Synthesis of 6-aryl-substituted azocino-[5,4-b]indoles from 1-aryl-substituted 2-ethyltetrahydro-β-carbolines

Article abstract of DOI:10.1007/s10593-014-1518-z

We optimized the reaction of tetrahydropyridine ring expansion in 1-aryl-substituted tetrahydro-β-carbolines by the action of activated alkynes and achieved higher than 70% yields of the target indoloazocines. The substituents in the 1-aryl ring and at th

Full text of DOI:10.1007/s10593-014-1518-z

Chemistry of Heterocyclic Compounds, Vol. 50, No. 5, August, 2014 (Russian Original Vol. 50, No. 5, May, 2014)
SYNTHESIS OF 6-ARYL-SUBSTITUTED AZOCINO-
[5,4-b]INDOLES FROM 1-ARYL-SUBSTITUTED
2-ETHYLTETRAHYDRO-β-CARBOLINES
L. G. Voskressensky1*, T. N. Borisova1, T. M. Chervyakova1, A. A. Titov1,
A. V. Kozlov1, E. A. Sorokina1, R. Samavati1, and A. V. Varlamov1
We optimized the reaction of tetrahydropyridine ring expansion in 1-aryl-substituted tetrahydro-
β-carbolines by the action of activated alkynes and achieved higher than 70% yields of the target
indoloazocines. The substituents in the 1-aryl ring and at the indole nitrogen atom were shown to affect
the rate and selectivity of this transformation.
Keywords: activated alkynes, azocinoindoles, domino reaction, ring expansion.
Indoles fused with medium-sized rings attract the attention of synthetic and medicinal chemists due to
their remarkable and diverse biological activity. Azocinoindoles containing two pharmacophore fragments are a
part of many alkaloids [1, 2]. However, only few methods for the synthesis of azocinoindoles have been
described, with multiple stages and low yields of the target products [3]. We have previously proposed a method
for the synthesis of tetrahydroazocino[5,4-b]- and tetrahydroazocino[4,5-b]indoles based on a domino reaction of
the tetrahydropyridine fragment expansion in β- and γ-carbolines, by using activated alkynes [4, 5]. The yields of
6-methyl(isopropyl, benzyl)tetrahydroazocino[5,4-b]indoles in acetonitrile were 40-50%. The reaction in
methanol was accompanied by cleavage of the carboline tetrahydropyridine ring with the participation of a
methanol molecule [5]. The 6-aryl-substituted tetrahydroazocino[5,4-b]indoles gave only 6-(2-fluorophenyl)-
and 6-(4-fluorophenyl)tetrahydroazocinoindoles in the aforementioned domino reaction.
In the case of 1-(m-fluorophenyl)-substituted β-carboline transformation by the action of dimethyl ester
of acetylene dicarboxylic acid (DMAD) in the presence of indole or 5-methoxyindole, the initial ammonium
zwitterion А was shown to undergo cleavage at the С(1)–N bond, giving an "open" cation В. The electrophilic
substitution of the latter in indole "trap" produced a diindolylarylmethane [6].
Initial biological screening showed that the azocino[5,4-b]- and azocino[4,5-b]indoles are effective
inhibitors of acetyl- and butyrylcholine esterases, and can be further developed as drugs against
neurodegeneration [5]. Azocines condensed with 4-aminopyrimidine fragment exhibited high cytotoxic activity
during the initial screening. However, no chemical transformations of tetrahydroazocinoindoles have been
studied thus far.
_______
*To whom correspondence should be addressed, e-mail: lvoskressensky@sci.pfu.edu.ru.
1Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 716-728, May, 2014. Original
article submitted March 21, 2014.
658
0009-3122/14/5005-0658©2014 Springer Science+Business Media New York

X
X
–
X
X
+
N
N
Et
Et
N
H
N
H
Ar
Ar
A
Et
X
–
N
Et
R
X
X
N
N
H
X
Ar
N
R
+
H
N
H
Ar
B
N
H
Ar = 3-FC6H4; R = H, OMe; X = CO2Me
Our research interests were focussed on the chemical transformations of 6-aryl-substituted azocino[5,4-b]-
indoles, the synthesis of which was accomplished by a domino reaction between 1-aryl-substituted tetrahydro-β-
carbolines and activated alkynes. This reaction had to be optimized in order to obtain good yields of the 6-aryl-
substituted tetrahydroazocinoindoles.
Therefore, we studied the influence of electronic effects due to the substituents at position 1 of the aryl
fragment, at the indole nitrogen atom, and alkyne substituents, as well as the type of solvent and catalysts on the
tetrahydropyridine ring expansion reaction rate and selectivity in carbolines.
The N-ethylcarbolines 1а,с-е were obtained from β-carbolines synthesized according to the literature
method [5] by treatment with ethyl iodide. Compound 1b was described in the same work.
EtI, DMF
K2CO3
ArCHO
NH2
NH
Ar
N
Et
room temp.
7 days
N
H
N
H
N
H
1a–e
Ar
1a,b
room temp.
50 min
NaH
DMF
N
N
Et
Et
EtI
75°C, 5 h
TsCl
75°C, 5 h
N
N
Ar
Ar
Et
Ts
2a,b
3a,b
a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 3-MeOC6H4, d Ar = 4-FC6H4, e Ar = 3-FC6H4
The 9-ethyl and 9-tosyl derivatives 2a,b and 3a,b were obtained by the action of ethyl iodide or tosyl
chloride on sodium derivatives of compounds 1a,b, formed in the reactions of compounds 1a,b with sodium
hydride in DMF.
The domino reaction of 1-aryl-substituted carbolines 1а-е with methyl propiolate, acetylacetylеne, and
DMAD was studied in dichloromethane, acetonitrile, and trifluoroethanol without catalysts, as well as in the
presence of CuI and 1-methylpyrrole. The yields of azocinoindoles depending on the reaction conditions are
presented in the Table 1.
659

TABLE 1. The Yields of Azocinoindoles 4-6 a-e Depending on the
Reaction Conditions*
Experi-
ment
Reaction
time
Azocine
Carboline
Alkyne
MP
Solvent
Catalyst*2
(yield, %)
1
2
3
4
5
6
7
8
1а
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CF3CH2OH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CF3CH2OH
MeCN
―
1-MePyr
CuI
―
7 days
10 days
10 days
2 days
2 days
15 days
8 days
10 days
1 h
2 days
15 days
3 days
5 days
3 days
3 days
2 days
15 days
4 days
4 days
9 days
2 days
7 days
7 days
4.5 h
4a (73)
4a (61)
4a (83)
5a (34)
5a (65)
6a (25)
4b (75)
4b (86)
4b (29)
5b (92)
6b (25)
4c (31)
4c (72)
4c (75)
4c (71)
5c (76)
6c (2)
АА
―
DMAD*3
MP
―
1b
1c
―
1-MePyr
―
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
АА
―
DMAD
MP
―
―
1-MePyr
CuI
―
АА
―
DMAD
MP
АА
―
1d
1e
―
4d (84)
5d (77)
6d (9)
―
DMAD
MP
―
―
4e (56)
4e (47)
4e (78)
4e (62)
4e (89)
5e (45)
5e (60)
5e (44)
6e (27)
1-MePyr
CuI
―
―
7 days
3 days
1 h
7 days
11 days
АА
CH2Cl2
CF3CH2OH
MeCN
―
―
―
DMAD
CH2Cl2
―
_______
*MP – methyl propiolate, АА – acetylacetylene, 1-MePyr – 1-methylpyrrole.
*21.2 equiv. of 1-methylpyrrole and 30 mol% of CuI were used.
*3The reactions with DMAD were performed at 40°С using 5 equiv. of alkyne.
Methyl propiolate and acetylacetylene reacted with the carbolines 1a-c in dichloromethane at 20°С,
forming the respective azocines 4-6 a-c in 31-92% yields. The interaction of DMAD with carbolines and excess
alkyne at 40°С occurred with difficulty, producing multicomponent mixtures, from which only low yields of the
azocines 6а-е could be isolated by chromatography (experiments 6, 11, 17, 20, 29). The yields of azocino-
indoles with para-substituted phenyl group (experiments 7, 10, 18, 19) were substantially higher than in the
case of meta-substituted aryl fragments (experiments 12, 16, 21, 26). The obtained results are in good
Et
11
10
2
3N
1
4
N
Y
Et
9
X
Y
+
5
7
6
20°C
8
N
H
N
Ar
X
H
1a–e
Ar
4–6 a–e
4 X = CO2Me, Y = H; 5 X = COMe, Y = H; 6 X = Y = CO2Me; a Ar = Ph,
b Ar = 4-MeOC6H4, c Ar = 3-MeOC6H4, d Ar = 4-FC6H4, e Ar = 3-FC6H4
660

