Synthesis of hexahydro[1,4]diazocino[7,8,1-jk]carbazoles and 1-methoxy-9-(β-vinylethylamino)ethylcarbazoles

Article abstract of DOI:10.1007/s10593-012-1035-x

3-Ethylhexahydropyrazino[3,2,1-jk]carbazole is converted into hexahydro[1,4]diazocino[7,8,1-jk]carb-azoles by the action of methyl propiolate and acetylacetylene in acetonitrile and into 1-methoxy-9-(β- vinylethylamino)ethylcarbazoles by the action of ace

Full text of DOI:10.1007/s10593-012-1035-x

Chemistry of Heterocyclic Compounds, Vol. 48, No. 4, July, 2012 (Russian Original Vol. 48, No. 4, April, 2012)
SYNTHESIS OF HEXAHYDRO[1,4]DIAZOCINO[7,8,1-jk]CARBAZOLES
AND 1-METHOXY-9-(β-VINYLETHYLAMINO)ETHYLCARBAZOLES
L. G. Voskressensky1**, V. G. Granik1*, T. N. Borisova1, A. A. Titov1,
E. I. Grishina1, E. A. Sorokina1, and A. V. Varlamov1
3-Ethylhexahydropyrazino[3,2,1-jk]carbazole is converted into hexahydro[1,4]diazocino[7,8,1-jk]carb-
azoles by the action of methyl propiolate and acetylacetylene in acetonitrile and into 1-methoxy-
9-(β-vinylethylamino)ethylcarbazoles by the action of acetylenedicarboxylic ester and methyl propiolate
in methanol. 3-Benzyl-substituted pyrazinocarbazole does not react with alkynes.
Keywords: hexahydrodiazocinocarbazoles, 1-methoxy-9-(β-vinylethylamino)ethylcarbazoles, pyrazine
ring cleavage domino reaction, pyrazine ring extension domino reaction,.
Earlier we have found that tetrahydropyrrolo[1,2-a]pyrazines are converted into tetrahydropyrrolo[1,2-d]-
[1,4]diazocines in domino transformations under the action of alkynes activated with electron-withdrawing
substituents in acetonitrile [1, 2]. In methanol, mixtures of the corresponding diazocines and the products of
cleavage of the tetrahydropyrazine ring involving a molecule of methanol, i.e., 2-methoxyethyl-
(methoxybenzyl)-substituted pyrroles, are mostly formed [1]. By means of the investigated reaction it is
possible to convert tetrahydropyridines and tetrahydropyrazines, fused with an aromatic and a heteroaromatic
ring, into the corresponding fused azocines and diazocines, which allowed to propose this approach as a general
method for construction such heterocyclic systems [3].
With the aim of extending the synthesis limits of the reaction we chose a heterocyclic system containing
partially hydrogenated pyrazine and carbazole fragments, i.e. 8-methyl-2,3,3a,4,5,6-hexahydro-
1H-pyrazino[3,2,1-jk]carbazole (1). This compound is used in medical practice as an antidepressant (Pyrazidol)
[4]. Alkylation of the pyrazinocarbazole 1 was realized by the action of ethyl iodide and benzyl chloride in
acetonitrile in the presence of Hünig's base. The 3-ethyl- and 3-benzyl-substituted hexahydropyrazinocarbazoles
2 and 3 were obtained with yields of 72% and 95% respectively.
5
6
7
4
Me
Me
RHal
8
9
3a
EtN(i-Pr)2
MeCN
R
3 N
NH
N
N
10
2
1
1
2 R = Et; 3 R = Bn
2, 3
_______
*Deceased.
**To whom correspondence should be addressed, e-mail: lvoskressensky@sci.pfu.edu.ru.
1People's Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 665-669, April, 2012. Original
article submitted July 1, 2011.
620
0009-3122/12/4804-0620©2012 Springer Science+Business Media, Inc.

