢀmembered (benzene), and one nineꢀmembered
(azonine)) fused rings (Fig. 1). The central nineꢀmemꢀ
bered ring adopts a distorted chair conformation; the N(1),
Scheme 5
X = H, Y = CO2Me (13, 78%); X = H, Y = COMe (14, 63%); X = Y = CO2Me (15, 73%)

1234
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Voskressensky et al.
Scheme 6
R = CO2Et, X = H, Y = CO2Me (16, 82%), X = H, Y = COMe (17, 45%), X = Y = CO2Me (18, 42%),
R = CH2OH, X = H, Y = CO2Me (19, 57%), X = H, Y = COMe (20, 29%), X = Y = CO2Me (21, 41%)
C(5), and C(6) atoms deviate from the mean plane passꢀ
ing through the other atoms of the ring by –0.802, 1.104,
and 1.252 Å, respectively. The angle between the planes of
the indole and benzene (C(2), C(3), C(9), C(10), C(11),
C(12)) groups is 83.2. The nitrogen atom N(1) has
a flattened configuration (the sum of the valence angles at
the nitrogen atom N(1) is 358.4) due to the conjugation
in the N(1)—C(20)=C(23)—C(24)=O(4) chain. The
orientation of the methoxycarbonyl group at the carbon
atom C(20) is determined by both the steric factors and
the strong intermolecular N(2)—H(2)...O(2) hydrogen
bond [x, –1 + y, z] (N...O, 2.935(2) Å; H...O, 2.11 Å;
N—H...O, 160). Molecules 10 are linked by these interꢀ
molecular hydrogen bonds to form hydrogenꢀbonded
chains along the b axis. Compound 10 is chiral and has
one asymmetric center at the carbon atom C(4). The crysꢀ
tal of compound 10 is a racemate.
Compound 11 is polycyclic and contains five (one fiveꢀ
membered (pyrrole), three sixꢀmembered (two benzene
and one tetrahydropyridine), and one nineꢀmembered
(azonine)) fused rings (Fig. 2). The central azonine ring
formed by the atoms C(4A), C(5), N(6), C(16), C(15),
C(8A), C(13A), C(14), and C(14A) adopts a chair conforꢀ
mation; the C(4A), C(14A), C(15), and C(16) atoms deꢀ
viate from the mean plane passing through the other atoms
of the ring by 0.983, 1.084, –1.044, and 1.248 Å, respecꢀ
tively. The planes of the benzene rings of the indole and
benzazonine moieties are nearly perpendicular to each other
(the angle between the corresponding planes is 80.7).
Despite the fact that there is the conjugation between the
nitrogen atom N(6) and the C(7)=C(8) double bond in
compound 11, as evidenced by the N(6)—C(7) bond length
(1.382(2) Å), the nitrogen atom N(6) has a pyramidalized
configuration (the sum of the valence angles at the nitroꢀ
gen atom N(6) is 351.8) due apparently to the strained
structure of the central bicyclic ring system. The nitrogen
atom N(13) is also pyramidalized (the sum of the valence
angles at the nitrogen atom N(13) is 353.3), which may
be attributed to steric factors (the presence of the bulky
tosyl substituent) and, as a consequence, to the absence of
the conjugation between the nitrogen atom N(13) and
the C(13A)=C(14) double bond, as evidenced by the
N(13)—C(13A) bond length (1.462(2) Å). The mutual
arrangement of two methoxycarbonyl substituents in molꢀ
ecule 11 is also determined by steric factors. Compound 11
is chiral and has one asymmetric center at the carbon
atom C(8A). The crystal of compound 11 is a racemate.
The structures of azecines 13—21 were confirmed by
spectroscopic data reported in the Experimental section
and by Xꢀray diffraction (for compound 16, Fig. 3).
In the crystal structure of compound 16, there are two
independent molecules per asymmetric unit, which differ
only by the conformations of the ethoxycarbonyl (the
C(22)—O(4)—C(23)—C(24) and C(22A)—O(4A)—
C(23A)—C(24A) torsion angles are –83.6 and 88.8, reꢀ
spectively) and propenoate (the C(1)—N(1)—C(18)—
C(19) and C(1A)—N(1A)—C(18A)—C(19A) torsion angles
are –9.1 and 170.2, respectively) substituents. Hence,
only one of two independent molecules 16 is disꢀ
cussed below.
O(2)
С(22)
O(4)
С(21)
O(3)
С(8)
С(6)
С(25)
С(7)
С(18)
С(17)
С(20)
N(1)
С(24)
С(16)
С(15)
С(23)
С(1)
С(2)
O(5)
С(4)
O(1)
С(5)
С(13)
С(14)
С(9)
С(3)
С(19)
N(2)
Compound 16 is polycyclic and contains four (one
fiveꢀmembered (pyrrole), two sixꢀmembered (one benzene
and one tetrahydropyridine), and one tenꢀmembered (azeꢀ
cine)) fused rings (see Fig. 3). The tenꢀmembered azecine
ring adopts a chair—chair conformation, and the sixꢀmemꢀ
С(10)
С(12)
С(11)
Fig. 1. Molecular structure of compound 10.

Synthesis of annulated azecines and azonines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1235
O(3)
C(18)
O(1)
C(20)
C(9)
C(19)
O(2)
C(7)
C(17)
N(6)
C(8)
O(4)
C(10)
C(8A)
C(15)
C(5)
C(4)
C(16)
C(4A)
C(8B)
C(11)
C(14A)
C(3)
C(13A)
C(14)
C(12A)
N(13)
C(2)
C(27)
C(1)
C(12)
C(25)
C(23)
C(22)
C(24)
C(21)
C(26)
S(1)
O(6)
O(5)
Fig. 2. Molecular structure of compound 11.
C(21A)
C(21)
O(1A)
O(2A)
O(2)
C(19)
O(1)
C(20A)
C(19A)
C(20)
N(1A)
C(18A)
C(1)
N(1)
C(1A)
C(2A)
C(18)
C(15)
C(15A)
C(14A)
C(2)
C(5)
C(14)
C(13A)
C(3A)
C(16A)
C(5A)
C(3)
C(16)
C(4)
C(13)
C(4A)
C(26A)
C(25A)
C(17A)
C(6)
C(17)
O(5)
C(26)
C(6A)
C(12)
C(25)
C(12A)
C(11A)
C(27A)
O(5A)
N(2A)
C(9A)
C(8A)
C(7)
C(27)
C(9)
N(2)
C(7A)
C(10A)
C(22A)
O(4A)
C(8)
C(11)
C(10)
C(22)
O(3)
O(4)
O(3A)
C(23A)
C(24A)
C(23)
C(24)
Fig. 3. Molecular structure of azecine 16 (two crystallographically independent molecules are shown).

1236
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Voskressensky et al.
bered tetrahydropyridine ring has a sofa conformation.
The propenoate substituent has an E configuration with
respect to the C(18)=C(19) double bond. Despite the presꢀ
ence of the conjugation between the nitrogen atom N(1)
and the C(18)=C(19) double bond in compound 16, as
evidenced by the N(1)—C(18) bond length (1.360(4) Å),
the nitrogen atom N(1) has a pyramidalized configuration
(the sum of the valence angles at the nitrogen atom N(1) is
357.9) due apparently to the strained structure of the polyꢀ
cyclic ring system. The nitrogen atom N(2) is also pyrꢀ
amidalized (the sum of the valence angles at the nitroꢀ
gen atom N(2) is 354.0). This may be attributed to sterꢀ
ic factors (the presence of the bulky ethoxycarbonyl subꢀ
stituent) and, as a consequence, to the absence of the
conjugation between the nitrogen atom N(2) and the
C(10)=C(11) double bond, which is confirmed by the
N(2)—C10 bond length (1.435(4) Å).
Compound 16 is chiral and has two asymmetric cenꢀ
ters at the carbon atoms C(12) and C(17). The crystal of
compound 16 is a racemate and consists of enantiomeric
pairs with the relative configuration racꢀ12S*,17R*.