agreement with our mechanistic interpretation of this process, including the formation of the "open" cation B,
the generation and stability of which is dictated by the electronic effects of the aryl ring substituents at the С-1
atom in accordance with the values of Hammett constants σ and σ+ for methoxy groups and fluorine atom [7].
The addition of 30 mol% CuI relative to carboline allowed to increase the yield of azocinoindoles 4a,c,e
(experiments 3, 14, 23) to 75-83% (i.e., by 22-41%). The presence of 1-methylpyrrole (1.2 equiv.) also
increased the yield of azocinoindoles 4b,с to 86 and 72%, respectively (experiments 8, 13). Using acetonitrile as
solvent allowed to substantially improve the yields of azocines 4c,e (experiments 15, 25).
Two published examples [8, 9] show that the interaction of N-tosylindolizinoindoles with DMAD is
accompanied by tetrahydropyridine fragment cleavage and the formation of a polycyclic structure featuring a
spiro[indole-3,4'-pyridine] fragment. This observation is explained by the decreased electron density at position
3 of the indole ring due to the electron-withdrawing effect of the tosyl group. In order to establish the effect of
substituents at the indole nitrogen atom on the transformation of tetrahydropyridine ring under the action of
alkynes, we studied the reactions of N-ethyl- and N-tosyl-substituted carbolines 2a,b and 3a,b with terminal
alkynes.
The carboline 2a reacts with methyl propiolate, acetylacetylene, and DMAD in dichloromethane at
30°C, forming the azocino[5,4-b]indoles 7а-с. The reaction of carboline 2b with methyl propiolate and
acetylacetylene occurs at room temperature, giving the azocines 7d,e.
Et
N
CH2Cl2
Y
X
Y
2a,b
+
N
X
Ar
Et
7a–e
7 a–c Ar = Ph, d,e Ar = 4-MeOC6H4; a,d X = CO2Me, Y = H; b,e X = COMe, Y = H; c X = Y = CO2Me
The higher reactivity of p-methoxyphenyl derivative 2b and the superior yields of the azocinoindoles
7d,e (63 and 68%) were apparently caused by the stabilization of the "open" cation B by the para-
methoxyphenyl radical.
The N-tosyl-substituted carboline 3a reacts with methyl propiolate only in refluxing acetonitrile or
dichloromethane. Furthermore, the completion of the reaction required a 10-fold excess of alkyne and a
considerable time (2-4 weeks). At the same time, the carboline 3a did not react with DMAD in dichloromethane
even after prolonged heating.
Et
N
HC
CO2Me
3a
+
Et
N
CH2Cl2
, 30 days
MeCN
, 15 days
8a (62%) +
CO2Me
Ph
N
CO2Me
N
Ph
Ts
Ts
9 (3%)
8a (54%)
The interaction of carboline 3a with methyl propiolate in acetonitrile resulted only in the isolation of
azocinoindole 8a, while the reaction with methyl propiolate in dichloromethane produced besides the
azocinoindole 8а also the spiro[indole-3,4'-pyridine] 9.
The para-methoxyphenyl-substituted N-tosylcarboline 3b was more reactive towards alkynes in
dichloromethane. Thus, interaction with acetylacetylene gave the azocinoindole 8b in 68% yield even at room
temperature. The reaction with methyl propiolate required 10 days at reflux, and the respective azocine 8c was
obtained in 77% yield.
661

Et
N
CH2Cl2
HC
X
3b
+
N
X
Ts
8b (68%, X = COMe);
8c (77%, X = CO2Me)
OMe
Therefore, we have demonstrated that the electronic effects and the location of substituent in the aryl
fragment of 1-aryl-2,3,4,9-tetrahydrocarbolines affects the reaction rate and selectivity of tetrahydropyridine
ring expansion in carbolines. The yield of the corresponding azocinoindoles, as a rule, was higher in the series
of derivatives with a para-substituted aryl group. The use of catalysts (CuI and 1-methylpyrrole), as well as the
optimization of solvent was shown to increase the yields of 6-aryl-3-ethyl-2,3,6,7-tetrahydro-1H-azocino[5,4-b]-
indoles above 70%, enabling the further study of their reactivity. The introduction of electron donating ethyl
group at the nitrogen atom of the carboline indole ring essentially did not change the nature of the
transformations. The presence of an electron-acceptor (tosyl) substituent at the nitrogen atom of the indole
fragment decreased the rate of carboline reaction with alkynes, and led to the formation of mainly
azocinoindoles.
EXPERIMENTAL
1
IR spectra were recorded on an Infralum FT-801 FTIR spectrometer in KBr pellets. H NMR spectra
were recorded on JEOL JNM-ECS400 (400 MHz, compounds 1а,с-е, 2а, 3b, 7c, 8b) and JEOL JNM-ECA 600
instruments (600 MHz, the rest of compounds). The solvent was DMSO-d6 (compound 5с) or CDCl3 (the rest of
compounds), internal standard was TMS or the residual solvent protons. The LC/MS data were obtained with a
system including Agilent 1100 Series liquid chromatograph, Agilent Technologies LC/MSD VL mass
spectrometer (electrospray), and ELSD Sedex 75 detector. Elemental analysis was performed on a EuroEA3000
instrument. Melting points were determined on an SMP 10 apparatus. Thin-layer chromatography was
performed on Sorbfil and Alufol plates (development with iodine vapor, KMnO4 and H2SO4 solutions), and
silica gel from Acros (0.04-0.06 mm), 60 Å was used for column chromatography.
All the solvents used in this work were purified by distillation. Methyl propiolate, acetylacetylene, and
DMAD were purchased from Acros Organics and used without additional purification.
Synthesis of the Starting N-Ethyl-substituted β-Carbolines 1a,с-e (General Method). Potassium
carbonate (4.47 g, 32 mmol) was added to a solution of the corresponding 1-aryl-β-carboline (18 mmol) in DMF
(45 ml). Then EtI (2.63 g, 23 mmol) was added dropwise. The reaction mixture was stirred for 7 days at room
temperature. The reaction progress was controlled by TLC (Sorbfil, EtOAc). Water (30 ml) was added, and the
product was extracted with a 1:1 mixture of EtOAc–Et2O. The organic layer was dried over MgSO4, the solvent
was distilled off under reduced pressure, the residual DMF was removed under vacuum (oil pump). The
obtained oil was crystallized from MeOH.
2-Ethyl-1-phenyl-2,3,4,9-tetrahydro-1Н-β-carboline (1а). Yield 2.73 g (55%), yellow crystals,
1
mp 134-136°С. H NMR spectrum, δ, ppm (J, Hz): 1.08 (3Н, t, J = 7.6, NCH2CH3); 2.41-2.45 (1Н, m,
NCHBCH3); 2.66-2.75 (2Н, m, 4-CHB, NCHACH3); 2.82-2.85 (1Н, m) and 3.31 (1Н, dt, J = 4.1, J = 11.7,
3-СН2); 2.93-3.01 (1Н, m, 4-CHA); 4.59 (1Н, s, 1-CН); 7.05-7.11 (2Н, m, H-6,7); 7.12-7.16 (1Н, m, H-5); 7.19
(1H, br. s, NH); 7.27-7.37 (5H, m, H Ph); 7.49-7.53 (1Н, m, H-8). Mass spectrum, m/z: 277 [M+Н]+. Found, %:
C 82.49; H 7.33; N 10.19. С19Н20N2. Calculated, %: С 82.57; Н 7.29; N 10.14.
662