3-Ethyl-substituted pyrazinocarbazole 2 reacts with methyl propiolate, acetylacetylene, and dimethyl
acetylene dicarboxylate (DMAD) at 30°C with formation of multicomponent mixtures, which are separated by
chromatography on aluminum oxide. From the products of the reaction of compound 2 with methyl propiolate
and acetylene in acetonitrile, derivatives of the previously unknown heterocyclic system [1,4]diazocino[7,8,1-jk]-
carbazole 4 and 5 were isolated chromatographically with yields of 34% and 41% respectively. In methanol,
1-methoxycarbazoles 6 and 7, i.e., the products of cleavage of the pyrazine fragment of compound 2 involving a
molecule of methanol, were obtained.
7
8
9
6
Me
10
Me
5 Y
X
Y
MeCN
Y
C
11
2
N
N+
Et
4
12
N
3
X
1
X
N
2
A
Et
4, 5
MeOH
3
4
5
8
2
Me
Me
O
1
6
H
Me
7
OMe
Y
N
N+
Et

C
Y
N

X
N
B
X
6, 7
Et
4, 6 X = H, Y = CO2Me; 5 X = H, Y = COMe; 7 X = Y = CO2Me
The domino transformations of pyrazinocarbazole 2 evidently begin with formation of a zwitterion of
the ammonium type A. In acetonitrile the extension of the pyrazine ring to diazocine then occurs as a result of
attack by the anionic center on the C-3a atom. The reaction in methanol probably takes place through the
transition state B, leading to the cleavage of the pyrazine ring with participation of a solvent molecule and
formation of products 6 and 7.
The 3-benzyl-substituted pyrazinocarbazole 3 does not enter into reaction with DMAD, methyl
propiolate, and acetylacetylene in acetonitrile or in methanol even in the presence of an excess of the reagents or
on refluxing. This may be due to screening of the lone pair of the nitrogen atom by the sterically bulky benzyl
radical, thereby impeding its attack by the alkyne.
Structure of the obtained compounds was confirmed by a number of spectral methods. In the IR spectra
of compounds 4, 6, and 7 in the region of 1685-1744 cm−1 there are bands for the stretching vibrations of C=O
in ester groups, and the stretching vibrations of the keto group in compound 5 appear at 1632 cm−1. The
1H-NMR spectra are characterized by the presence of a signal in the region of 7.20-7.25 ppm, corresponding to
the H-4 atom of the enamino fragment in compounds 4 and 5. The trans substitution of the enamine fragment in
compound 6 is confirmed by the spin-spin coupling constant J = 13.1 Hz. The proton of the vinyl group of
compound 7 is observed in the form of a broad singlet at 4.72 ppm. In the spectra of 1-methoxycarbazoles 6 and
7 there are signals for the 1-MeO group in the form of a singlet at 3.47 ppm.
Thus, it has been shown for the first time that the tetrahydropyrazine fragment in pyrazino[3,2,1-jk]-
carbazoles can undergo extension to diazocine under the action of alkynes in acetonitrile, and cleavage with the
formation of 1-methoxycarbazoles in methanol. A benzyl substituent at the nitrogen atom of the pyrazine ring
prevents the tandem transformation reactions under the action of alkynes activated with electron-withdrawing
substituents.
621

