Reaction of 1-substituted tetrahydro-β-carbolines with activated alkynes - A new original approach to the synthesis of tetrahydroazocino[5,4-b] indoles

Article abstract of DOI:10.1007/s10593-007-0093-y

The transformations of 1-substituted tetrahydro-β-carbolines by the action of activated alkynes were studied. The action of dimethyl acetylenedicarboxylate in methanol gives products of the opening of the tetrahydropyridine fragment, namely, 2-methoxyalkylindoles. The action of ethyl propiolate in ethanol and of tosylacetylene in methanol gives mixtures of azocino[5,4-b]indoles and 2-alkoxyindoles. The action of ethyl propiolate in acetonitrile gives azocinoindoles.

Full text of DOI:10.1007/s10593-007-0093-y

Chemistry of Heterocyclic Compounds, Vol. 43, No. 5, 2007
REACTION OF 1-SUBSTITUTED TETRAHYDRO-β-CARBOLINES
WITH ACTIVATED ALKYNES – A NEW ORIGINAL APPROACH
TO THE SYNTHESIS OF TETRAHYDROAZOCINO[5,4-b]INDOLES
L. G. Voskressensky, T. N. Borisova, L. N. Kulikova, E. G. Dolgova,
A. I. Kleimenov, E. A. Sorokina, A. A. Titov, and A. V. Varlamov
The transformations of 1-substituted tetrahydro-β-carbolines by the action of activated alkynes were
studied. The action of dimethyl acetylenedicarboxylate in methanol gives products of the opening of the
tetrahydropyridine fragment, namely, 2-methoxyalkylindoles. The action of ethyl propiolate in ethanol
and of tosylacetylene in methanol gives mixtures of azocino[5,4-b]indoles and 2-alkoxyindoles. The
action of ethyl propiolate in acetonitrile gives azocinoindoles.
Keywords: azocino[5,4-b]indoles, 2-alkoxyalkylindoles, activated alkynes, tetrahydro-β-carbolines, ring
expansion.
Azocinoindoles with different fusion of the azocine and indole systems are a structural fragment in many
alkaloids displaying a broad range of biological activity. The major efforts of synthetic organic chemists have
been directed toward the development of methods to synthesize analogs of natural products. There have been
only a few reports on methods for the synthesis of azocinoindoles. These methods involve multiple steps and, as
a rule, give a low yield of the desired products.
We have recently described a new method for the synthesis of tetrahydroazocino[4,5-b]indoles
employing tandem transformations of tetrahydro-γ-carbolines by the action of dimethyl acetylenedicarboxylate
and ethyl propiolate in methanol and ethanol [1]. This two-step method involving the formation of
3-alkoxyalkyl-2-[N-alkyl-N-dimethoxycarbonyl(ethoxycarbonyl)vinyl]aminoethylindoles and their cyclization
to azocinoindoles by the action of aluminum chloride in a one-pot procedure provides tetrahydroazocinoindoles
at room temperature in 40-75% yield. Preliminary screening of tetrahydroazocino[4,5-b]indoles has revealed
their strong tendency to inhibit acetyl- and butyrylcholinesterases [2].
We thus found both theoretical and practical interest in the study of the transformations of 1-substituted
tetrahydro-β-carbolines by the action of activated alkynes in order to develop a general approach toward the
synthesis of isomeric azocinoindoles from tetrahydrocarbolines, determine the effect of the position of the
nitrogen atom in the tetrahydropyridine fragment of the tetrahydrocarbolines on the direction of the tandem
transformations by the action of activated alkynes and the effects of solvent and substituents at C(1), and provide
methods for the preparation of tetrahydroazocino[5,4-b]indoles, which hold promise for biological screening.
1-Substituted tetrahydro-β-carbolines were obtained by N-ethylation (1-5) and N-methylation (6) of the
corresponding 1-substituted NH-β-carbolines obtained in the Pictet–Spengler reaction [3].
__________________________________________________________________________________________
Peoples'
Friendship
University
of
Russia,
117198 Moscow,
Russia;
e-mail:
lvoskressensky@sci.pfu.edu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 703-715,
May, 2007. Original article submitted December 12, 2006.
0009-3122/07/4305-0587©2007 Springer Science+Business Media, Inc.
587