2-Ethyl-1-(3-methoxyphenyl)-2,3,4,9-tetrahydro-β-carboline (1с). Yield 3.03 g (55%), yellow
1
amorphous material, mp 82-84°С. H NMR spectrum, δ, ppm (J, Hz): 1.07 (3H, t, J = 6.9, NCH2CH3);
2.38-2.42 (1H, m, NCHBCH3); 2.64-2.74 (2Н, m, 4-CHB, NCHACH3); 2.79-2.85 (1H, m, 4-CHA); 2.92-3.00
(1H, m) and 3.31 (1H, dt, J = 3.4, J = 11.7, 3-CH2); 3.74 (3H, s, OCH3); 4.54 (1H, s, 1-CH); 6.83 (1H, dd,
J = 2.0, J = 8.2, H Ar); 6.91 (1H, br. s, H Ar); 6.94 (1H, d, J = 7.6, H Ar); 7.03-7.09 (2H, m, H-6,7); 7.12-7.16
(1H, m, H Ar); 7.21-7.27 (1H, m, H-5); 7.49 (1H, d, J = 8.2, H-8); 7.67 (1H, br. s, NH). Mass spectrum, m/z:
307 [М+H]+. Found, %: C 78.36; H 7.27; N 9.11. C20H22N2O. Calculated, %: C 78.40; H 7.24; N 9.14.
2-Ethyl-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1Н-β-carboline (1d). Yield 2.70 g (51%), colorless
crystals, mp 120-122°С. 1H NMR spectrum, δ, ppm (J, Hz): 1.12 (3Н, t, J = 7.2, NCH2CH3); 2.44-2.51 (1Н, m)
and 2.69-2.74 (1Н, m, 4-СН2); 2.76-2.82 (1Н, m) and 3.37 (1Н, dt, J = 4.8, J = 11.7, 3-СН2); 2.87-2.91 (1Н, m)
and 2.96-3.04 (1Н, m, NCH2CH3); 4.71 (1H, s, 1-CH); 7.02-7.04 (2Н, m, H Ar); 7.07-7.14 (2H, m, H Ar); 7.19
(1H, d, J = 7.6, H-5); 7.31 (1Н, br. s, NH); 7.32-7.37 (2H, m, H-6,7); 7.52 (1Н, d, J = 7.6, H-8). Mass spectrum,
m/z: 295 [М+H]+. Found, %: С 77.92; Н 6.21; N 9.72. С19Н19FN2. Calculated, %: C 77.52; H 6.51; N 9.52.
2-Ethyl-1-(3-fluorophenyl)-2,3,4,9-tetrahydro-β-carboline (1е). Yield 3.97 g (75%), yellow
1
amorphous material, mp 106-108°С. H NMR spectrum, δ, ppm (J, Hz): 1.07 (3Н, t, J = 6.9, NCH2CH3);
2.39-2.43 (1Н, m, NCHBCH3); 2.64-2.72 (2Н, m, 4-CHB, NCHACH3); 2.80-2.85 (1Н, m, 4-CHA); 2.89-2.98
(1Н, m) and 3.24-3.30 (1Н, m, 3-CH2); 4.58 (1Н, s, 1-CН); 6.97 (1Н, td, J = 2.8, J = 11.0, Н Ar); 7.04-7.11
(3Н, m, Н-6,7, H Ar); 7.14 (1Н, d, J = 7.6, Н-5); 7.18 (1Н, dd, J = 1.4, J = 6.9, H Ar); 7.21 (1Н, s, NН);
7.26-7.31 (1Н, m, H Ar); 7.50 (1Н, d, J = 7.6, H-8). Mass spectrum, m/z: 295 [М+H]+. Found, %: C 77.54;
H 6.52; N 9.54. C19H19FN2. Calculated, %: C 77.52; H 6.51; N 9.52.
Synthesis of β-Carbolines 2a,b and 3a,b (General Method). A solution of β-carboline 1а,b (8 mmol)
in anhydrous DMF (25 ml) at room temperature under argon atmosphere was treated with portions of NaH
(0.4 g, 10 mmol, 60% suspension in oil), followed after 50 min by dropwise addition of EtI (1.4 g, 9 mmol) or
TsCl (1.4 g, 1.1 mmol). The reaction mixture was stirred for 5 h at 75°C. The reaction progress was controlled
by TLC (Sorbfil, 1:5 EtOAc–hexane). The solvent was removed, the residue was purified by chromatography
on a silica gel column (1.5×20 cm), eluent 1:20 EtOAc–hexane. Compounds 2а,b were isolated as brown oils,
compounds 3а,b were colorless crystals.
1
2,9-Diethyl-1-phenyl-2,3,4,9-tetrahydro-1Н-β-carboline (2а). Yield 2.1 g (84%). H NMR spectrum,
δ, ppm (J, Hz): 0.95 (3H, t, J = 7.3, 2-CH2CH3); 1.22 (3H, t, J = 7.2, 9-CH2CH3); 2.61-2.72 (2H, m, 2-CH2CH3);
2.76-2.81 (1H, m, 4-CHВ); 2.88-3.09 (3H, m, 3-CH2, 4-CHА); 3.64-3.73 (1H, m) and 3.78-3.87 (1H, m,
9-CH2CH3); 4.91 (1H, s, 1-CH); 7.10-7.14 (1H, m, H Ar); 7.17-7.20 (3H, m, H Ar); 7.23-7.31 (4H, m, Н Ar);
7.58 (1H, d, J = 7.8, H-5). Mass spectrum, m/z (Irel, %): 304 [M]+ (28), 303 (7), 248 (16), 247 (80), 246 (92),
232 (14), 230 (14), 228 (19), 227 (100), 218 (18), 217 (38), 216 (10), 197 (8), 172 (6), 152 (6), 143 (7), 128 (5),
115 (10), 104 (4), 91 (6), 77 (9), 56 (10), 42 (16). Found, %: C 82.90; H 7.94; N 9.11. C21H24N2. Calculated, %:
C 82.85; H 7.95; N 9.20.
2,9-Diethyl-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1Н-β-carboline (2b). Yield 2.0 g (68%).
1H NMR spectrum, δ, ppm (J, Hz): 0.98 (3H, t, J = 7.2, 2-CH2CH3); 1.22 (3H, t, J = 7.2, 9-CH2CH3); 2.60-2.66
(1H, m) and 2.67-2.73 (1H, m, 2-CH2CH3); 2.76-2.80 (1H, m) and 2.94-2.99 (1H, m, 4-CH2); 2.90 (1H, ddd,
J = 3.1, J = 5.2, J = 12.0) and 3.04 (1H, ddd, J = 4.6, J = 9.4, J = 12.0, 3-CH2); 3.67-2.73 (1H, m) and 3.80-3.87
(1H, m, 9-CH2CH3); 3.78 (3H, s, OCH3); 4.88 (1H, s, 1-CH); 6.82 (2H, d, J = 8.9, Н Ar); 7.10-7.13 (3H, m,
Н Ar); 7.17-7.19 (1H, m, Н Ar); 7.26 (1H, d, J = 7.6, H-8); 7.58 (1H, d, J = 8.3, H-5). Mass spectrum, m/z (Irel,
%): 334 [M]+ (28), 333 (8), 305 (5), 278 (19), 277 (72), 276 (58), 262 (22), 247 (24), 246 (96), 245 (12), 234
(11), 233 (10), 232 (9), 230 (15), 228 (18), 227 (100), 218 (22), 217 (37), 205 (24), 204 (36), 197 (12), 172
(10), 168 (9), 167 (15), 156 (6), 143 (8), 138 (6), 130 (7), 121 (11), 115 (12), 102 (5), 91 (5), 77 (11), 56 (18),
42 (18). Found, %: C 79.28; H 7.60; N 8.56. C22H26N2O. Calculated, %: C 79.01; H 7.84; N 8.38.
2-Ethyl-9-[(4-methylphenyl)sulfonyl]-1-phenyl-2,3,4,9-tetrahydro-1Н-β-carboline
(3a).
Yield
1
2.68 g (78%). Mp 182-184°C. IR spectrum, ν, cm-1: 1168 (S=O), 1364 (S=O). H NMR spectrum, δ, ppm (J,
663