EXPERIMENTAL
The IR spectra of the synthesized compounds were recorded in pellets with KBr on an Infralum FT
Fourier spectrometer. The 1H NMR spectra were recorded on Bruker-400 and JEOL JNM-ECA600
spectrometers (400 and 600 MHz respectively). The 13C spectra were recorded on a Bruker-400 spectrometer
(100 MHz). The residual signals of the solvent or TMS were used as internal standard. The mass spectra were
recorded on a Thermo Scientific MAT 95 XL chromato-mass spectrometer with direct injection into the ion
source at 70 eV (EI ionization). The LC/MS spectra were recorded on a system including an Agilent 100 Series
liquid chromatograph, an Agilent Technologies LC/MSD VL mass spectrometer (electrospray, CI at
atmospheric pressure), and a Sedex 75 ELSD detector. Elemental analysis was performed on a Carlo Erba 1106
instrument. The melting points of the synthesized compounds were determined on an SMP instrument. For thin-
layer chromatography, we used Sorbfil and Alufol plates (development with iodine vapor), and for column
chromatography we used neutral Fluka-507C Al2O3 (0.05-0.15 mm) and Acros silica gel (0.04-0.06 mm), 60 Å.
All the solvents used in the study were purified by distillation. The methyl propiolate, acetylacetylene,
and DMAD from Acros Organics were used without further purification.
3-Ethyl-8-methyl-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole (2). Hünig's base (0.94 g,
7.3 mmol) and EtI (0.84 g, 5.4 mmol) were added to a solution of pyrazinocarbazole 1 (1.10 g, 4.9 mmol) in
MeCN (20 ml) with constant stirring. The reaction was monitored by TLC (Sorbfil, EtOAc). The reaction was
finished after stirring for four days at room temperature. The precipitate was then filtered off and recrystallized
from a mixture of EtOAc and hexane. Yield 0.89 g (72%). Colorless crystals; mp 104-106°C (105-106°C
(MeOH) [5]); Rf 0.46 (Sorbfil, EtOAc–hexane, 1:1). 1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.17 (3Н, t,
J = 7.2, CH2CH3); 1.47-1.54 (1Н, m) and 1.81-1.89 (1Н, m, 5-СН2); 2.17-2.22 (1Н, m) and 2.30-2.34 (1Н, m,
4-CH2); 2.41-2.47 (1Н, m) and 3.06 (1Н, dq, J = 7.2, J = 13.1, NCH2CH3); 2.46 (3Н, s, 8-CH3); 2.64-2.68 (1Н,
m) and 2.74-2.78 (1Н, m, 6-CH2); 2.71-2.75 (1Н, m) and 3.33 (1Н, ddd, J = 1.1, J = 5.0, J = 12.1, 2-CH2); 3.42-
3.44 (1Н, m, Н-3а); 3.77-3.82 (1Н, m) and 4.15 (1Н, ddd, J = 1.1, J = 4.4, J = 11.0, 1-CH2); 6.97 (1Н, dd, J = 1.5,
J = 8.2, Н-9); 7.13 (1Н, d, J = 8.2, Н-10); 7.25 (1Н, br. s, Н-7). Mass spectrum, m/z (Irel, %): 254 [M]+ (37), 253
(14), 227 (16), 226 (100), 197 (28), 182 (9), 167 (5), 127 (7), 115 (5), 105 (13), 91 (3), 42 (4). Found, %:
C 80.11; H 8.58; N 10.94. C17H22N2. Calculated, %: C 80.27; H 8.72; N 11.01.
3-Benzyl-8-methyl-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole (3). Hünig's base (0.73 g,
5.4 mmol) and benzyl chloride (0.52 g, 4.1 mmol) were added with constant stirring to a solution of
pyrazinocarbazole 1 (0.85 g, 3.8 mmol) in MeCN (20 ml). The reaction was monitored by TLC (Alufol, EtOAc).
The reaction was finished after stirring at room temperature for seven days. The precipitate was then filtered off
and recrystallized from a mixture of EtOAc and hexane. Yield 1.13 g (95%). Colorless crystals; mp 173-175°C
(EtOAc–hexane); Rf 0.89 (Alufol, EtOAc). 1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.53-1.67 (1Н, m) and
1.83-1.96 (1Н, m, 5-CH2); 2.18-2.22 (1Н, m) and 2.37-2.44 (1Н, m, 4-CH2); 2.44 (3Н, s, 8-CH3); 2.60-2.66 (1Н,
m) and 3.13 (1Н, dd, J = 4.3, J = 12.3, 2-CH2); 2.64-2.72 (1Н, m) and 2.79 (1Н, dd, J = 6.2, J = 15.6, 6-CH2); 3.20
(1Н, d, AB-system, J = 13.2) and 4.29 (1Н, d, AB-system, J = 13.2, CH2Ph); 3.48-3.54 (1Н, m, Н-3а); 3.69 (1Н,
dt, J = 4.6, J = 11.7) and 4.03 (1Н, dd, J = 3.1, J = 10.8, 1-CH2); 6.96 (1Н, J = 8.1, Н-9); 7.10 (1Н, d, J = 8.1, Н-10);
7.25-7.39 (6Н, m, Н-7, Н Ph). Mass spectrum, m/z (Irel, %): 316 [M]+ (47), 315 (17), 289 (15), 288 (82), 225 (12),
223 (10), 198 (13), 197 (100), 196 (22), 195 (12), 182 (20), 181 (15), 180 (9), 178 (7), 177 (7), 154 (7), 141 (4),
115 (4), 91 (53), 65 (9). Found, %: C 83.34; H 7.52; N 8.74. C22H24N2. Calculated, %: C 83.50; H 7.64; N 8.85.
Methyl 3-Ethyl-10-methyl-2,3,5a,6,7,8-hexahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole-5-carboxyla-
te (4). Methyl propiolate (0.20 g, 2.4 mmol) was added to a solution of pyrazinocarbazole 2 (0.40 g, 1.6 mmol)
in MeCN (20 ml). The reaction was finished after five days at 30°C. It was monitored by TLC (Sorbfil,
EtOAc–hexane, 1:1). The solvent was evaporated under vacuum, and the residue was separated by column
chromatography (SiO2) with 1:15 EtOAc–hexane as eluent. Yield 0.18 g (34%). Yellow oil, solidifying on
1
standing; Rf 0.75 (Sorbfil, EtOAc–hexane, 1:1). IR spectrum, ν, cm−1: 1686 (C=O). H NMR spectrum (600
MHz), δ, ppm (J, Hz): 1.03 (3Н, t, J = 7.2, NCH2CH3); 1.71-1.80 (1Н, m), 2.02-2.10 (2Н, m) and 2.28-2.36 (1Н,
622