The tandem transformations of fused indolizines and
quinolizines by the action of alkynes can be considered as
a new efficient method for the synthesis of fused azonines
and azecines.
acetylene, the indolizine moiety is retained and the Stevens
rearrangement product is generated, whereas in the reacꢀ
tion with DMAD this ring is cleaved to form a polycyclic
system containing the spiro[indolineꢀ3,4´ꢀtetrahydroꢀ
pyridine] moiety.
Experimental
The IR spectra were recorded on an Infralyum FTꢀ801 Fouꢀ
rierꢀtransform infrared spectrometer as KBr pellets or in films
(for liquid samples). The elemental analysis was performed on
a Carlo Erba 1106 instrument. The 1H and 13C NMR spectra were
measured on Brukerꢀ300, Brukerꢀ400, and JEOL JNMꢀECA600
1
instruments (for H, operating at 300, 400, and 600 MHz) in
CDCl3, DMSOꢀd6, and CD3OD using residual signals of the
solvent or SiMe4 as the internal standard. Mass spectra were
recorded on a Finnigan MAT 95 XL gas chromatography/mass
spectrometer (EI, 70 eV). The LCMS spectra were obtained
using a system composed of an Agilent 1100 Series liquid chroꢀ
matograph, an Agilent Technologies LC/MSD VL mass spectroꢀ
meter (electrospray ionization, APCI), and an ELSD Sedex 75
detector. Thinꢀlayer chromatography was performed on Silufol
UVꢀ254 and Alufol plates (visualization using iodine vapor). Colꢀ
umn chromatography was carried out on neutral alumina (Fluka,
II activity grade, 60 mesh).
The unit cell parameters and intensities of reflections were
measured on an Enraf Nonius CADꢀ4 automated diffractometer
((MoꢀK) radiation,  filter, /2ꢀscanning technique) for
compound 10, a Bruker SMART 1K CCD automated diffractoꢀ
meter ((MoꢀK) radiation, graphite monochromator, ꢀ and
ꢀscanning technique) for compound 11, and a Bruker SMART
APEX II CCD automated diffractometer ((MoꢀK) radiation,
graphite monochromator, ꢀ and ꢀscanning technique) for
compound 16. Principal crystallographic data are given in Table 1.
The structures of all compounds were solved by direct methods
and refined by the fullꢀmatrix leastꢀsquares method with anisoꢀ
tropic displacement parameters for nonhydrogen atoms. The
hydrogen atom of the amino group in molecule 10 was located in
difference Fourier maps and refined with fixed positional and
thermal parameters. The other hydrogen atoms were positioned
geometrically and refined isotropically with fixed positional
(a riding model) and thermal (Uiso(H) = 1.5Ueq(C) for Me groups
and Uiso(H) = 1.2Ueq(C) for all other groups) parameters. All
calculations were carried out with the use of the SHELXTL
program package.12
13ꢀ[(4ꢀMethylphenyl)sulfonyl]ꢀ7,8,13,13bꢀtetrahydroꢀ5Hꢀ
benzo[1,2]indolizino[8,7ꢀb]indole (2). Sodium hydride (0.30 g,
60%; 6.9 mmol) was added portionwise with stirring to a solution
of benzoindolizinoindole 1 (1.2 g, 4.6 mmol) in anhydrous DMF
(20 mL) under argon atmosphere at 5 C. After 45 min, tosyl
chloride (1.06 g, 5.5 mmol) was added. After the completion of
the reaction (monitoring by TLC, Sorbfil, ethyl acetate), water
(20 mL) was added to the reaction mixture, and the mixture was
extracted with dichloromethane (3×50 mL). The extract was
dried with MgSO4, the solvent was evaporated in vacuo, and
the residue was recrystallized from an ethyl acetate—hexane
mixture. NꢀTosylbenzoindolizinoindole 2 was obtained in a yield
of 0.44 g (23%), yellow crystals, m.p. 159—162 C (ethyl
acetate—hexane). Found (%): C, 72.17; H, 5.27; N, 6.69.
C25H22N2O2S. Calculated (%): C, 72.44; H, 5.35; N, 6.76. IR,
In the N. N. Blokhin Russian Cancer Research Center
of the Russian Academy of Medical Sciences, the cytoꢀ
toxic activity of azonine 8 and azecines 16 and 17 at
a concentration of 10 mol L–1 was studied in vitro. The
results of the study are given below.
Compound
Survival rate (%)
8
16
17
8.6
8.2
6.2
The assays were performed with the use of LS174T
human rectal carcinoma cells. The cell culture was grown
in the RPMI1640 medium supplemented with 10% fetal
calf serum.
Compounds 8, 16, and 17 exhibit high cytotoxic activꢀ
ity in the LS174T cell line. Hence, these compounds can
be recommended for the further in vivo study of cytotoxic
activity.
Therefore, alkaloids of the eburnamenine series (Vinꢀ
camine, Vinpocetine, and the hydroxymethyl analog of
the latter) readily react with alkynes in methanol to form
fused octahydroꢀ7,9ꢀethano(etheno)azecino[5,4ꢀb]indoles
in moderate to high yields as products of the cleavage of
the bridging bond in the hexahydroquinolizine moiety.
In methanol, the hexahydroindolizine moiety in benzoꢀ
indolizinoindoles is cleaved by the action of alkynes to
give azonines fused to the corresponding aromatic rings.
In dichloromethane, the pathway of the transformation of
Nꢀtosylꢀsubstituted hexahydrobenzoindolizinoindole deꢀ
pends on the nature of alkyne. In the reaction with acetylꢀ

Synthesis of annulated azecines and azonines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1237
Table 1. Principal crystallographic characteristics and the structure refinement statistics for 10, 11, and 16
Parameter
10
11
16
Molecular formula
Molecular weight
T/K
C25H26N2O5
434.48
C31H28N2O6S
556.61
120
C27H34N2O5
466.56
296
293
Crystal system
Space group
a/Å
b/Å
c/Å
/deg
/deg
Triclinic
Monoclinic
P21/c
12.2439(6)
8.4320(4)
26.2594(13)
90
95.993(1)
90
2696.2(2)
4
Monoclinic
P21
8.5296(7)
22.2119(19)
13.5706(11)
90
97.210(1)
90
2550.7(4)
4
–
P1
8.763(2)
9.278(2)
14.675(3)
80.03(3)
86.77(3)
71.81(3)
1116.4(4)
2
/deg
V/Å3
Z
dcalc/g cm–3
1.293
460
0.091
1.371
1168
0.169
1.215
1000
0.084
F(000)
/mm–1
2max/deg
51
58
59
Number of measured reflections
Number of unique reflections
Number of reflections with I > 2(I)
Number of parameters in refinement
R1 (I > 2(I))
4322
4148
2984
290
0.033
0.102
28931
7168
5372
364
0.058
19133
12582
6078
613
0.060
wR2 (based on all data)
0.149
0.146
GOF
1.084
1.000
0.999
1
/cm–1: 1365 (SO); 1169 (SO). H NMR (400 MHz, CDCl3),
: 2.28 (s, 3 H, ArCH3); 2.62 (dddd, 1 H, CH2, J = 16.3 Hz,
J = 7.0 Hz, J = 5.3 Hz, J = 1.9 Hz); 2.78 (td, 1 H, CH2, J = 10.1 Hz,
J = 5.3 Hz); 2.91—3.04 (m, 2 H, CH2); 4.05 (d, 1 H, H(5),
J = 13.9 Hz); 4.37 (d, 1 H, H(5), J = 13.9 Hz); 5.98 (s, 1 H,
C(13b)H); 7.09 (d, 2 H, Ar, J = 8.3 Hz); 7.18—7.30 (m, 6 H,
Ar); 7.55 (d, 2 H, Ar, J = 8.3 Hz); 7.97 (d, 1 H, Ar, J = 7.5 Hz);
8.14 (d, 1 H, Ar, J = 7.5 Hz). MS, m/z (Irel (%)): 414 [M]+ (5),
270 (3), 260 (7), 259 (44), 258 (100), 257 (61), 256 (18), 255 (12),
243 (4), 242 (4), 241 (3), 231 (6), 230 (23), 229 (5), 228 (5), 217
(3), 130 (5), 91 (16), 89 (3), 65 (4).