Hz): 1.27 (3H, t, J = 6.9, NCH2CH3); 2.28 (3H, s, ArCH3); 2.57-2.63 (2H, m, 4-CH2); 2.67-2.73 (1H, m,
NCHВCH3); 2.86-2.92 (2H, m, 3-CHВ, NCHАCH3); 2.95-3.01 (1H, m, 3-CHА); 5.62 (1H, s, 1-CH); 6.99 (2H, d,
J = 8.3, H Ar); 7.10 (2H, d, J = 7.6, H Ar); 7.20-7.24 (3H, m, H Ar); 7.27-7.30 (3H, m, H Ar); 7.33-7.35 (1H,
m, H Ar); 7.48 (1H, d, J = 7.6, H Ar); 8.16 (1H, d, J = 8.3, H Ar). Mass spectrum, m/z: 431 [M+H]+. Found, %:
C 72.45; H 6.02; N 6.48. C26H26N2O2S. Calculated, %: C 72.53; H 6.09; N 6.51.
2-Ethyl-1-(4-methoxyphenyl)-9-[(4-methylphenyl)sulfonyl]-2,3,4,9-tetrahydro-1Н-β-carboline (3b).
1
Yield 1.66 g (45%). Mp 105-107°C (Et2O–hexane). IR spectrum, ν, cm-1: 1169 (S=O), 1365 (S=O). H NMR
spectrum, δ, ppm (J, Hz): 1.27 (3H, t, J = 7.3, NCH2CH3); 2.30 (3H, s, АrСН3); 2.56-2.62 (2H, m, 4-CH2); 2.65-
2.72 (1H, m, NCHВCH3); 2.87-2.92 (2H, m, 3-CHВ, NCHАCH3); 2.95-3.00 (1H, m, 3-CHА); 3.79 (3H, s,
OCH3); 5.58 (1H, s, 1-CH); 6.74 (2H, d, J = 8.9, H Ar); 7.00-7.01 (4H, m, H Ar); 7.28-7.31 (3H, m, H Ar);
7.33-7.36 (1H, m, H Ar); 7.48 (1H, d, J = 7.6, H Ar); 8.17 (1H, d, J = 8.3, H Ar). Mass spectrum, m/z: 461
[M+H]+. Found, %: C 70.78; H 6.00; N 6.30. C27H28N2O3S. Calculated, %: C 70.41; H 6.13; N 6.08.
The Interaction of Carbolines 1a-e, 2a,b, 3a,b with Alkynes. A solution of β-carboline 1а-е, 2a,b, 3a,b
(1.09 mmol) in CH2Cl2, MeCN, or CF3CH2OH (10 ml) was treated with methyl propiolate or acetylacetylene
(2.18 mmol), or with DMAD (5.45 mmol). The reaction mixture was stirred at 20°С for the duration indicated
in Table 1, while controlling the reaction progress by TLC (Sorbfil, 1:3 EtOAc–hexane). The reaction with
DMAD was performed at 40°С. The solvent was removed under vacuum, the residue was recrystallized.
Azocines 6а,b, 7b,c,d, 8b, 9 were isolated by chromatography on a silica gel column (1.5×20 cm), the eluents
are described in the experimental details for each compound. The yields of azocines depending on the reagents
and reaction conditions used are given in Table 1.
The Interaction of Tetrahydrocarbolines 1а-c,e with Methyl Propiolate in the Presence of
N-Methylpyrrole (General Method). A solution of β-carboline 1а-c,e (1.09 mmol) in CH2Cl2 (10 ml) was treated
with methyl propiolate (0.110 g, 1.20 mmol) and N-methylpyrrole (0.105 g, 1.30 mmol). The reaction mixture
was stirred at 30°С for the duration indicated in Table 1. The reaction progress was controlled by TLC (Sorbfil,
1:3 EtOAc–hexane). The solvent was removed under vacuum, the residue was crystallized from Et2O. The
yields of azocines 4а-c,e are reported in Table 1.
The Interaction of Tetrahydrocarbolines 1а,c,e with Methyl Propiolate in the Presence of СuI
(General Method). A solution of β-carboline 1а,с,е (1.09 mmol) in CH2Cl2 (10 ml) was treated with methyl
propiolate (0.110 g, 1.20 mmol) and CuI (0.062 g, 0.32 mmol). The reaction mixture was stirred at 30°С for the
duration indicated in Table 1. The reaction progress was controlled by TLC (Sorbfil, 1:3 EtOAc–hexane). The
solvent was removed under vacuum, the residue was crystallized from Et2O. The yields of azocines 4a,c,e are
reported in Table 1.
The compounds obtained by using N-methylpyrrole or CuI had identical physicochemical and spectral
characteristics to the compounds obtained in the absence of catalysts.
Methyl 3-Ethyl-6-phenyl-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-5-carboxylate (4а). Colorless
crystals, mp 186-188°С (Et2O). IR spectrum, ν, cm-1: 1644 (С=О). 1H NMR spectrum, δ, ppm (J, Hz): 1.14 (3Н,
t, J = 6.9, NCH2CH3); 2.72 (1Н, td, J = 2.5, J = 15.8) and 3.65 (1Н, td, J = 2.5, J = 15.8, 2-СН2); 2.96 (1Н, dt,
J = 4.1, J = 14.4) and 3.09-3.15 (1Н, m, 1-СН2); 3.15-3.26 (2Н, m, NCH2CH3); 3.75 (3Н, s, ОCH3); 5.94 (1Н, s,
6-CН); 7.08-7.14 (3H, m, Н Ph); 7.15-7.18 (2H, m, Н Ph); 7.24 (2Н, t, J = 7.6, Н-9,10); 7.33 (1H, d, J = 8.3,
H-11); 7.48 (1Н, d, J = 7.6, H-8); 7.73 (1Н, s, Н-4); 8.14 (1Н, s, NH). Mass spectrum, m/z: 361 [M+H]+. Found,
%: C 76.56; H 6.74; N 7.82. С23Н24N2O2. Calculated, %: С 76.64; Н 6.71; N 7.77.
Methyl
3-Ethyl-6-(4-methoxyphenyl)-2,3,6,7-tetrahydro-1Н-azocino[5,4-b]indole-5-carboxylate
1
(4b). Colorless crystals, mp 232-234°C (Et2O). IR spectrum, ν, cm-1: 1603 (C=O). H NMR spectrum, δ, ppm
(J, Hz): 1.19 (3Н, t, J = 7.6, NCH2CH3); 2.72 (1Н, dt, J = 2.0, J = 13.9) and 3.80 (1H, td, J = 2.0, J = 13.9,
2-СН2); 2.99 (1Н, dt, J = 3.4, J = 15.1) and 3.16 (1Н, td, J = 4.1, J = 13.7, 1-СН2); 3.20-3.31 (2Н, m,
NCH2CH3); 3.74 (3Н, s, СO2СН3); 3.75 (3Н, s, ArOСН3); 6.25 (1H, s, 6-CH); 6.74 (2Н, d, J = 8.3, H Ar); 6.93
(2H, d, J = 8.3, H Ar); 7.10 (1Н, t, J = 7.6, Н-9); 7.15 (1H, t, J = 7.6, Н-10); 7.32 (1Н, d, J = 8.3, Н-11); 7.47
664