m, 6,7-CH2); 2.46 (3Н, s, 10-CH3); 2.71-2.74 (2Н, m, 8-CH2); 2.91-2.97 (2Н, m, NCH2CH3); 3.28-3.34 (1Н, m)
and 3.46 (1Н, ddd, J = 2.6, J = 4.7, J = 13.9, 2-CH2); 3.71 (3Н, s, CO2CH3); 4.04-4.05 (1Н, m, Н-5а); 4.10-4.15
(1Н, m) and 4.41 (1Н, ddd, J = 2.6, J = 9.9, J = 14.9, 1-CH2); 6.96 (1Н, dd, J = 1.5, J = 8.3, Н-11); 7.10 (1Н, d,
J = 8.3, Н-12); 7.20 (1Н, s, Н-4); 7.28 (1Н, br. s, Н-9). 13C NMR spectrum, δ, ppm: 14.6; 21.3; 21.4; 23.2; 29.3;
33.5; 43.4; 50.9; 52.6; 52.7; 107.8; 109.6; 112.4; 117.9; 121.9; 127.8; 128.1; 134.7; 138.2; 148.7; 168.6. Mass
spectrum, m/z (Irel, %): 338 [M]+ (100), 309 (8), 293 (13), 280 (23), 279 (97), 278 (15), 251 (15), 249 (11), 244
(12), 243 (15), 220 (10), 209 (19), 208 (23), 194 (18), 181 (10), 168 (10), 59 (39), 56 (21), 42 (15), 41 (10).
Found, %: C 74.34; H 7.61; N 8.20. C21H26N2O2. Calculated, %: C 74.53; H 7.74; N 8.28.
1-(3-Ethyl-10-methyl-2,3,5a,6,7,8-hexahydro-1H-[1,4]diazocino[7,8,1-jk]carbazol-5-yl)ethanone
(5). Acetylacetylene (0.10 g, 1.5 mmol) was added to a solution of pyrazinocarbazole 2 (0.30 g, 1.2 mmol) in
MeCN (15 ml). The reaction was finished after four days at 30°C. The reaction was monitored by TLC (Sorbfil,
EtOAc–hexane, 1:1). The solvent was evaporated under vacuum, and the residue was separated by column
chromatography (SiO2) with 1:5 EtOAc–hexane as eluent. Yield 0.16 g (41%). Yellow oil, solidifying on
1
standing; Rf 0.37 (Alufol, EtOAc–heptane, 1:4). IR spectrum, ν, cm−1: 1632 (C=O). H NMR spectrum (600
MHz), δ, ppm (J, Hz): 1.05 (3Н, t, J = 7.2, NCH2CH3); 1.69-1.76 (1Н, m), 1.91-2.01 (2Н, m), and 2.21-2.27
(1Н, m, 6,7-CH2); 2.27 (3Н, s, СОCH3); 2.44 (3Н, s, 10-CH3); 2.69-2.72 (2Н, m, 8-CH2); 2.90-2.96 (2Н, m,
NCH2CH3); 3.27-3.34 (1Н, m) and 3.40 (1Н, ddd, J = 3.0, J = 4.5, J = 13.7, 2-CH2); 4.09-4.14 (2Н, m) and 4.15
(1Н, ddd, J = 3.0, J = 9.7, J = 14.9, Н-5а, 1-CH2); 6.94 (1Н, dd, J = 1.2, J = 8.3, Н-11); 6.99 (1Н, s, Н-4); 7.07
(1Н, d, J = 8.3, Н-12); 7.25 (1Н, br. s, Н-9). Mass spectrum, m/z (Irel, %): 322 [M]+ (31), 280 (5), 279 (23), 251
(3), 234 (9), 194 (5), 181 (4), 150 (3), 56 (5), 43 (100). Found, %: C 78.04; H 8.00; N 8.62. C21H26N2O.
Calculated, %: C 78.22; H 8.13; N 8.69.
Methyl (2E)-3-{Ethyl[2-(1-methoxy-6-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)ethyl]amino}-acryla-
te (6). Methyl propiolate (0.12 g, 1.4 mmol) was added to a solution of pyrazinocarbazole 2 (0.30 g, 1.2 mmol)