(75), 251 (25), 237 (30), 224 (47), 223 (16), 209 (19), 197 (16),
196 (16), 180 (30), 169 (18), 168 (41), 167 (40), 144 (15), 115
(16), 70 (18), 67 (19), 59 (27), 55 (23), 43 (61), 42 (100), 41 (71).
Ethyl eburnamenine 14ꢀcarboxylate (4) was isolated from the
drug Vinpocetine. Vinpocetine pellets (6 g) were ground to powꢀ
der, alkalified with a 20% sodium carbonate aqueous solution,
and extracted with diethyl ether. The extract was dried with
MgSO4. Ethyl ether was evaporated in vacuo. Compound 4 was
obtained in a yield of 3 g (50%), colorless crystals, m.p. 146—148 C
(ethyl acetate) (cf. lit. data14: m.p. 144 C (anhydrous ethanol)).
Found (%): C, 75.26; H, 7.37; N, 7.91. C22H26N2O2. Calculatꢀ
ed (%): C, 75.40; H, 7.48; N, 7.99. IR, /cm–1: 1717 (CO).
1H NMR (400 MHz, CDCl3). : 0.94—1.06 (m, 1 H, CH2); 1.01
(t, 3 H, CH2CH3, J = 7.4 Hz); 1.35—1.43 (m, 1 H, CH2); 1.39
(t, 3 H, OCH2CH3, J = 7.1 Hz); 1.46—1.55 (m, 1 H, CH2);
1.63—1.80 (m, 1 H, CH2CH3); 1.82—1.99 (m, 2 H, CH2,
CH2CH3); 2.50 (dd, 1 H, CH2, J = 16.2 Hz, J = 2.6 Hz);
2.58—2.64 (m, 2 H, CH2); 2.95—3.09 (m, 1 H, CH2); 3.18—3.40
(m, 2 H, CH2); 4.14 (s, 1 H, C(3)H); 4.37—4.47 (m, 2 H,
OCH2CH3); 6.11 (s, 1 H, C(15)H); 7.08—7.19 (m, 2 H, Ar);
7.21—7.26 (m, 1 H, Ar); 7.44—7.49 (m, 1 H, Ar). MS, m/z
(Irel (%)): 350 [M]+ (33), 322 (21), 321 (100), 220 (17), 293 (10),
292 (11), 281 (17), 280 (100), 252 (38), 250 (14), 249 (13), 248
(12), 247 (11), 237 (14), 220 (13), 219 (11), 218 (10), 206 (23),
204 (10), 193 (20), 192 (14), 191 (13), 42 (26), 41 (15).
Methyl 14ꢀhydroxyꢀ14,15ꢀdihydroeburnamenineꢀ14ꢀcarbꢀ
oxylate (3). Methyl 14ꢀhydroxyꢀ14,15ꢀdihydroeburnamenineꢀ
14ꢀcarboxylate (periwinkle alkaloid) was isolated from the drug
Vincamine. Vincamine pellets (6 g) were ground to powder, alꢀ
kalified with a 25% ammonia aqueous solution, and extracted
with a 1 : 1 diethyl ether—ethyl acetate mixture. The extract was
dried with MgSO4. The solvents were evaporated in vacuo. Comꢀ
pound 3 was obtained in a yield of 4.8 g (79%), colorless crystals,
m.p. 232—233 C (ethyl acetate—hexane) (cf. lit. data13: m.p.
225—227 C (CH2Cl2)). Found (%): C, 70.98; H, 7.23; N, 7.76.
C21H26N2O3. Calculated (%): C, 71.16; H, 7.39; N, 7.90. IR,
/cm–1: 1748 (CO). 1H NMR (600 MHz, CDCl3), : 0.90 (t, 3 H,
CH2CH3, J = 7.6 Hz); 1.36—1.39 (m, 1 H, CH2); 1.43—1.50
(m, 2 H, CH2); 1.65—1.77 (m, 2 H, CH2, CH2CH3); 2.12 (d, 1 H,
C(15)H, J = 14.2 Hz); 2.21—2.27 (m, 2 H, C(15)H, CH2CH3);
2.48—2.56 (m, 2 H, CH2); 2.58—2.62 (m, 1 H, CH2); 2.95—3.01
(m, 1 H, CH2); 3.25—3.35 (m, 2 H, CH2); 3.81 (s, 3 H,
CO2CH3); 3.91 (s, 1 H, OH); 4.61 (s, 1 H, C(3)H); 7.08—7.14
(m, 3 H, Ar); 7.47—7.49 (m, 1 H, Ar). MS, m/z (Irel (%)): 354
[M]+ (56), 353 (20), 307 (8), 295 (24), 267 (41), 266 (19), 252
Eburnamenineꢀ14ꢀylmethanol (5). Compound 4 (2.4 g,
6.86 mmol) was added portionwise with stirring to a suspension
of LiAlH4 (0.78 g, 20.6 mmol) in anhydrous THF (50 mL). The
reaction mixture was refluxed. After the completion of the reacꢀ
tion (monitoring by TLC, Sorbfil, ethyl acetate) ethyl acetate
(10 mL) and water (50 mL) were added, and the mixture was

1238
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Voskressensky et al.
extracted with ethyl acetate (3×50 mL). The extracts were dried
with MgSO4. The solvent was distilled off in vacuo. The residue
was recrystallized from a hexane—ethyl acetate mixture. Comꢀ
pound 5 was obtained in a yield of 1.67 g (79%), colorless crysꢀ
tals, m.p. 149—152 C (ethyl acetate—hexane) (cf. lit. data15:
foamed oil). Found (%): C, 77.72; H, 7.73; N, 8.94. C20H24N2O.
Calculated (%): C, 77.89; H, 7.84; N, 9.08. The 1H NMR specꢀ
trum corresponds to the published data.15 MS, m/z (Irel (%)):
308 [M]+ (67), 307 (38), 280 (21), 279 (100), 252 (18), 251 (25),
250 (35), 249 (21), 236 (16), 222 (18), 208 (38), 206 (20), 193
(31), 180 (21), 167 (12), 154 (13), 125 (16), 42 (24), 41 (25).
Eburnamenineꢀ14ꢀylmethyl acetate (6). Acetic anhydride
(0.28 g, 2.76 mmol) was added to a solution of eburnamenineꢀ
14ꢀylmethanol 5 (0.85 g, 2.76 mmol) in triethylamine (0.334 g,
3.31 mmol). The reaction mixture was refluxed for 1.5 h (moniꢀ
toring by TLC, Sorbfil, 7 : 1 ethyl acetate—ethanol). Then the
reaction mixture was cooled, poured into cold water (50 mL),
and extracted with diethyl ether (3×40 mL). The extract was
dried over MgSO4. The solvent and excess triethylamine were
removed. After the distillation, the yellow oil was purified on
alumina. Compound 6 was obtained in a yield of 0.78 g (81%),
yellow oil. Found (%): C, 75.19; H, 7.30; N, 7.85. C22H26N2O2.
Calculated (%): C, 75.40; H, 7.48; N, 7.99. IR, /cm–1: 1738
tion (in the case of 8) or chromatography on alumina using
a 1 : 3 ethyl acetate—hexane mixture as the eluent (in the case of
9 and 10) was performed.
Methyl (2E)ꢀ3ꢀ{14ꢀmethoxyꢀ7,8,13,14ꢀtetrahydroindoloꢀ
[3,2ꢀe][2]benzazoninꢀ6(5H)ꢀyl}acrylate (8). Yield 0.38 g (50%),
beige crystals, m.p. 215—217 C (ethyl acetate—hexane).
Found (%): C, 73.22; H, 6.38; N, 7.30. C23H24N2O3. Calculatꢀ
ed (%): C, 73.38; H, 6.43; N, 7.44. IR, /cm–1: 1681 (CO).