(1H, d, J = 8.3, Н-8); 7.49 (1Н, s, H-4); 8.33 (1Н, s, NH). Mass spectrum, m/z: 391 [M+H]+. Found, %: C 73.87;
H 6.65; N 7.37. С24Н26N2О3. Calculated, %: C 73.82; H 6.71; N 7.17.
Methyl 3-Ethyl-6-(3-methoxyphenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-5-carboxylate (4c).
1
Light-yellow crystals, mp 184-186°С (Et2O). IR spectrum, ν, cm-1: 1647 (С=О). H NMR spectrum, δ, ppm (J,
Hz): 1.09 (3Н, t, J = 7.6, NCH2CH3); 2.73 (1Н, dt, J = 2.8, J = 15.5) and 2.93 (1Н, dt, J = 2.8, J = 15.5, 1-CH2);
3.06-3.12 (1Н, m) and 3.62-3.66 (1Н, m, 2-CH2); 3.12-3.20 (2Н, m, NCH2CH3); 3.67 (3Н, s, ArOCH3); 3.69 (3Н,
s, CO2CH3); 5.86 (1Н, s, 6-CН); 6.62-6.70 (3Н, m, Н Ar); 7.06 (1Н, t, J = 7.6, Н Ar); 7.08-7.15 (2Н, m, Н-9,10);
7.28 (1Н, d, J = 8.2, H-11); 7.42 (1Н, d, J = 7.6, H-8); 7.66 (1Н, s, Н-4); 8.15 (1Н, s, NH). Mass spectrum, m/z:
391 [М+H]+. Found, %: C 73.97; H 6.76; N 7.11. C24H26N2O3. Calculated, %: C 73.82; H 6.71; N 7.17.
Methyl 3-Ethyl-6-(4-fluorophenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-5-carboxylate (4d).
1
Colorless crystals, mp 161-163°С (Et2O). IR spectrum, ν, cm-1: 1646 (С=О). H NMR spectrum, δ, ppm (J, Hz):
1.17 (3Н, t, J = 6.9, NCH2CH3); 2.73 (1Н, dt, J = 2.8, J = 16.5) and 3.14-3.19 (1Н, m, 1-CH2); 3.00 (1Н, dt,
J = 4.1, J = 15.1) and 3.61-3.67 (1Н, m, 2-СH2); 3.19-3.30 (2Н, m, NСH2CH3); 3.76 (3Н, s, СО2СН3); 5.89 (1Н, s,
6-CН); 6.94 (2Н, t, J = 8.9, Н Ar); 7.06-7.11 (2Н, m, Н Ar); 7.13 (1H, t, J = 6.9, Н-10); 7.19 (1H, t, J = 8.3, Н-9);
7.35 (1Н, d, J = 7.6, H-11); 7.49 (1H, d, J = 8.3, Н-8); 7.74 (1Н, s, H-4); 8.11 (1Н, s, NH). Mass spectrum, m/z:
379 [M+H]+. Found, %: C 72.92; H 6.16; N 7.48. С23Н23FN2О2. Calculated, %: С 73.00; Н 6.13; N 7.40.
Methyl 3-Ethyl-6-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-5-carboxylate (4e).
1
Light-gray crystals, mp 208-212°С (Et2O). IR spectrum, ν, cm-1: 1602 (С=О). H NMR spectrum, δ, ppm
(J, Hz): 1.16 (3Н, t, J = 6.9, NCH2CH3); 2.74-2.77 (1Н, m, 1-СНВ); 2.99-3.02 (1Н, m) and 3.58-3.62 (1Н, m,
2-СН2); 3.15-3.25 (3Н, m, NCH2CH3, 1-СНА); 3.76 (3Н, s, CO2CH3); 5.93 (1Н, s, 6-CН); 6.82-6.85 (2Н, m,
Н Ar); 6.89 (1Н, d, J = 8.3, Н Ar); 7.12 (1Н, t, J = 7.6, Н-10); 7.17-7.20 (2Н, m, Н-9, Н Ar); 7.33 (1Н, d,
J = 8.3, Н-11); 7.48 (1Н, d, J = 7.6, Н-8); 7.73 (1Н, s, Н-4); 8.19 (1Н, s, NH). Mass spectrum, m/z: 379
[М+H]+. Found, %: C 73.11; H 5.88; N 7.47. C23H23FN2O2. Calculated, %: C 73.00; H 6.13; N 7.40.
1-(3-Ethyl-6-phenyl-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indol-5-yl)ethanone (5a). Colorless crystals,
1
mp 280-283°С (Et2O). IR spectrum, ν, cm-1: 1633 (С=О). H NMR spectrum, δ, ppm (J, Hz): 1.05 (3Н, t,
J = 6.9, NCH2CH3); 2.28 (3Н, s, СОCH3); 2.54-2.56 (1Н, m, 1-СНВ); 3.00-3.14 (2Н, m, 2-СНВ, NCHВCH3);
3.23-3.29 (2Н, m, 1-СНА, NCHАCH3); 3.41-3.54 (1Н, m, 2-СНА); 6.19 (1Н, s, 6-CH); 6.85 (2Н, d, J = 7.8,
Н-11, Н Ph); 6.92 (1H, t, J = 7.3, Н Ph); 6.94-6.96 (1Н, m, H Ph); 7.00 (1H, t, J = 7.3, Н-10); 7.08 (1Н, t,
J = 7.3, H-9); 7.20 (2H, t, J = 7.3, Н Ph); 7.36 (1Н, d, J = 7.9, H-8); 7.64 (1Н, s, H-4). Mass spectrum, m/z: 345
[M+H]+. Found, %: C 80.12; H 7.05; N 8.21. С23Н24N2O. Calculated, %: С 80.20; Н 7.02; N 8.13.
1-[3-Ethyl-6-(4-methoxyphenyl)-2,3,6,7-tetrahydro-1Н-azocino[5,4-b]indol-5-yl]ethanone (5b). Color-
less crystals, mp 248-250°С (Et2O). IR spectrum, ν, cm-1: 1555 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.18
(3Н, t, J = 7.6, NCH2CH3); 2.34 (3Н, s, СОCH3); 2.75 (1Н, dt, J = 2.0, J = 15.1) and 2.99 (1Н, dt, J = 3.8,
J = 15.1, 1-СН2); 3.16 (1Н, td, J = 3.8, J = 13.0) and 3.80 (1H, td, J = 2.0, J = 13.0, 2-СН2); 3.20-3.31 (2Н, m,
NCH2CH3); 3.74 (3Н, s, OCH3); 6.25 (1H, s, 6-CH); 6.74 (2Н, d, J = 8.3, H Ar); 6.92 (2H, d, J = 8.3, H Ar);
7.10 (1Н, t, J = 7.5, Н-10); 7.15 (1H, t, J = 7.5, Н-9); 7.32 (1Н, d, J = 8.0, Н-11); 7.47 (1H, d, J = 8.3, Н-8);
7.49 (1Н, s, H-4); 8.33 (1Н, s, NH). Mass spectrum, m/z: 375 [M+H]+. Found, %: C 77.02; H 6.94; N 7.28.
С24Н26N2О2. Calculated, %: C 76.98; H 7.00; N 7.48.
1-[3-Ethyl-6-(3-methoxyphenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indol-5-yl]ethanone (5c). Color-
1
less crystals, mp >292°С (decomp., Et2O). IR spectrum, ν, cm-1: 1650 (С=О). H NMR spectrum, δ, ppm
(J, Hz): 1.06 (3H, t, J = 6.9, NCH2CH3); 2.24 (3H, s, СOCH3); 2.54-2.62 (1H, m) and 3.46-3.55 (1H, m,
2-CH2); 3.03-3.14 (1H, m, 1-CHВ); 3.24-3.36 (3H, m, 1-CHА, NCH2CH3); 3.60 (3H, s, OCH3); 6.15 (1H, s,
6-CH); 6.38 (1H, s, Н Ar); 6.46 (1H, d, J = 7.6, Н Ar); 6.74 (1H, d, J = 7.6, Н Ar); 6.92 (1H, t, J = 7.6, H-10);
7.00 (1H, t, H-9); 7.13 (1H, t, J = 7.6, Н Ar); 7.21 (1H, d, J = 7.6, H-11); 7.36 (1H, d, J = 7.6, H-8); 7.62 (1H, s,
H-4); 10.92 (1H, s, NH). Mass spectrum, m/z: 375 [М+H]+. Found, %: C 76.92; H 6.97; N 7.55. C24H26N2O2.
Calculated, %: C 76.98; H 7.00; N 7.48.
665