in MeOH (15 ml). The reaction was finished after three days at 30°C. The reaction was monitored by TLC
(Alufol, EtOAc–heptane, 1:2). The solvent was evaporated under vacuum, and the residue was separated by
column chromatography (Al2O3) with 1:10 EtOAc–hexane as eluent. Yield 0.10 g (23%). Colorless crystals; mp
1
92-93°C (EtOAc–hexane); Rf 0.71 (Alufol, EtOAc–heptane, 1:2). IR spectrum, ν, cm−1: 1693 (C=O). H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 1.01 (3Н, t, J = 7.0, NCH2CH3); 1.77-1.97 (3Н, m) and 2.20-2.29 (1Н, m,
2,3-CH2); 2.44 (3Н, s, 6-CH3); 2.50-2.61 (1Н, m) and 2.76-3.01 (3Н, m, 4-CH2, NCH2CH3); 3.47 (3Н, s,
1-ОСНз); 3.47-3.51 (2Н, m, α-СН2); 3.69 (3Н, s, СO2СН3); 4.07-4.13 (1Н, m) and 4.29-4.40 (1Н, m, β-СН2);
4.44 (1Н, t, J = 3.4, Н-1); 4.73 (1Н, m, СН=СНСO2Ме); 7.04 (1Н, d, J = 8.3, Н-7); 7.15 (1Н, d, J = 8.3, Н-8);
7.30 (1Н, s, Н-5); 7.45 (Н, d, J = 13.1, СН=СНСO2Ме). Mass spectrum, m/z (Irel, %): 371 [М+Н]+. Found, %:
С 71.14; Н 8.01; N 7.44. С22H30N2O3. Calculated, %: С 71.32; Н 8.16; N 7.56.
Dimethyl 2-{Ethyl[2-(1-methoxy-6-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)ethyl]amino}but-
2-enedioate (7). DMAD (0.19 g, 1.3 mmol) was added to a solution of pyrazinocarbazole 2 (0.28 g, 1.1 mmol)
in MeOH (15 ml). The reaction was finished after seven days at 30°C. The reaction was monitored by TLC
(Alufol, EtOAc–heptane, 1:2). The solvent was evaporated under vacuum, and the residue was separated by
column chromatography (Al2O3) with 1:10 EtOAc–heptane as eluent. Yield 0.18 g (38%). Yellow crystals; mp
95-97°C (EtOAc–hexane); Rf 0.75 (Alufol, EtOAc–heptane, 1:2). IR spectrum, ν, cm−1: 1744 (С=O), 1697 (С=O).
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.00 (3Н, t, J = 7.0, NCH2CH3); 1.79-1.96 (3Н, m) and
2.21-2.31 (1Н, m, 2,3-СН2); 2.44 (3Н, s, 6-СН3); 2.51-2.62 (1Н, m), 2.68-2.82 (2Н, m), and 2.92-3.00 (1Н, m,
4-СН2, NCH2CH3); 3.44-3.52 (2Н, m, α-СН2); 3.47 (3Н, s, 1-ОСН3); 3.67 (3Н, s, СO2СН3); 3.95 (3Н, s,
СO2СН3); 4.12 (1Н, dt, J = 5.2, J = 11.1) and 4.39-4.50 (1Н, m, β-СН2); 4.49 (1Н, t, J = 3.6, Н-1); 4.72 (1Н, s,
СН=); 7.05 (1Н, d, J = 8.2, Н-7); 7.21 (1Н, d, J = 8.2, Н-8); 7.29 (Н, s, Н-5). GC/MS (ESI) spectrum, m/z: 429
[М+Н]+. Found, %: С 67.13; Н 7.40; N 6.44. C24H32N2O5. Calculated, %: С 67.27; Н 7.53; N 6.54.
The authors thank the team at the Collective Use Center, People's Friendship University of Russia for
assistance in the recording of the spectra.
623

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