The activated alkynes studied were dimethyl acetylenedicarboxylate (DMAC), ethyl propiolate,
tosylacetylene, and acetylacetylene. Acetonitrile, methanol, and ethanol served as the solvents. All the
transformations were carried out at room temperature.
R1
R1I
RCHO
H+
N
R
NH2
NH
R
DMF
K2CO3
N
H
N
N
H
H
1–6
1 R = Me, 2, 6 R = i-Pr, 3 R = Bn, 4 R = C6H4F-o, 5 R = C6H4F-p;
1−5 R1 = Et, 6 R1 = Me
In contrast to tetrahydro-γ-carbolines, which give polymeric products by the action of DMAC in
acetonitrile, tetrahydro-β-carbolines 1-3 and 6 are cleaved under these conditions to give 2-vinylindole 7 in the
case of carboline 1 and azocino[5,4-b]indole 8 in the case of carboline 3.
E
E
R1
Me
N
N
E
AlCl3
DMAC
MeOH
OMe
R
1–3, 6
E
N
N
H
H
Pr
-i
9–12
MeCN
13
DMAC
Et
2
1
N
3
11
8
E
10
9
E
4
E
5
E
6
N
H
7
N
Et
n
B
8
N
H
7
E = CO2Me; 9 R = Me, 10, 12 R = i-Pr, 11 R = Bn; 9−11 R1 = Et, 12 R1 = Me
1-Isopropylcarbinols 2 and 6 form multicomponent reaction mixtures, which could not be separated into
1
pure products. However, the finding of singlets in the H NMR spectra of these mixtures at 4.68 and 4.72 ppm
due to the terminal protons of the C(CO2Me)=C(CO2Me)H group [4] suggest that opening of the
tetrahydropyridine fragment also occurs in these cases.
Dimethyl acetylenedicarboxylate in methanol cleaves the tetrahydropyridine fragment of β-carbolines to
give 2-methoxyalkyl-3-(N-alkyl-N-dimethoxycarbonylvinyl)aminoethylindoles 9-12. Indole 12 was converted
by the action of AlCl3 in acetonitrile to azocinoindole 13.
588

We assume that the reaction of tetrahydro-β-carbolines with alkynes, as in the case of
tetrahydro-γ-carbolines, starts with nucleophilic attack of the amine nitrogen atom on the triple bond of the
alkynes, leading to zwitter-ion A.
R1
DMAC
N
R
N
H
R1
–
E
R1
E
MeOH
+
N
O
+
N
E
E
N R
H
–
H
N
R
H
Me
A
B
7,8
9–12
E = CO2Me
Nucleophilic attack in acetonitrile on the substituent at C(1) (Hoffman cleavage) or at C(1) in the ring (ring
expansion) leads to 7 or 8, respectively. An increase in the electron-donor properties of substituent R should
presumably facilitate cleavage of the C(1)–N+ bond. Even formation of a carbocation and the corresponding
transformations are possible. The formation of multicomponent mixtures in the reactions of carbolines 2 and 6
(R = i-Pr) is probably related to the abovementioned processes. Cleavage of the C(1)–N+ bond in methanol is
facilitated by the cooperative action of the alcohol and proceeds through six-membered transition state B.
Ethyl propiolate reacts with carbolines 1-3 and 6 much more rapidly, probably due to less delocalization
of the negative charge in intermediate zwitter-ion A. Mixtures of azocino[5,4-b]indoles and
2-ethoxyalkyl-3-(N-alkyl-N-ethoxycarbonylvinyl)aminoethylindoles of varying composition are formed in
absolute ethanol. We separated azocine 14 from carboline 1, azocines 15 and 16 and the corresponding
indoles 17 and 18 from carbolines 2 and 3, but only indole 19 from carboline 6. The action of ethyl propiolate in
acetonitrile on tetrahydrocarbolines 1-3 gave only the corresponding azocino[5,4-b]indoles 14-16 in 30-75%
yield.
E
Et
N
N
R1
EP
1–3, 6
+
EtOH
E
OEt
N
H
R
N
H
MeCN EP
R
14–16
17–19
14–16
14 R = Me, 15, 17, 19 R = i-Pr, 16, 18 R = Bn; 17, 18 R1 = Et, 19 R1 = Me;
E = CO2Et; EP − ethyl propiolate
589