1H NMR (300 MHz, CDCl3), : 2.96—3.05 (m, 1 H, CH2);
3.10—3.25 (m, 2 H, CH2); 3.36 (s, 3 H, OMe); 3.60 (s, 3 H,
CO2Me); 3.63—3.75 (m, 2 H, CH2, C(5)H); 4.31 (d, 1 H, C(5)H,
J = 15.8 Hz); 4.74 (br.s, 1 H, CH=CHCO2Me); 5.54 (br.s, 1 H,
C(14)H); 7.11—7.30 (m, 5 H, Ar); 7.36 (d, 1 H, CH=CHCO2Me,
J = 13.1 Hz); 7.44 (t, 1 H, Ar, J = 7.9 Hz); 7.57 (d, 1 H, Ar,
J = 7.9 Hz); 7.89 (s, 1 H, NH); 7.96 (d, 1 H, Ar, J = 7.9 Hz).
13C NMR (100 MHz, CDCl3), : 21.4, 50.5, 56.3, 57.3, 58.9,
73.6, 86.4, 96.0, 111.1, 118.2, 119.5, 122.6, 125.5, 126.3, 127.7,
128.7, 130.4, 132.4, 133.6, 136.1, 138.7, 150.0, 169.7. MS, m/z
(Irel (%)): 376 [M]+ (35), 345 (43), 344 (16), 249 (18), 248 (100),
246 (15), 232 (21), 231 (32), 230 (79), 218 (25), 217 (48), 216
(33), 202 (14), 159 (35), 144 (22), 143 (54), 134 (21), 130 (16),
119 (21), 115 (24).
(3E)ꢀ4ꢀ{14ꢀMethoxyꢀ7,8,13,14ꢀtetrahydroindolo[3,2ꢀe]ꢀ
[2]benzazoninꢀ6(5H)ꢀyl}butꢀ3ꢀenꢀ2ꢀone (9). Yield 0.20 g (28%),
yellow crystals, m.p. 177—179 C (ethyl acetate—hexane).
Found (%): C, 76.41; H, 6.58; N, 7.64. C23H24N2O2. Calculatꢀ
ed (%): C, 76.64; H, 6.71; N, 7.77. IR, /cm–1: 1652 (CO).
1H NMR (400 MHz, CD3OD), : 1.70 (br.s, 3 H, COMe);
2.99—3.03 (m, 1 H, CH2); 3.13—3.33 (m, 2 H, CH2); 3.35 (s, 3 H,
OMe); 3.63—3.67 (m, 1 H, CH2); 3.92 (d, 1 H, C(5)H,
J = 14.9 Hz); 4.53 (d, 1 H, C(5)H, J = 14.9 Hz); 4.99 (d, 1 H,
CH=CHCOMe, J = 13.7 Hz); 5.59 (br.s, 1 H, C(14)H);
7.00—7.08 (m, 2 H, Ar); 7.21—7.33 (m, 4 H, Ar, CH=CHCOMe);
7.44—7.56 (m, 2 H, Ar); 7.84—7.97 (m, 2 H, NH, Ar). MS, m/z
(Irel (%)): 360 [M]+ (65), 345 (54), 329 (32), 328 (16), 260 (17),
249 (19), 248 (100), 246 (16), 244 (21), 232 (25), 231 (34), 230
(100), 218 (24), 217 (55), 216 (39), 159 (21), 144 (20), 143 (35),
119 (18), 115 (20).
1
(CO). H NMR (600 MHz, CDCl3), : 0.98 (t, 3 H, CH3CH2,
J = 7.5 Hz); 1.11 (td, 1 H, CH2, J = 13.7 Hz, J = 3.9 Hz);
1.39—1.46 (m, 2 H, CH2); 1.67—1.78 (m, 2 H, CH2, MeCH2);
1.90—1.94 (m, 1 H, MeCH2); 2.07 (s, 3 H, MeCO); 2.50 (ddd, 1 H,
CH2, J = 15.9 Hz, J = 5.0 Hz, J = 1.7 Hz); 2.63—2.66 (m, 1 H,
CH2); 2.69—2.73 (m, 1 H, CH2); 2.99—3.06 (m, 1 H, CH2);
3.22—3.27 (m, 1 H, CH2); 3.36 (dd, 1 H, CH2, J = 13.7 Hz,
J = 5.5 Hz); 4.20 (s, 1 H, C(3)H); 4.92 (d, 1 H, CH2OAc,
J = 13.2 Hz); 5.17 (s, 1 H, C(15)H); 5.33 (d, 1 H, CH2OAc,
J = 13.2 Hz); 7.09—7.12 (m, 1 H, Ar); 7.14—7.17 (m, 1 H, Ar);
7.36 (d, 1 H, Ar, J = 8.3 Hz); 7.47 (d, 1 H, Ar, J = 7.5 Hz). MS,
m/z (Irel (%)): 350 [M]+ (11), 321 (26), 280 (26), 261 (8), 248 (3),
233 (3), 221 (5), 220 (5), 219 (5), 206 (5), 205 (6), 204 (6), 193
(4), 191 (4), 43 (100), 42 (48), 41 (15).
Methyl (2E)ꢀ3ꢀ{8,13ꢀdihydroꢀ5Hꢀbenzo[1,2]indolizino[8,7ꢀb]ꢀ
indoleꢀ13b(7H)ꢀyl}acrylate (7). A solution of benzoindolizinoꢀ
indole 1 (0.28 g, 1.06 mmol) and methyl propiolate (0.36 g,
4.23 mmol) in acetonitrile (15 mL) was refluxed until the reacꢀ
tion was completed (monitoring by TLC, Sorbfil, ethyl acetate).
The solvent was distilled off in vacuo, and the residue was chroꢀ
matographed on alumina using a 1 : 10 ethyl acetate—hexane
mixture as the eluent. Compound 7 was obtained in a yield of
15 mg (4%), yellow crystals, m.p. 168—170 C (ethyl acetate—hexꢀ
ane). Found (%): C, 76.50; H, 5.72; N, 8.00. C22H20N2O2. Calꢀ
culated (%): C, 76.72; H, 5.85; N, 8.13. IR, /cm–1: 1724 (CO).
1H NMR (300 MHz, CDCl3), : 2.63 (dd, 1 H, CH2, J = 3.7 Hz,
J = 15.8 Hz); 3.11—3.22 (m, 1 H, CH2); 3.28—3.45 (m, 2 H,
CH2); 3.74 (s, 3 H, OMe); 4.18—4.27 (m, 2 H, C(5)H); 4.22
(d, 1 H, CH=CHCO2Me, J = 15.7 Hz); 7.08—7.37 (m, 8 H, Ar,
CH=CHCO2Me); 7.51 (d, 1 H, Ar, J = 7.4 Hz); 7.74 (s, 1 H,
NH). MS, m/z (Irel (%)): 344 [M]+ (19), 285 (6), 260 (18), 259
(100), 258 (7), 257 (14), 256 (11), 255 (6), 254 (7), 129 (10), 128 (9).
Reactions of benzoindolizinoindole 1 with methyl propiolate,
acetylacetylene, and DMAD (general procedure). A solution of
benzoindolizinoindole 1 (2 mmol) and methyl propiolate, acetylꢀ
acetylene, or DMAD (3 mmol) in methanol (20 mL) was kept at
40 C until the reaction was completed (TLC monitoring, Sorbꢀ
fil, ethyl acetate). After distillation of methanol, the crystallizaꢀ
Dimethyl (2E)ꢀ2ꢀ{14ꢀmethoxyꢀ7,8,13,14ꢀtetrahydroindoꢀ
lo[3,2ꢀe][2]benzazoninꢀ6(5H)ꢀyl}butꢀ2ꢀenedioate (10). Yield
0.21 g (24%), colorless crystals, m.p. 210—212 C (ethyl aceꢀ
tate—hexane). Found (%): C, 68.92; H, 5.89; N, 6.31. C25H26N2O5.