1-[3-Ethyl-6-(4-fluorophenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indol-5-yl]ethanone (5d). Colorless
1
crystals, mp 193-194°С (Et2O). IR spectrum, ν, cm-1: 1551 (С=С), 1628 (С=О). H NMR spectrum, δ, ppm (J,
Hz): 1.18 (3Н, t, J = 7.6, NCH2CH3); 2.33 (3Н, s, СОСН3); 2.73 (1Н, dt, J = 3.4, J = 16.5) and 3.00 (1Н, dt,
J = 4.8, J = 16.5, 1-СН2); 3.17 (1Н, td, J = 4.8, J = 13.8) and 3.65-3.68 (1Н, m, 2-СН2); 3.20-3.31 (2Н, m,
NCH2CH3); 6.28 (1Н, s, 6-CH); 6.86 (2Н, t, J = 8.9, Н Ar); 6.90-6.97 (2H, m, Н Ar); 7.10 (1H, t, J = 7.6, Н-9);
7.15 (1Н, t, J = 7.6, H-10); 7.32 (1H, d, J = 7.6, Н-8); 7.46 (1Н, d, J = 8.3, Н-11); 7.49 (1H, s, H-4); 7.66 (1Н,
s, NH). Mass spectrum, m/z: 363 [M+H]+. Found, %: C 76.14; H 6.43; N 7.78. С23Н23FN2O. Calculated, %:
С 76.22; Н 6.40; N 7.73.
1-[3-Ethyl-6-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indol-5-yl]ethanone (5e). Colorless
crystals, mp >278°С (decomp., Et2O). IR spectrum, ν, cm-1: 1609 (С=С), 1633 (С=О). 1H NMR spectrum, δ, ppm (J,
Hz): 1.20 (3Н, s, NCH2CH3); 2.34 (3Н, s, COCH3); 2.78 (1Н, dt, J = 2.7, J = 15.8) and 3.02 (1Н, dt, J = 2.7,
J = 15.8, 1-СН2); 3.16 (1Н, dd, J = 4.6, J = 13.7) and 3.68 (1Н, td, J = 2.3, J = 13.3, 2-СН2); 3.20-3.34 (2Н, m,
NCH2CH3); 6.32 (1Н, s, 6-CН); 6.70-6.78 (1Н, m, Н Ar); 6.77-6.84 (2Н, m, Н-10, Н Ar); 7.07 (3Н, m, Н-9, Н Ar);
7.33 (1Н, d, J = 7.6, Н-11); 7.47 (1Н, d, J = 7.8, Н-8); 7.50 (1Н, s, Н-4); 8.30 (1Н, s, NH). Mass spectrum, m/z: 363
[М+H]+. Found, %: C 76.20; H 6.40; N 7.67. C23H23FN2O. Calculated, %: C 76.22; H 6.40; N 7.73.
Dimethyl 3-Ethyl-6-phenyl-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-4,5-dicarboxylate (6a). The
eluent for column chromatography was 1:1 EtOAc–hexane. Yellow crystals, mp 198-200°С (EtOAc–hexane).
1
IR spectrum, ν, cm-1: 1683, 1727 (С=О). H NMR spectrum, δ, ppm (J, Hz): 0.91 (3Н, t, J = 6.9, NCH2CH3);
2.43 (1H, dd, J = 3.7, J = 14.4, 1-СНВ); 2.80-2.84 (1H, m, NCHВCH3); 3.04-3.21 (2H, m, 1-СНА, NCHАCH3);
3.25 (1Н, dd, J = 5.9, J = 15.1) and 3.53 (1Н, dd, J = 4.1, J = 14.4, 2-СН2); 3.73 (3Н, s, СО2СН3); 3.79 (3Н, s,
СО2СН3); 5.99 (1Н, s, 6-CН); 7.13 (1H, d, J = 7.3, H Ph); 7.15-7.20 (4H, m, H Ph); 7.23 (2Н, t, J = 7.3, H-9,10);
7.36 (1H, d, J = 7.8, Н-11); 7.49 (1Н, d, J = 7.8, H-8); 8.19 (1Н, s, NH). Mass spectrum, m/z: 419 [M+H]+.
Found, %: C 71.67; H 6.29; N 6.76. С25Н26N2O4. Calculated, %: С 71.75; Н 6.26; N 6.69.
Dimethyl 3-Ethyl-6-(4-methoxyphenyl)-2,3,6,7-tetrahydro-1Н-azocino[5,4-b]indole-4,5-dicarboxylate
(6b). The eluent for column chromatography was 1:5 EtOAc–hexane. Yield 0.12 g (25%), colorless crystals, mp
1
209-211°C (Et2O). IR spectrum, ν, cm-1: 1681, 1717 (C=O). H NMR spectrum, δ, ppm (J, Hz): 0.91 (3Н, t,
J = 7.2, NCH2CH3); 2.44 (1Н, dd, J = 3.7, J = 16.1, 1-СНВ); 2.78-2.84 (1Н, m, NCHВCH3); 3.16-3.25 (2Н, m,
1-СНА, NCHАCH3); 3.25 (1Н, dd, J = 4.8, J = 13.8) and 3.58 (1Н, dt, J = 4.3, J = 13.8, 2-СН2); 3.72 (3Н, s,
ArOСН3); 3.76 (3H, s, СО2СН3); 3.78 (3H, s, СО2СН3); 5.92 (1H, s, 6-CH); 6.76 (2Н, d, J = 8.9, H Ar); 6.98
(2H, d, J = 8.9, H Ar); 7.12 (1Н, t, J = 7.6, Н-10); 7.18 (1H, t, J = 7.6, Н-9); 7.34 (1H, d, J = 8.3, Н-11); 7.49
(1Н, d, J = 8.3, H-8); 8.15 (1Н, s, NH). Mass spectrum, m/z: 449 [M+H]+. Found, %: C 69.78; H 6.45; N 6.00.
С26Н28N2О5. Calculated, %: C 69.63; H 6.29; N 6.25.
Dimethyl 3-Ethyl-6-(3-methoxyphenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-4,5-dicarboxylate
1
(6c). Colorless crystals, mp 131-132°С (Et2O). IR spectrum, ν, cm-1: 1669, 1738 (С=О). H NMR spectrum, δ,
ppm (J, Hz): 0.91 (3Н, t, J = 7.3, NCH2CH3); 2.49 (1Н, dd, J = 4.0, J = 16.0) and 3.17 (1Н, dd, J = 5.9,
J = 16.0, 1-СН2); 2.79-2.83 (1Н, m) and 3.05-3.14 (1Н, m, NCH2CH3); 3.26 (1Н, dd, J = 5.9, J = 15.1) and 3.59
(1Н, td, J = 4.1, J = 15.1, 2-СН2); 3.69 (3H, s, ArОCH3); 3.72 (3H, s, CO2CH3); 3.77 (3Н, s, CO2CH3); 5.95
(1Н, s, 6-CН); 6.64 (1Н, s, H Ar); 6.68-6.71 (2Н, m, Н-9,10); 7.12 (1Н, t, J = 7.3, H Ar); 7.13-7.20 (2Н, m,
H Ar); 7.36 (1Н, d, J = 7.8, Н-11); 7.48 (1Н, d, J = 7.8, Н-8); 8.11 (1Н, s, NH). Mass spectrum, m/z: 449
[М+H]+. Found, %: C 69.49; H 6.25; N 6.37. C26H28N2O5. Calculated, %: C 69.63; H 6.29; N 6.25.
Dimethyl 3-Ethyl-6-(4-fluorophenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-4,5-dicarboxyl-
ate (6d). Yellow crystals, mp 208-210°С (Et2O). IR spectrum, ν, cm-1: 1686, 1727 (С=О). 1H NMR spectrum, δ,
ppm (J, Hz): 0.91 (3Н, t, J = 6.9, NCH2CH3); 2.43 (1H, dd, J = 7.3, J = 16.2) and 3.16 (1Н, td, J = 5.5, J = 16.2,
1-СН2); 2.78-2.83 (1H, m) and 3.06-3.12 (1H, m, NCH2CH3); 3.27 (1Н, dd, J = 5.5, J = 14.4) and 3.49 (1Н, td,
J = 3.4, J = 14.4, 2-СН2); 3.73 (3Н, s, СО2CH3); 3.78 (3Н, s, СО2CH3); 5.93 (1Н, s, 6-CН); 6.90-6.93 (2Н, m,
H Ar); 6.29-7.07 (2H, m, H Ar); 7.13 (1H, t, J = 7.6, Н-10); 7.19 (1Н, t, J = 7.6, H-9); 7.35 (1H, d, J = 7.6,
Н 11); 7.49 (1Н, d, J = 7.6, H-8); 8.16 (1Н, s, NH). Mass spectrum, m/z: 437 [M+H]+. Found, %: C 68.71;
H 5.80; N 6.47. С25Н25FN2O4. Calculated, %: С 68.79; Н 5.77; N 6.42.
666