TABLE 1. Characteristics of the Products Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
[М]+●
mp, °C* Rf Alufol*2 Yield, %
C
H
N
1
C14H18N2
78.56
78.46
79.34
79.29
82.87
82.72
77.30
77.52
77.68
77.52
79.15
78.90
67.54
67.40
72.03
72.22
64.67
64.93
66.02
66.32
69.93
69.81
65.53
65.65
67.90
68.09
73.20
73.05
73.93
74.08
77.05
77.29
71.57
71.47
74.55
74.62
70.87
70.94
75.93
76.22
76.45
76.22
70.35
70.16
69.93
70.16
68.53
68.75
8.56
8.47
9.30
9.15
7.85
7.64
6.35
6.51
6.71
6.51
8.70
8.83
6.70
6.71
6.75
6.48
6.95
7.27
7.90
7.74
7.12
6.94
7.75
7.51
7.20
7.07
7.50
7.69
8.63
8.29
7.50
7.26
8.94
8.87
7.95
7.89
8.73
8.66
6.58
6.40
6.70
6.40
5.40
5.73
5.87
5.73
6.30
6.17
13.19
13.07
11.63
11.56
9.35
9.65
9.40
9.52
9.45
9.52
12.20
12.27
7.78
7.87
6.25
6.48
7.50
7.27
6.82
6.73
5.95
6.03
7.15
6.96
7.49
7.56
8.85
8.97
8.01
8.23
7.12
7.21
7.31
7.25
6.30
6.45
7.46
7.52
7.90
7.73
7.52
7.73
6.03
5.90
5.75
5.90
5.35
5.53
214
242
290
294
294
228
356
432
388
416
464
402
370
312
340
388
386
434
372
362
362
474
474
507
390
390
Oil
Oil
0.60
0.55
0.55
—
65
67
60
73
76
64
35
48
75
89
73
78
27
75
70
71
45
46
63
67
35
62
34
58
27
28
2
C16H22N2
3
C20H22N2
Oil
4
C19H19FN2
95-97
5
C19H19FN2
96-98
—
6
C15H20N2
Oil
0.55
0.60
0.50
0.55
0.45
0.60
0.48
0.55
0.55
0.50
0.53
0.55
0.60
0.60
—
7
C20H24N2О4
C26H28N2О4
C21H28N2О5
C23H32N2О5
C27H32N2О5
C22H30N2О5
C21H26N2О4
C19H24N2О2
C21H28N2О2
C25H28N2О2
C23H34N2О3
C27H34N2О3
C22H32N2О3
C23H23FN2О
C23H23FN2О
C28H27FN2О2S
C28H27FN2О2S
C29H31FN2О3S
C25H30N2О2
C25H30N2О2
Oil
8
148-150
136–138
148-150
144-146
112-116
175-177
188-190
222-224
246-248
88-90
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25а
25b
Oil
79-81
271-273
268-270
266-268
263-265
115-117
Oil
—
—
—
—
76.95
76.89
76.98
76.89
7.84
7.74
7.57
7.74
7.11
7.17
7.32
7.17
0.60
0.40
Oil
_______
* Solvent: acetone (4, 5), ethyl acetate–hexane (8-12, 17, 24), ethyl acetate
(13-16, 20-23), hexane (19).
*2 1:3 ethyl acetate–hexane (1, 7, 9-12, 14-19), 1:1 ethyl acetate–hexane
(2, 3, 6, 8, 13), 1:2 ethyl acetate–hexane (25a, 25b).
590