Calculated (%): C, 69.11; H, 6.03; N, 6.45. IR, /cm–1: 1737
(CO), 1692 (CO). 1H NMR (300 MHz, CDCl3), : 3.02 (d, 1 H,
C(5)H, J = 15.8 Hz); 3.09—3.29 (m, 2 H, CH2); 3.42 (s, 3 H,
MeO); 3.56 (s, 3 H, CO2Me); 3.68 (br.s, 3 H, CO2Me);
3.74—3.82 (m, 2 H, CH2); 4.43 (d, 1 H, C(5)H, J = 15.8 Hz);
4.68 (s, 1 H, =CHCO2Me); 5.92 (s, 1 H, C(14)H); 7.07—7.25
(m, 5 H, Ar); 7.41 (t, 1 H, Ar, J = 7.9 Hz); 7.55 (d, 1 H, Ar,
J = 7.9 Hz); 7.81 (s, 1 H, NH); 7.97 (d, 1 H, Ar, J = 7.9 Hz).
13C NMR (150 MHz, CDCl3). : 23.5, 51.0, 52.8, 54.0, 56.5,
58.7, 73.0, 100.0, 111.2, 111.3, 118.3, 119.5, 122.7, 124.9, 126.3,
127.6, 128.5, 130.1, 132.8, 133.1, 136.3, 139.4, 153.9, 166.1,
167.9. MS, m/z (Irel (%)): 434 [M]+ (5), 403 (5), 375 (4), 343 (5),
276 (4), 260 (10), 250 (5), 249 (15), 248 (100), 246 (6), 244 (6),
233 (5), 232 (12), 231 (13), 230 (40), 218 (13), 217 (34), 216 (21),
202 (4), 159 (4), 144 (4), 143 (9), 134 (7), 119 (9), 115 (9).
Dimethyl 13ꢀ[(4ꢀmethylphenyl)sulfonyl]ꢀ5,13ꢀdihydroꢀ6,8aꢀ
ethanoindolo[3,2ꢀe][2]benzazonineꢀ7,8ꢀdicarboxylate (11). A soꢀ
lution of benzoindolizinoindole 2 (0.20 g, 0.48 mmol) and
DMAD (0.14 g, 0.96 mmol) in dichloromethane (12 mL) was

Synthesis of annulated azecines and azonines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1239
stirred at 20 C until the reaction was completed (TLC monitorꢀ
ing, Sorbfil, ethyl acetate). Dichloromethane was distilled off
in vacuo, and the residue was crystallized from an ethyl aceꢀ
tate—hexane mixture. Benzazonine 11 was obtained in a yield of
0.11 g (39%), yellow crystals, m.p. 198—200 C (ethyl acetate—hexꢀ
ane). Found (%): C, 66.76; H, 4.99; N, 4.96. C31H28N2O6S.
Calculated (%): C, 66.89; H, 5.07; N, 5.03. IR, /cm–1: 1725
1.23—1.30 (m, 1 H, CH2); 1.50—1.64 (m, 2 H, CH2); 1.72—1.91
(m, 4 H, CH2, CH2Me, C(15)H); 2.31 (dd, 1 H, CH2, J = 9.3 Hz,
J = 13.8 Hz); 2.75 (d, 1 H, C(15)H, J = 13.4 Hz); 2.84—2.99
(m, 2 H, CH2); 3.19—3.26 (m, 1 H, CH2); 3.22 (s, 3 H, OMe);
3.54—3.58 (m, 1 H, CH2); 3.70—3.73 (m, 1 H, CH2); 3.72 (s, 3 H,
CO2Me); 3.83 (s, 3 H, CO2Me); 4.20 (s, 1 H, OH); 4.60 (s, 1 H,
C(8)H); 4.83 (d, 1 H, CH=CHCO2Me, J = 13.1 Hz); 7.14—7.22
(m, 3 H, Ar); 7.53 (d, 1 H, Ar, J = 6.9 Hz); 7.60 (d, 1 H,
CH=CHCO2Me, J = 13.1 Hz). 13C NMR (100 MHz, CDCl3),
: 8.0, 20.3, 22.5, 26.9, 33.1, 40.3, 40.8, 50.9, 54.4, 55.5, 56.3,
60.6, 75.4, 82.9, 86.5, 112.1, 113.5, 118.5, 120.5, 123.0, 128.0,
133.2, 135.3, 150.4, 169.8, 174.9. MS, m/z (Irel (%)): 471 (22),
470 [M]+ (79), 456 (26), 455 (100), 452 (32), 439 (44), 438 (15),
437 (20), 423 (49), 421 (19), 405 (32), 380 (22), 379 (83), 186
(49), 174 (17), 168 (17), 167 (16), 158 (17), 156 (20), 82 (29).
Methyl 7ꢀethylꢀ14ꢀhydroxyꢀ8ꢀmethoxyꢀ3ꢀ[(1E)ꢀ3ꢀoxobutꢀ1ꢀ
enꢀ1ꢀyl]ꢀ1,2,3,4,5,6,7,8ꢀoctahydroꢀ7,9ꢀethanoazecino[5,4ꢀb]ꢀ
indoleꢀ14ꢀcarboxylate (14). Yield 0.29 g (63%), colorless crysꢀ
tals, m.p. 221—222 C (ethyl acetate). Found (%): C, 68.47;
H, 7.39; N, 6.02. C26H34N2O5. Calculated (%): C, 68.70;
H, 7.54; N, 6.16. IR, /cm–1: 1745 (CO), 1652(CO). 1H NMR
(400 MHz, CDCl3), : 0.86 (t, 3 H, CH2CH3, J = 7.5 Hz);
1.26—1.30 (m, 1 H, CH2); 1.53—1.62 (m, 2 H, CH2); 1.69—1.91
(m, 4 H, CH2, CH2Me, C(15)H); 2.18 (s, 3 H, COMe); 2.36
(dd, 1 H, CH2, J = 8.7 Hz, J = 13.1 Hz); 2.75 (d, 1 H, C(15)H,
J = 13.4 Hz); 2.90—2.99 (m, 2 H, CH2); 3.19—3.26 (m, 1 H,
CH2); 3.21 (s, 3 H, OMe); 3.56—3.60 (m, 1 H, CH2); 3.73—3.76
(m, 1 H, CH2); 3.83 (s, 3 H, CO2Me); 4.16 (s, 1 H, OH); 4.64
(s, 1 H, C(8)H); 5.33 (br.s, 1 H, CH=CHCOMe); 7.14—7.23
(m, 3 H, Ar); 7.53 (d, 1 H, Ar, J = 6.9 Hz); 7.61 (d, 1 H,
CH=CHCOMe, J = 13.7 Hz). 13C NMR (100 MHz, CDCl3),
: 8.0, 20.5, 22.8, 27.0, 28.6, 33.1, 40.3, 40.7, 54.4, 55.2, 56.2,
60.6, 75.4, 82.9, 98.9, 112.2, 113.3, 118.5, 120.5, 123.1, 127.9,
133.3, 135.4, 149.7, 174.8, 195.6. MS, m/z (Irel (%)): 454 [M]+
(24), 439 (54), 436 (25), 422 (27), 421 (79), 238 (25), 224 (46),
194 (29), 186 (100), 182 (26), 180 (44), 174 (26), 168 (62),
167 (73), 158 (53), 156 (35), 154 (23), 144 (34), 143 (26), 140
(38), 43 (31).