Dimethyl 3-Ethyl-6-(3-fluorophenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-4,5-dicarboxyl-
1
ate (6e). Dark-yellow crystals, mp 202-205°С (Et2O). IR spectrum, ν, cm-1: 1683, 1728 (С=О). H NMR
spectrum, δ, ppm (J, Hz): 0.89 (3Н, t, J = 6.9, NCH2CH3); 2.44 (1Н, dd, J = 2.8, J = 14.7) and 3.47 (1Н, td, J = 4.1,
J = 14.7, 2-СН2); 3.04-3.12 (2Н, m, NCH2CH3); 3.15 (1Н, dd, J = 5.5, J = 16.5) and 3.26 (1Н, dd, J = 5.5,
J = 16.5, 1-СН2); 3.71 (3Н, s, CO2CH3); 3.76 (3Н, s, CO2CH3); 5.95 (1Н, s, 6-CН); 6.76 (1Н, d, J = 10.3,
H Ar); 6.83 (2Н, t, J = 8.3, Н-9,10); 7.10 (1Н, t, J = 6.9, H Ar); 7.13-7.18 (2Н, m, Н-11, H Ar); 7.32 (1Н, d,
J = 7.6, H Ar); 7.47 (1Н, d, J = 8.3, Н-8); 8.18 (1Н, s, NH). Mass spectrum, m/z: 437 [М+H]+. Found, %:
C 68.85; H 5.58; N 6.43. C25H25FN2O4. Calculated, %: C 68.79; H 5.77; N 6.42.
Methyl 3,7-Diethyl-6-phenyl-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-5-carboxylate (7а). The
carboline 2а reacted with methyl propiolate in CH2Cl2 at 30°C over 5 days. Yield 0.21 g (50%), colorless
crystals, mp 148-150°С (EtOAc–hexane). IR spectrum, ν, cm-1: 1684 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
1.13 (3H, t, J = 7.3, 3-CH2CH3); 1.32 (3H, t, J = 7.3, 7-CH2CH3); 2.69-2.74 (1H, m) and 2.95 (1H, ddd, J = 2.5, J
= 4.5, J = 14.8, 1-CH2); 3.16-3.24 (3H, m, 3-CH2CH3, 2-CHВ); 3.60-3.65 (1H, m, 2-CHА); 3.77 (3H, s,
CO2CH3); 4.23-4.29 (1H, m) and 4.36-4.42 (1H, m, 7-CH2CH3); 6.30 (1H, s, 6-CH); 7.10-7.17 (4H, m, H Ph);
7.22 (1H, t, J = 7.3, H Ph); 7.25-7.27 (2H, m, Н-9,10); 7.35 (1H, d, J = 8.3, H-11); 7.50 (1H, d, J = 8.3, H-8);
7.74 (1H, s, H-4). Mass spectrum, m/z (Irel, %): 388 [M]+ (69), 359 (4), 357 (5), 332 (6), 331 (16), 330 (10), 329
(31), 317 (15), 311 (12), 284 (14), 272 (16), 260 (11), 258 (18), 256 (16), 230 (16), 225 (18), 217 (12), 194
(23), 180 (10), 172 (15), 171 (100), 156 (14), 154 (20), 143 (32), 128 (10), 115 (13), 105 (4), 91 (10), 77 (5), 58
(8), 56 (6). Found, %: C 76.90; H 7.50; N 7.05. C25H28N2O2. Calculated, %: C 77.29; H 7.26; N 7.21.
1-(3,7-Diethyl-6-phenyl-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indol-5-yl)ethanone
(7b).
The
carboline 2а reacted with acetylacetylene in CH2Cl2 at 30°С over 5 days. The eluent for column
chromatography was 1:2 EtOAc–hexane. Yield 0.11 g (28%), colorless crystals, mp 170-172°С (EtOAc–
hexane). IR spectrum, ν, cm-1: 1638 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.18 (3H, t, J = 7.2, 3-CH2CH3);
1.29 (3H, t, J = 6.9, 7-CH2CH3); 2.37 (3H, s, COCH3); 2.74 (1H, dt, J = 2.8, J = 16.5, 1-CHВ); 2.98 (1H, ddd,
J = 2.5, J = 5.0, J = 14.7) and 3.72 (1H, dt, J = 2.8, J = 14.7, 2-CH2); 3.19-3.30 (3H, m, 1-CHА, 3-CH2CH3);
4.20-4.26 (1H, m) and 4.29-4.36 (1H, m, 7-CH2CH3); 6.72 (1H, s, 6-CH); 7.05 (2H, d, J = 7.6, H Ph); 7.10-7.15
(2H, m, H Ph); 7.20-7.25 (3H, m, Н-9,10, Н Ph); 7.34 (1H, d, J = 8.3, H-11); 7.50 (1H, d, J = 7.6, H-8); 7.52
(1H, s, H-4). Mass spectrum, m/z (Irel, %): 372 [M]+ (88), 329 (30), 316 (9), 315 (19), 301 (64), 300 (20), 299
(13), 286 (14), 285 (23), 272 (66), 259 (29), 258 (100), 243 (19), 230 (18), 217 (11), 186 (8), 172 (14), 171
(42), 156 (12), 143 (29), 128 (11), 115 (19), 91 (10), 72 (8), 58 (42), 44 (10), 43 (38). Found, %: C 80.25;
H 7.70; N 7.32. C25H28N2O. Calculated, %: C 80.61; H 7.58; N 7.52.
Dimethyl 3,7-Diethyl-6-phenyl-2,3,6,7-tetrahydro-1Н-azocino[5,4-b]indole-4,5-dicarboxylate (7c).
The carboline 2а reacted with DMAD in CH2Cl2 at 30°С over 5 days. The eluent for column chromatography
was 1:15 EtOAc–hexane. Yield 0.21 g (41%), colorless crystals, mp 180-182°C (EtOAc–hexane). IR spectrum,
1
ν, cm-1: 1678 (C=O), 1730 (C=O). H NMR spectrum, δ, ppm (J, Hz): 0.89 (3H, t, J = 7.1, 3-CH2СH3); 1.33
(3H, t, J = 7.1, 7-CH2CH3); 2.43 (1H, dd, J = 3.9, J = 16.3) and 3.11-3.20 (1H, m, 1-CH2); 2.72-2.81 (1H, m)
and 2.99-3.08 (1H, m, 3-CH2CH3); 3.23-3.28 (1H, m) and 3.53 (1H, dt, J = 4.4, J = 14.1, 2-CH2); 3.77 (3H, s,
CO2CH3); 3.78 (3H, s, CO2CH3); 4.24-4.37 (2H, m, 7-CH2CH3); 6.32 (1H, s, 6-CH); 7.11-7.14 (3H, m, H Ph);
7.16-7.19 (1H, m, H Ph); 7.21-7.27 (3H, m, Н-9,10, Н Ph); 7.37 (1H, d, J = 8.2, H-11); 7.51 (1H, d, J = 7.8,
H-8). Mass spectrum, m/z: 447 [M+Н]+. Found, %: C 72.59; H 6.46; N 6.21. C27H30N2O4. Calculated, %:
C 72.62; H 6.77; N 6.27.
Methyl
3,7-Diethyl-6-(4-methoxyphenyl)-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-5-carboxylate
(7d). The carboline 2b reacted with methyl propiolate in CH2Cl2 at room temperature over 4 weeks. The eluent
for column chromatography was 1:2 EtOAc–hexane. Yield 0.29 g (63%), yellow crystals, mp 64-67°C (EtOAc–
hexane). IR spectrum, ν, cm-1: 1669 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.13 (3H, t, J = 6.9, 3-СH2CH3);
1.31 (3H, t, J = 7.3, 7-СH2CH3); 2.71 (1Н, dt, J = 2.8, J = 16.5, 1-СНВ); 2.95 (1Н, ddd, J = 2.6, J = 5.0,
J = 14.5) and 3.69 (1Н, dt, J = 2.8, J = 14.5, 2-СН2); 3.14-3.25 (3Н, m, 3-CH2CH3, 1-СНА); 3.76 (3Н, s,
ArOСН3); 3.77 (3Н, s, СО2СН3); 4.22-4.28 (1Н, m) and 4.34-4.40 (1Н, m, 7-CH2CH3); 6.22 (1Н, s, 6-CH);
667