Carbolines 4 and 5 are transformed by the action of acetylacetylene in methanol and acetonitrile and by
the action of tosylacetylene in acetonitrile into 5-acetyl-6-fluorophenyl- 20, 21 and 5-tosylazocino-[5,4-b]indoles
22, 23. In methanol, 1-o-fluorophenylcarboline 4 and tosylacetylene give a ~1:1 mixture of azocinoindole 22 and
2-(o-fluorophenyl)-2-methoxymethylindole 24.
Et
N
H
COMe
MeOH, MeCN
4, 5
COMe
MeOH,
MeCN
N
H
Ts
H
R
20, 21
Ts
Et
N
N
Et
+
OMe
Ts
N
H
N
R
R
H
24
22, 23
20, 22, 24 R = C6H4F-o, 21, 23 R = C6H4F-p
These results are in good accord with the formation of an intermediate zwitter-ion A and the electronic
effects of the substituents and solvents on the direction of the transformation of this intermediate.
Azocinoindole 16 was reduced by sodium cyanoborohydride to the corresponding hexahydro
derivative 25, which is formed as a ~1:1 mixture of geometric isomers by interchange of the benzyl and
ethoxycarbovinyl groups and separated into pure products by column chromatography. Unfortunately, an
unequivocal assignment of the NMR signals could not be made due to the complexity of these spectra.
Et
N
NaCNBH3
16
CO2Et
MeOH
N
H
Bn
25
1
The H NMR spectra of indoles 9-12, 17-19, and 24, azocinoindoles 13-16 and 20-23 show the signals
for all the protons in their structures. The spectra of indoles 9-12 show a singlet for the dimethoxycarbonylvinyl
group at 4.50-4.80 ppm, while indoles 17-19 and 24 show two doublets for the protons of the double bond of the
N-ethoxycarbonyl and N-tosylvinyl fragments at 4.45 and 7.40 ppm and a coupling constant of 12.7 Hz. The
spectra of azocinoindoles 14-16 and 20-23 show a characteristic singlet at 7.35-7.69 ppm due to H-4.
Thus, we have developed an original preparative two-step approach to the synthesis of
tetrahydroazocino[5,4-b]indoles.
591

592

EXPERIMENTAL
The IR spectra of the products were taken neat (for oils) on a Specord IR-75 spectrometer. The electron
impact ionization mass spectra were taken on a Finnigan MAT 95 XL GC/MS with direct sample inlet into the
ion source at 70 eV. The 1H NMR spectra were taken on Bruker WP-400 spectrometers at 400 MHz in CDCl3 at
23°C with TMS as the internal standard. Alufol alumina plates were used for the thin-layer chromatography and
Fluka-507C (0.05-0.15 mm granularity) alumina was used for the column chromatography. The physicochemical
and elemental analysis data are given in Table 1, while the 1H NMR spectral data are given in Tables 2-4.
1-R-2-R1-2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indoles 1-6 (General Procedure). A solution of
tryptamine (0.03 mol) and the corresponding aldehyde (0.03 mol) was heated at reflux in benzene or toluene
(100 ml) with a Dean–Stark trap until the theoretically calculated amount of water was removed. The solvent
was evaporated. Then, water (100 ml) and 2 N sulfuric acid (16 ml) were added to the residue and heated for
48 h at 50°C with monitoring by thin-layer chromatography. The mixture was cooled and brought to pH 9 by
adding 20% aq. NaOH. Crystals of indoles 1-6 were filtered off, dried, and alkylated with methyl or ethyl iodide
as follows. A solution of pyridoindole (5 mmol), corresponding alkyl iodide (8 mmol), and potassium
carbonate (16 mmol) in absolute DMF (10 ml) was heated for 4 h at 50°C with monitoring by thin-layer
chromatography. Then, water (10 ml) was added and the mixture was extracted with ether (3×100 ml). The
extract was dried over MgSO4. After distilling off the ether, the residue was subjected to chromatography on an
alumina column to give 2-alkyltetrahydropyridoindoles 1-6 as yellow oils.
Reaction of Tetrahydro-β-carbolines 1-3 and 6 with Dimethyl Acetylenedicarboxylate (General
Procedure). DMAC (1.2 mmol) was added to a solution of carboline 1-3 or 6 (1 mmol) in absolute methanol
(10 ml) or in acetonitrile (10 ml) at 20°C. The mixture was monitored for 24 h by thin-layer chromatography and
the solvent was evaporated. When the reaction was carried out in methanol, the residue was purified on alumina
to give dimethyl (2E)-2-[ethyl(2-{2-[methoxy-(R)-methyl]-1H-indol-3-yl]-ethyl}amino]but- 2-enedioates 9-12.
When the reaction was carried out in acetonitrile, the residue was subjected to column chromatography using
1:10
and
1:5 ethyl acetate–hexane
as
the
eluent.
Carboline 1
gave
dimethyl
(2E)-2-{ethyl[2-(2-vinyl-1H-indol-3-yl)ethyl]amino}but-2-endioate (7), while carboline 3 gave 6-benzyl-
3-ethyl-4,5-dimethoxycarbonyl-1,2,3,6-tetrahydroazocino[5,4-b]indole (8).
Reaction of Tetrahydro-β-carbolines 1-3 and
6
with Ethyl Propiolate and of
Tetrahydro-β-carbolines 4 and 5 with Acetylacetylene and Tosylacetylene (General Procedure).
Corresponding activated alkyne (1.2 mmol) was added to a solution of tetrahydro-β-carboline (1 mmol) in
ethanol, methanol, or acetonitrile (10 ml) at 20°C with monitoring by thin-layer chromatography. The reaction
with ethyl propiolate is complete after 3-5 h, while the reactions with tosylacetylene and acetylacetylene were
complete after 120 h. The solvent was evaporated off. The residue was either crystallized from ethyl acetate to
give azocino[5,4-b]indoles 14-16 and 20-23 or subjected to column chromatography, isolating
azocino[5,4-b]indoles 15, 16, and 20 and the corresponding 2-aminoalkyl-3-(N-ethyl(methyl)-N-vinyl-
aminoethylindoles 17-19 and 24.
6-Isopropyl-3-methyl-4,5-dimethyloxycarbonyl-1,2,3,6-tetrahydroazocino[5,4-b]indole (13). AlCl3
(~3 mg) was added to a solution of 2-(1-methoxyisobutyl)indole (12) (0.6 mmol) in acetonitrile (10 ml) at 20°C.
The mixture was monitored by thin-layer chromatography for 24 h and methanol was then evaporated in
vacuum. The residue was subjected to column chromatography. Elution with 1:5 ethyl acetate–hexane gave
60 mg (27%) azocinoindole 13.
6-Benzyl-5-ethoxycarbonyl-3-ethyl-1,2,3,4,5,6-hexahydroazocino[5,4-b]indole (25). Sodium cyano-
borohydride (30 mg, 0.5 mmol) was added to a solution of acozinoindole 16 (0.2 g, 0.5 mmol) in methanol
(10 ml) and heated at reflux for 2 h with monitoring by thin-layer chromatography. The solvent was
593