Dimethyl (2E)ꢀ2ꢀ[7ꢀethylꢀ14ꢀhydroxyꢀ8ꢀmethoxyꢀ14ꢀ(methꢀ
oxycarbonyl)ꢀ1,4,5,6,7,8ꢀhexahydroꢀ7,9ꢀethanoazecino[5,4ꢀb]ꢀ
indolꢀ3(2H)ꢀyl]butꢀ2ꢀenedioate (15). Yield 0.39 g (73%), colorꢀ
less crystals, m.p. 201—203 C (ethyl acetate). Found (%):
C, 63.37; H, 6.71; N, 5.22. C28H36N2O8. Calculated (%):
C, 63.62; H, 6.86; N, 5.30. IR, /cm–1: 1755 (CO), 1739 (CO),
1671 (CO). 1H NMR (400 MHz, CDCl3), : 0.83 (t, 3 H,
CH2CH3, J = 7.5 Hz); 1.18—1.22 (m, 1 H, CH2); 1.53—1.60
(m, 2 H, CH2Me, CH2); 1.62—1.70 (m, 1 H, CH2); 1.78—1.88
(m, 3 H, CH2, CH2Me, C(15)H); 2.27 (ddd, 1 H, CH2, J = 14.3 Hz,
J = 6.9 Hz, J = 1.9 Hz); 2.73 (d, 1 H, C(15)H, J = 13.7 Hz);
2.83—2.89 (m, 1 H, CH2); 2.98 (dd, 1 H, CH2, J = 14.9 Hz,
J = 4.4 Hz); 3.21 (ddd, 1 H, CH2, J = 14.3 Hz, J = 11.8 Hz,
J = 1.9 Hz); 3.32 (s, 3 H, OMe); 3.59 (dd, 1 H, CH2, J = 14.4 Hz,
J = 8.3 Hz); 3.68 (s, 3 H, CO2Me); 3.77—3.82 (m, 1 H, CH2);
3.82 (s, 3 H, CO2Me); 3.97 (s, 3 H, CO2Me); 4.48 (s, 1 H, OH);
4.57 (s, 1 H, C(8)H); 4.69 (s, 1 H, CH=); 7.13—7.21 (m, 3 H,
Ar); 7.48 (d, 1 H, Ar, J = 8.1 Hz). 13C NMR (150 MHz, CDCl3),
: 8.1, 20.1, 22.7, 24.6, 26.3, 33.0, 39.0, 41.0, 51.1, 53.0,
54.5, 56.2, 58.1, 74.5, 82.9, 88.8, 112.2, 112.6, 118.5, 120.5,
123.1, 127.8, 133.2, 135.4, 154.4, 166.6, 167.9, 174.9. MS,
m/z (Irel (%)): 528 [M]+ (72), 514 (29), 513 (100), 510 (20), 497
(30), 496 (17), 495 (35), 469 (47), 437 (26), 356 (19), 266 (16),
1
(CO), 1708 (CO), 1354 (SO), 1169 (SO). H NMR (400 MHz,
CDCl3), : 1.40 (t, 2 H, CH2, J = 7.8 Hz); 2.41 (s, 3 H, ArMe);
2.94—3.02 (m, 1 H, CH2); 3.06—3.13 (m, 1 H, CH2); 3.31 (s, 3 H,
CO2Me); 3.40 (s, 3 H, CO2Me); 4.13 (d, 1 H, C(5)H,
J = 11.8 Hz); 4.32 (d, 1 H, C(5)H, J = 11.8 Hz); 6.87 (d, 1 H, Ar,
J = 7.4 Hz); 7.03 (t, 1 H, Ar, J = 7.4 Hz); 7.07—7.11 (m, 2 H, Ar,
C(14)H); 7.20—7.30 (m, 6 H, Ar); 7.70 (d, 2 H, Ar, J = 8.2);
7.86 (d, 1 H, Ar, J = 8.2 Hz). 13C NMR (150 MHz, CDCl3),
: 21.8, 41.1, 49.1, 50.8, 51.8, 52.3, 57.5, 117.4, 122.0, 122.1,
125.5, 126.8, 127.6 (2 C), 128.3, 128.4, 129.7 (2 C), 130.6, 130.8,
132.5, 132.8, 135.4, 135.6, 136.3, 139.6, 142.2, 145.0, 145.8,
164.0, 166.8. MS, m/z (Irel (%)): 557 (0.1), 556 [M]+ (0.3), 526
(0.2), 525 (0.5), 497 (0.3), 492 (0.2), 442 (0.2), 402 (20.3), 401
(80.5), 374 (22.8), 373 (100.0), 341 (10.2), 327 (8.4), 326 (35.6),
314 (8.0), 283 (14.8), 282 (18.8), 281 (14.5), 256 (19.3), 255
(49.2), 254 (42.0), 253 (13.4), 241 (7.8), 230 (12.4), 228 (8.5),
115 (13.5), 91 (38.2).
(3E)ꢀ4ꢀ{13ꢀ[(4ꢀMethylphenyl)sulfonyl]ꢀ8,13ꢀdihydroꢀ5Hꢀ
benzo[1,2]indolizino[8,7ꢀb]indolꢀ13b(7H)ꢀyl}butꢀ3ꢀenꢀ2ꢀone
(12). A solution of benzoindolizinoindole 2 (0.19 g, 0.46 mmol)
and acetylacetylene (0.11 g, 1.61 mmol) in dichloromethane
(12 mL) was stirred at 20 C until the reaction was completed
(TLC monitoring, Sorbfil, ethyl acetate). The solvent was disꢀ
tilled off in vacuo. The residue was chromatographed on SiO2.
Compound 12 was eluted with a 1 : 1 ethyl acetate—hexane mixꢀ
ture; the yield was 0.10 g (44%), orange oil. Found (%): C, 71.94;
H, 5.31; N, 5.68. C29H26N2O3S. Calculated (%): C, 72.17;
H, 5.43; N, 5.80. IR, /cm–1: 1668 (CO), 1362 (SO), 1169 (SO).
1H NMR (400 MHz, CDCl3), : 2.28 (s, 3 H, ArMe); 2.36 (s, 3 H,
COMe); 2.58 (dd, 1 H, CH2, J = 17.6 Hz, J = 5.1 Hz); 2.78
(ddd, 1 H, CH2, J = 17.6 Hz, J = 11.8 Hz, J = 6.1 Hz); 2.58 (dd,
1 H, CH2, J = 14.5 Hz, J = 6.1 Hz); 2.78 (ddd, 1 H, CH2,
J = 14.5 Hz, J = 11.8 Hz, J = 5.1 Hz); 4.00 (d, 1 H, C(5)H,
J = 12.4 Hz); 4.05 (d, 1 H, C(5)H, J = 12.4 Hz); 6.33 (d, 1 H,
CH=CHCOMe, J = 16.1 Hz); 7.05 (d, 2 H, Ar, J = 8.5 Hz);
7.10—7.14 (m, 1 H, Ar); 7.18—7.23 (m, 3 H, Ar); 7.32 (d, 2 H,
Ar, J = 8.5 Hz); 7.35—7.37 (m, 1 H, Ar); 7.46—7.53 (m, 1 H,
Ar); 7.65 (d, 1 H, CH=CHCOMe, J = 16.1 Hz); 7.82—7.84
(m, 1 H, Ar); 8.28—8.30 (m, 1 H, Ar). MS, m/z (Irel (%)): 483
[M + H]+ (100).
Reactions of eburnamenine derivative 3 with methyl propiolꢀ
ate, acetylacetylene, and DMAD (general procedure). A solution
of eburnamenine 3 (1 mmol) and methyl propiolate, acetylacetꢀ
ylene, or DMAD (1.5 mmol) in methanol (60 mL) was refluxed
until the reaction was completed (TLC monitoring, Sorbfil, ethyl
acetate). Methanol was distilled off in vacuo, and the residue was
crystallized from ethyl acetate.
Methyl 7ꢀethylꢀ14ꢀhydroxyꢀ8ꢀmethoxyꢀ3ꢀ[(1E)ꢀ3ꢀmethoxyꢀ
3ꢀoxopropꢀ1ꢀenꢀ1ꢀyl]ꢀ1,2,3,4,5,6,7,8ꢀoctahydroꢀ7,9ꢀethanoꢀ
azecino[5,4ꢀb]indoleꢀ14ꢀcarboxylate (13). Yield 0.37 g (78%),
colorless crystals, m.p. 205—206 C (ethyl acetate). Found (%):
C, 66.15; H, 7.12; N, 5.80. C26H34N2O6. Calculated (%):
C, 66.36; H, 7.28; N, 5.95. IR, /cm–1: 1742 (CO), 1668(CO).