6.80 (2Н, d, J = 8.9, H Ar); 7.02-7.04 (2Н, m, H Ar); 7.10-7.12 (1Н, m, H-9(10)); 7.19-7.22 (1Н, m, H-10(9));
7.34 (1Н, d, J = 8.3, H-11); 7.49 (1Н, d, J = 8.3, H-8); 7.73 (1Н, s, Н-4). Mass spectrum, m/z (Irel, %): 418 [M]+
(100), 417 (34), 400 (12), 363 (34), 361 (28), 360 (22), 359 (20), 343 (22), 333 (14), 315 (15), 302 (65), 301
(25), 300 (30), 288 (30), 273 (26), 253 (13), 252 (22), 251 (16), 250 (14), 230 (18), 225 (30), 223 (17), 207
(32), 195 (19), 181 (30), 172 (38), 171 (29), 169 (24), 156 (34), 143 (32), 133 (28), 127 (19), 126 (39), 114
(26), 102 (25), 80 (9), 78 (17), 71 (40), 64 (13), 62 (19), 55 (31), 53 (30), 42 (12). Found, %: C 74.78; H 7.00;
N 6.20. C26H30N2O3. Calculated, %: C 74.61; H 7.22; N 6.69.
1-[3,7-Diethyl-6-(4-methoxyphenyl)-2,3,6,7-tetrahydro-1Н-azocino[5,4-b]indol-5-yl]ethanone (7e).
The carboline 2b reacted with acetylacetylene in CH2Cl2 at room temperature for 4 weeks. Yield from CH2Cl2
was 0.30 g (68%), colorless crystals, mp 169-172°С (EtOAc–hexane). IR spectrum, ν, cm-1: 1650 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 1.18 (3H, t, J = 7.3, 3-CH2CH3); 1.28 (3H, t, J = 6.9, 7-CH2CH3); 2.35 (3H,
s, СОСН3); 2.73 (1H, dt, J = 2.8, J = 16.5, 1-СНВ); 2.98 (1H, ddd, J = 2.5, J = 5.2, J = 14.8) and 3.74-3.80 (1Н,
m, 2-СН2); 3.19-3.29 (3Н, m, 3-CH2CH3 and 1-CHА); 3.76 (3Н, s, ArОСН3); 4.19-4.25 (1Н, m) and 4.28-4.34
(1Н, m, 7-CH2CH3); 6.63 (1Н, s, 6-CH); 6.78 (2Н, d, J = 8.3, H Ar); 6.94 (2Н, d, J = 8.3, H Ar); 7.09-7.12 (1Н,
m, H-9(10)); 7.19-7.22 (1Н, m, H-10(9)); 7.33 (1Н, d, J = 8.3, H-11); 7.49 (1Н, d, J = 7.6, H-8); 7.50 (1Н, s,
Н-4). Mass spectrum, m/z (Irel, %): 402 [M]+ (100), 359 (32), 345 (24), 344 (12), 332 (20), 331 (67), 330 (13),
316 (12), 315 (21), 314 (13), 303 (18), 302 (72), 301 (11), 289 (27), 288 (99), 171 (21), 143 (13), 58 (16), 43
(11). Found, %: C 77.90; H 7.50; N 7.05. C26H30N2O2. Calculated, %: C 77.58; H 7.51; N 6.96.
Methyl
3-Ethyl-7-[(4-methylphenyl)sulfonyl]-6-phenyl-2,3,6,7-tetrahydro-1H-azocino[5,4-b]indole-
5-carboxylate (8а). The carboline 3а was refluxed for 15 days with a 10-fold excess of methyl propiolate in
MeCN. Yield 0.30 g (54%), colorless crystals, mp 197-199°C (EtOAc–hexane). IR spectrum, ν, cm-1: 1169
(S=O), 1365 (S=O), 1671 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.99 (3H, t, J = 7.2, NCH2CH3); 2.27 (3H, s,
ArCH3); 2.40 (1H, ddd, J = 2.1, J = 3.4, J = 16.7) and 3.52 (1H, ddd, J = 5.7, J = 13.8, J = 16.7, 1-СH2); 2.87 (1H,
ddd, J = 2.1, J = 5.9, J = 14.8) and 3.47-3.53 (1H, m, 2-СH2); 3.06-3.12 (1H, m) and 3.14-3.20 (1H, m, NCH2СH3);
3.78 (3H, s, CO2СH3); 6.86 (2H, d, J = 7.6, Н Ar); 6.97 (1H, s, 6-CH); 7.04 (2H, d, J = 8.3, Н Ar); 7.08 (1H, d,
J = 6.9, Н Ar); 7.09-7.12 (2H, m, Н Ar); 7.27-7.30 (1H, m, Н-9(10)); 7.34-7.37 (1H, m, Н-10(9)); 7.39 (1H, d,
J = 7.6, Н-11); 7.61 (2H, d, J = 8.3, Н Ar); 7.72 (1H, s, H-4); 8.37 (1H, d, J = 8.3, Н-8). Mass spectrum, m/z: 515
[M+H]+. Found, %: C 69.93; H 5.86; N 5.41. C30H30N2O4S. Calculated, %: C 70.02; H 5.88; N 5.44.
Refluxing the carboline 3а for 30 days with a 10-fold excess of methyl propiolate in CH2Cl2 produced
besides the azocinoindole 8а (62% yield) also the spiro[indole-3,4'-pyridine] 9 (3% yield).
1-{3-Ethyl-6-(4-methoxyphenyl)-7-[(4-methylphenyl)sulfonyl]-2,3,6,7-tetrahydro-1H-azocino[5,4-b]-
indol-5-yl}ethanone (8b). The carboline 3b reacts with acetylacetylene in CH2Cl2 at room temperature over the
course of 4 days. The eluent for column chromatography was 1:1 EtOAc–hexane. Yield 0.37 g (68%), colorless
1
crystals, mp 230-232°С (EtOAc). IR spectrum, ν, cm-1: 1169 (S=O), 1367 (S=O), 1655 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 1.03 (3Н, t, J = 7.3, NCH2CH3); 2.26 (3H, s, ArCH3); 2.32 (3H, s, COCH3); 2.39 (1H,
ddd, J = 1.8, J = 3.8, J = 16.9) and 3.05 (1H, ddd, J = 5.9, J = 13.8, J = 16.9, 1-CH2); 2.91 (1H, ddd, J = 1.8,
J = 5.9, J = 14.8) and 3.56-3.61 (1H, m, 2-CH2); 3.10-3.16 (1H, m) and 3.17-3.23 (1H, m, NCH2CH3); 3.72 (3H,
s, OСН3); 6.60 (2H, d, J = 8.9, Н Ar); 6.62-6.64 (2H, m, Н Ar); 6.99 (1H, s, 6-CH); 7.05 (2Н, d, J = 8.6, Н Ar);
7.27-7.30 (1Н, m, Н-9(10)); 7.34-7.36 (1Н, m, Н-10(9)); 7.40 (1Н, d, J = 7.6, Н-11); 7.50 (1Н, s, Н-4); 7.69
(2Н, d, J = 8.6, Н Ar); 8.39 (1Н, d, J = 8.3, Н-8). Mass spectrum, m/z: 529 [M+Н]+. Found, %: C 70.36; H 6.06;
N 5.27. C31H32N2O4S. Calculated, %: C 70.43; H 6.10; N 5.30.
Methyl 3-Ethyl-6-(4-methoxyphenyl)-7-[(4-methylphenyl)sulfonyl]-2,3,6,7-tetrahydro-1H-azocino-
[5,4-b]indole-5-carboxylate (8c). The carboline 3b reacts with methyl propiolate upon refluxing in CH2Cl2 over
the course of 10 days. Yield 0.36 g (77%), colorless crystals, mp 205-207°С (EtOAc). IR spectrum, ν, cm-1:
1171 (S=O), 1369 (S=O), 1667 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.99 (3H, t, J = 7.3, NCH2CH3); 2.28
(3H, s, ArCH3); 2.41 (1H, ddd, J = 2.1, J = 3.4, J = 16.7) and 3.02 (1H, ddd, J = 5.7, J = 13.5, J = 16.7, 1-СH2);
2.88 (1H, ddd, J = 2.1, J = 5.7, J = 14.8) and 3.53-3.58 (1H, m, 2-СH2); 3.06-3.12 (1H, m) and 3.14-3.20 (1H,
m, NCH2СH3); 3.74 (3H, s, ArOCH3); 3.77 (3H, s, CO2СH3); 6.65 (2H, d, J = 8.9, Н Ar); 6.77-6.78 (2H, m, Н
668

Ar); 6.88 (1H, s, 6-CH); 7.05 (2H, d, J = 8.3, Н Ar); 7.27-7.29 (1H, m, Н-9(10)); 7.33-7.36 (1H, m, Н-10(9));
7.39 (1H, d, J = 7.6, Н-11); 7.61 (2H, d, J = 8.3, Н Ar); 7.70 (1H, s, H-4); 8.36 (1H, d, J = 8.9, Н-8). Mass
spectrum, m/z: 545 [M+H]+. Found, %: C 68.12; H 5.90; N 5.42. C31H32N2O5S. Calculated, %: C 68.36; H 5.92;
N 5.14.
Methyl (2Z)-2-benzylidene-1'-ethyl-1-[(4-methylphenyl)sulfonyl]-1,2,5',6'-tetrahydro-1'H-spiro-
[indole-3,4'-pyridine]-3'-carboxylate (9) was obtained as by-product upon refluxing the carboline 3а with
methyl propiolate in CH2Cl2, followed by separation of the mixture by column chromatography (eluent 1:5
EtOAc–hexane). Yield 0.02 g (3%), yellow crystals, mp 144-146°C (EtOAc–hexane). IR spectrum, ν, cm-1:
1170 (S=O), 1364 (S=O), 1685 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.82 (1H, ddd, J = 3.4, J = 5.2, J = 13.3)
and 2.86 (1H, dt, J = 4.5, J = 13.3, 5'-СH2); 1.14-1.19 (1H, m) and 3.17-3.21 (1H, m, 6'-СH2); 1.26 (3H, t,
J = 7.2, NCH2CH3); 2.34 (3H, s, ArCH3); 3.25-3.33 (2H, m, NCH2СH3); 3.31 (3H, s, CO2СH3); 6.04 (1H, s,
=CH–Ph); 6.89 (1H, d, J = 6.9, Н Ar); 7.08-7.11 (3H, m, Н Ar); 7.18-7.20 (1H, m, Н Ar); 7.25-7.26 (1H, m,
Н Ar); 7.30-7.32 (2H, m, Н Ar); 7.45 (2H, d, J = 8.3, Н Ar); 7.56 (2H, d, J = 7.6, Н Ar); 7.68 (1H, s, H-2'); 7.78
(1H, d, J = 8.3, Н-4). Mass spectrum, m/z: 515 [M+H]+. Found, %: C 69.95; H 5.85; N 5.40. C30H30N2O4S.
Calculated, %: C 70.02; H 5.88; N 5.44.
The work received support from the Russian Foundation for Basic Research (grants 14-03-0031 and
13-03-90431 Ukr_f_a).
The authors would like to express their gratitude to the Collective Use Center for Physical and Chemical
Investigations of the Peoples' Friendship University for performing elemental analyses and recording the IR
spectra.
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