594

595

596

597

evaporated and water (10 ml) was added to the residue. The mixture was extracted with ethyl acetate. The
extract was dried over magnesium sulfate. Filtration and evaporation gave 0.13 g (55%) of a light-yellow, oily
residue, which was subjected to column chromatography, eluting with from 1:3 to 1:1 ethyl acetate–hexane to
give consecutives 0.05 g (27%) isomer with Rf 0.60 [IR spectrum, ν, cm-1: 1658 (CO2Et). 1H NMR spectrum, δ,
ppm (J, Hz): 0.98 (3H, t, J = 7.0, N-CH2CH3); 1.23 (3H, t, J = 7.0, OCH2CH3); 2.12-2.16 (2H, m); 2.53-2.83
(4H, m); 2.91-3.00 (2H, m); 3.18-3.24 (1H, m); 3.37-3.43 (1H, m); 4.03-4.14 (4H, m); 7.00-7.48 (9H, m); 8.75
(1H, br. s, NH). Mass spectrum, m/z (Irel, %): 390 [M]+ (100), 376 (10), 345 (16), 317 (16), 299 (58), 260 (16),
245 (22), 242 (66), 233 (46), 219 (18), 199 (26), 168 (54), 156 (22), 143 (26), 115 (14), 91 (32), 85 (14), 72
1
(38), 42 (14)] and 0.06 g (28%) of an isomer with Rf 0.40 [IR spectrum, ν, cm-1: 1653 (CO2Et). H NMR
spectrum, δ, ppm (J, Hz): 0.96 (3H, t, J = 7.0, N-CH2CH3); 1.33 (3H, t, J = 7.0, OCH2CH3); 2.29 (1H, dd,
J = 3.5, J = 14.6); 2.51-2.59 (4H, m); 2.79-3.05 (6H, m); 3.27 (1H, dd, J = 4.0, J = 14.6); 4.15-4.17 (1H, m);
4.22 (2H, dq, J = 1.2, J = 7.1), CH3CH2O); 7.05-7.22 (7H, m); 7.27 (1H, dd, J = 1.2, J = 7.0, H-11); 7.47 (1H, d,
J = 7.4, H-8); 7.85 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 390 [M]+ (100), 389 (10), 345 (18), 317 (14),
299 (66), 260 (14), 245 (30), 242 (86), 233 (54), 218 (14), 199 (34), 186 (18), 168 (62), 156 (30), 143 (34), 130
(18), 128 (14), 91 (30), 85 (22), 72 (66), 57 (22), 42 (16)].
This work was carried out with the financial support of the Russian Basic Research Fund (RFFI)
(Project No. 05-03-08419).
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