1H NMR (400 MHz, CDCl3), : 0.86 (t, 3 H, CH2CH3, J = 7.5 Hz);

1240
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
Voskressensky et al.
224 (19), 186 (35), 180 (17), 168 (18), 167 (18), 158 (20),
156 (17), 144 (18).
CH2); 1.39 (t, 3 H, OCH2CH3, J = 7.1 Hz); 1.47—1.69 (m, 2 H,
CH2, CH2Me); 1.72—1.84 (m, 1 H, CH2Me); 1.86—1.97 (m, 1 H,
CH2); 2.37 (dd, 1 H, CH2, J = 14.5 Hz, J = 5.1 Hz); 2.93—3.04
(m, 2 H, CH2); 3.16—3.27 (m, 1 H, CH2); 3.32 (s, 3 H, OMe);
3.52 (dd, 1 H, CH2, J = 14.0 Hz, J = 8.6 Hz); 3.68 (s, 3 H,
CO2Me); 3.83—3.92 (m, 1 H, CH2); 3.93 (s, 3 H, CO2Me); 4.37
(s, 1 H, C(8)H); 4.41 (q, 2 H, OCH2Me, J = 7.1 Hz); 4.64 (s, 1 H,
CH=); 6.34 (s, 1 H, C(15)H); 7.14—7.27 (m, 2 H, Ar); 7.31 (d, 1 H,
Ar, J = 8.1 Hz); 7.47 (d, 1 H, Ar, J = 7.5 Hz). MS, m/z (Irel (%)):
524 [M]+ (67), 509 (24), 495 (21), 494 (11), 493 (24), 465 (11),
352 (27), 324 (15), 312 (13), 311 (56), 310 (100), 309 (20), 308
(13), 294 (14), 282 (13), 280 (26), 266 (10), 252 (16), 214 (13).
Methyl (2E)ꢀ3ꢀ{7ꢀethylꢀ14ꢀ(hydroxymethyl)ꢀ8ꢀmethoxyꢀ
1,4,5,6,7,8ꢀhexahydroꢀ7,9ꢀethenoazecino[5,4ꢀb]indolꢀ3(2H)ꢀ
yl}acrylate (19). Yield 0.24 g (57%), colorless crystals, m.p.
136—138 C (ethyl acetate). Found (%): C, 70.49; H, 7.44;
N, 6.48. C25H32N2O4. Calculated (%): C, 70.73; H, 7.60;
N, 6.60. IR, /cm–1: 1696 (CO). 1H NMR (400 MHz, CDCl3),
: 0.93 (t, 3 H, CH2CH3, J = 7.4 Hz); 1.23—1.46 (m, 2 H, CH2);
1.59—1.78 (m, 4 H, CH2, CH2Me); 2.33 (s, 1 H, CH2OH); 2.56
(dd, 1 H, CH2, J = 13.6 Hz, J = 2.0 Hz); 2.86—2.98 (m, 2 H,
CH2); 3.10—3.39 (m, 2 H, CH2); 3.16 (s, 3 H, OMe); 3.71 (s, 3 H,
CO2Me); 3.75—3.81 (m, 1 H, CH2); 4.02 (s, 1 H, C(8)H); 4.61
(d, 1 H, CH2OH, J = 13.4 Hz); 4.81 (d, 1 H, CH=CHCO2Me,
J = 13.4 Hz); 4.90 (d, 1 H, CH2OH, J = 13.4 Hz); 5.09 (s, 1 H,
C(15)H); 7.16—7.21 (m, 1 H, Ar); 7.26—7.31 (m, 1 H, Ar); 7.53
(d, 1 H, Ar, J = 7.8 Hz); 7.57 (d, 1 H, CH=CHCO2Me,
J = 13.4 Hz); 7.78 (d, 1 H, Ar, J = 8.4 Hz). MS, m/z (Irel (%)):
424 [M]+ (44), 409 (11), 395 (20), 393 (30), 377 (17), 363 (23),
282 (13), 269 (30), 268 (100), 252 (20), 239 (10), 238 (40), 236
(16), 223 (13), 222 (12), 208 (16), 206 (10), 193 (11), 180 (10).
(3E)ꢀ4ꢀ{7ꢀEthylꢀ14ꢀ(hydroxymethyl)ꢀ8ꢀmethoxyꢀ1,4,5,6,
7,8ꢀoctahydroꢀ7,9ꢀethenoazecino[5,4ꢀb]indolꢀ3(2H)ꢀyl}butꢀ3ꢀ
enꢀ2ꢀone (20). Yield 0.12 g (28%), colorless crystals, m.p.
139—141 C (ethyl acetate). Found (%): C, 73.22; H, 7.75;
N, 6.77. C25H32N2O3. Calculated (%): C, 73.50; H, 7.90; N, 6.86.
Reactions of eburnamenine derivatives 4 and 5 with methyl
propiolate, acetylacetylene, and DMAD (general procedure).
A solution of compound 4 or 5 (1 mmol) and methyl propiolate,
acetylacetylene, or DMAD (2 mmol) in methanol (20 mL) was
kept at 40 C until the reaction was completed (monitoring by
TLC, Sorbfil, ethyl acetate). Methanol was distilled off in vacuo.
The residue was chromatographed on alumina using a 1 : 5 ethyl
acetate—hexane mixture as the eluent for compounds 16—18
and ethyl acetate as the eluent for compounds 19—21.
Ethyl 7ꢀethylꢀ8ꢀmethoxyꢀ3ꢀ[(1E)ꢀ3ꢀmethoxyꢀ3ꢀoxopropꢀ1ꢀ
enꢀ1ꢀyl]ꢀ1,2,3,4,5,6,7,8ꢀoctahydroꢀ7,9ꢀethenoazecino[5,4ꢀb]ꢀ
indoleꢀ14ꢀcarboxylate (16). Yield 0.38 g (82%), colorless crysꢀ
tals, m.p. 157—159 C (ethyl acetate—hexane). Found (%):
C, 69.25; H, 7.22; N, 5.88. C27H34N2O5. Calculated (%):
C, 69.50; H, 7.35; N, 6.00. IR, /cm–1: 1721 (CO), 1693 (CO).
1H NMR (400 MHz, CDCl3), : 0.86—1.02 (m, 1 H, CH2); 0.97
(t, 3 H, CH2CH3, J = 7.4 Hz); 1.34—1.47 (m, 1 H, CH2); 1.39
(t, 3 H, OCH2CH3, J = 7.2 Hz); 1.56—1.88 (m, 4 H, CH2,
CH2Me); 2.48 (dd, 1 H, CH2, J = 14.1 Hz, J = 4.9 Hz);
2.92—3.00 (m, 2 H, CH2); 3.19—3.38 (m, 2 H, CH2); 3.22
(s, 3 H, OMe); 3.71 (s, 3 H, CO2Me); 3.73—3.82 (m, 1 H, CH2);
4.08 (s, 1 H, C(8)H); 4.42 (q, 2 H, OCH2Me, J = 7.2 Hz); 4.79
(d, 1 H, CH=CHCO2Me, J = 13.1 Hz); 6.22 (s, 1 H, C(15)H);
7.16—7.24 (m, 2 H, Ar); 7.31—7.34 (m, 1 H, Ar); 7.51—7.57
(m, 2 H, Ar, CH=CHCO2Me). MS, m/z (Irel (%)): 466 [M]+ (27),
437 (15), 435 (16), 419 (13), 407 (10), 324 (14), 311 (42), 310
(100), 296 (10), 294 (16), 282 (24), 280 (28), 266 (16), 252 (35),
250 (10), 237 (16), 220 (12), 206 (10), 203 (16), 193 (12).
Ethyl 7ꢀethylꢀ8ꢀmethoxyꢀ3ꢀ[(1E)ꢀ3ꢀoxobutꢀ1ꢀenꢀ1ꢀyl]ꢀ
1,2,3,4,5,6,7,8ꢀoctahydroꢀ7,9ꢀethenoazecino[5,4ꢀb]indoleꢀ14ꢀ
carboxylate (17). Yield 0.19 g (43%), colorless crystals, m.p.
156—158 C (ethyl acetate—hexane). Found (%): C, 71.69;
H, 7.48; N, 6.14. C27H34N2O4. Calculated (%): C, 71.97; H, 7.61;
N, 6.22. IR, /cm–1: 1722 (CO), 1662 (CO). 1H NMR (400 MHz,
CDCl3), : 0.88—1.02 (m, 1 H, CH2); 0.97 (t, 3 H, CH2CH3,
J = 7.3 Hz); 1.36—1.46 (m, 1 H, CH2); 1.40 (t, 3 H, OCH2CH3,
J = 7.1 Hz); 1.60—1.82 (m, 4 H, CH2, CH2Me); 2.15 (s, 3 H,
COMe); 2.50—2.60 (m, 1 H, CH2); 2.92—3.10 (m, 2 H, CH2);
3.17—3.41 (m, 2 H, CH2); 3.21 (s, 3 H, OMe); 3.76—3.85
(m, 1 H, CH2); 4.04 (s, 1 H, C(8)H); 4.42 (q, 2 H, OCH2Me,
J = 7.1 Hz); 5.29 (br.s, 1 H, CH=CHCOMe); 6.21 (s, 1 H,
C(15)H); 7.17—7.25 (m, 2 H, Ar); 7.31—7.36 (m, 1 H, Ar);
7.50—7.57 (m, 2 H, Ar, CH=CHCOMe). 13C NMR (100 MHz,
DMSOꢀd6), : 7.6, 13.9, 20.8, 20.9, 26.5, 26.9, 30.0, 42.8, 54.1,
55.3, 55.8, 61.5, 73.4, 98.5, 112.4, 115.9, 118.9, 120.6, 123.1,
127.8, 128.9, 129.1, 132.8, 135.2, 152.0, 163.0, 194.8. MS, m/z
(Irel (%)): 450 [M]+ (94), 435 (30), 434 (26), 421 (38), 419 (23),
389 (14), 377 (17), 338 (47), 325 (14), 324 (14), 311 (22), 310
(100), 294 (13), 282 (23), 280 (33), 266 (21), 252 (35), 252 (45),
237 (25), 220 (20), 206 (14), 204 (12), 193 (15), 180 (12), 140
(72), 43 (12).
1
IR, /cm–1: 1643 (CO). H NMR (400 MHz, CDCl3), : 0.93
(t, 3 H, CH2CH3, J = 7.4 Hz); 1.17—1.37 (m, 1 H, CH2);
1.57—1.69 (m, 3 H, CH2, CH2Me); 2.13—2.19 (m, 2 H, CH2);
2.16 (s, 3 H, COMe); 2.38 (t, 1 H, CH2OH, J = 6.0 Hz); 2.63
(d, 1 H, CH2, J = 13.0 Hz); 2.90—3.04 (m, 2 H, CH2); 3.12—3.38
(m, 2 H, CH2); 3.14 (s, 3 H, OMe); 3.81 (td, 1 H, CH2,
J = 13.8 Hz, J = 2.8 Hz); 3.98 (s, 1 H, C(8)H); 4.61 (dd, 1 H,
CH2OH, J = 13.5 Hz, J = 6.0 Hz); 4.90 (dd, 1 H, CH2OH,
J = 13.5 Hz, J = 6.0 Hz); 5.07 (s, 1 H, C(15)H); 5.31 (br.s, 1 H,
CH=CHCOMe); 7.17—7.21 (m, 1 H, Ar); 7.26—7.31 (m, 1 H,
Ar); 7.53 (d, 1 H, Ar, J = 7.4 Hz); 7.55 (d, 1 H, CH=CHCOMe,
J = 13.3 Hz); 7.78 (d, 1 H, Ar, J = 8.4 Hz). MS, m/z (Irel (%)):
408 [M]+ (40), 393 (49), 379 (18), 377 (16), 347 (16), 282 (15),
269 (22), 268 (100), 252 (28), 250 (18), 239 (19), 238 (68), 236
(31), 223 (27), 222 (17), 221 (14), 220 (17), 204 (14), 140 (59).
Dimethyl (2E)ꢀ2ꢀ{7ꢀethylꢀ14ꢀ(hydroxymethyl)ꢀ8ꢀmethoxyꢀ
1,4,5,6,7,8ꢀhexahydroꢀ7,9ꢀethenoazecino[5,4ꢀb]indolꢀ3(2H)ꢀ
yl}butꢀ2ꢀenedioate (21). Yield 0.19 g (40%), colorless crystals,
m.p. 133—135 C (ethyl acetate). Found (%): C, 66.96; H, 6.97;
N, 5.74. C27H34N2O6. Calculated (%): C, 67.20; H, 7.10; N, 5.81.
IR, /cm–1: 1742 (CO), 1698 (CO). 1H NMR (400 MHz,
CDCl3), : 0.77—0.87 (m, 1 H, CH2); 0.93 (t, 3 H, CH2CH3,
J = 7.5 Hz); 1.25—1.33 (m, 1 H, CH2); 1.45—1.55 (m, 1 H, CH2);
1.57—1.67 (m, 1 H, CH2); 1.71—1.86 (m, 2 H, CH2Me); 2.31
(t, 1 H, CH2OH, J = 6.0 Hz); 2.46 (ddd, 1 H, CH2, J = 14.6 Hz,
Dimethyl (2E)ꢀ2ꢀ{14ꢀ(ethoxycarbonyl)ꢀ7ꢀethylꢀ8ꢀmethoxyꢀ
1,4,5,6,7,8ꢀhexahydroꢀ7,9ꢀethenoazecino[5,4ꢀb]indolꢀ3(2H)ꢀ
yl}butꢀ2ꢀenedioate (18). Yield 0.22 g (42%), colorless crystals,
m.p. 154—156 C (ethyl acetate—hexane). Found (%): C, 66.21;
H, 6.80; N, 5.26. C29H36N2O7. Calculated (%): C, 66.39;
H, 6.92; N, 5.34. IR, /cm–1: 1738 (CO), 1725 (CO), 1701
1
(CO). H NMR (400 MHz, CDCl3), : 0.51—0.62 (m, 1 H,
CH2); 0.97 (t, 3 H, CH2CH3, J = 7.4 Hz); 1.10—1.30 (m, 1 H,

Synthesis of annulated azecines and azonines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1241
J = 5.8 Hz, J = 2.4 Hz); 2.91—3.02 (m, 2 H, CH2); 3.19 (ddd,
1 H, CH2, J = 15.0 Hz, J = 11.8 Hz, J = 1.9 Hz); 3.26 (s, 3 H,
OMe); 3.48—3.55 (m, 1 H, CH2); 3.67 (s, 3 H, CO2Me); 3.86
(ddd, 1 H, CH2, J = 14.9 Hz, J = 4.3 Hz, J = 2.2 Hz); 3.91 (s, 3 H,
CO2Me); 4.30 (s, 1 H, C(8)H); 4.61 (dd, 1 H, CH2OH,
J = 13.5 Hz, J = 6.0 Hz); 4.67 (s, 1 H, CH=); 4.88 (dd, 1 H,
CH2OH, J = 13.5 Hz, J = 6.0 Hz); 5.22 (s, 1 H, C(15)H); 7.17
(t, 1 H, Ar, J = 7.4 Hz); 7.23—7.31 (m, 1 H, Ar); 7.48 (d, 1 H,
Ar, J = 7.8 Hz); 7.77 (d, 1 H, Ar, J = 8.4 Hz). MS, m/z (Irel (%)):
482 [M]+ (74), 467 (57), 453 (38), 451 (35), 435 (18), 423 (25),
422 (27), 421 (100), 310 (21), 282 (17), 269 (26), 268 (61), 252
(21), 250 (18), 238 (29), 222 (24), 208 (32), 193 (25), 180 (23).
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T. J. Rayl, I. Hwang, D. L. Boger, J. Am. Chem. Soc., 2009,
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Received May 16, 2011;
in revised form November 30, 2012