Synthesis of hydrogenated 2,7-dimethylpyrrolo[3,4-b]indoles - Analogs of dimebon

Article abstract of DOI:10.1007/s10593-010-0488-z

A schemes have been proposed for the synthesis of novel 4-substituted 2,7-dimethyl-3,4-dihydro-1H- and previously unknown 2,7-dimethyl-cis-1,2,3,3a,4, 8b-hexahydropyrrolo[3,4-b]indoles. In the case of the Dimebon structural analog 2,7-dimethyl-4-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrrolo-[3.4-b] indole a broad spectrum of pharmacological activity was found in the hydrogenated pyrroloindoles suitable for the development of medicines via the "magic bullet" concept. A strong dependence of the antagonist relationship of the synthesized compounds towards histamine H1 and serotonin 5-HT6 receptors with the nature of the substituent in the 4 position and the degree of hydrogenation of the pyrrolo[3,4-b]indoles was demonstrated.

Full text of DOI:10.1007/s10593-010-0488-z

Chemistry of Heterocyclic Compounds, Vol. 46, No. 2, 2010
SYNTHESIS OF HYDROGENATED
2,7-DIMETHYLPYRROLO[3,4-b]INDOLES –
ANALOGS OF DIMEBON
A. V. Ivachtchenko1,2, E. B. Frolov2, O. D. Mitkin2*,
S. E. Tkachenko2, and A. V. Khvat2
A schemes have been proposed for the synthesis of novel 4-substituted 2,7-dimethyl-3,4-dihydro-1H-
and previously unknown 2,7-dimethyl-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indoles. In the case of
the Dimebon structural analog 2,7-dimethyl-4-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrrolo-
[3,4-b]indole a broad spectrum of pharmacological activity was found in the hydrogenated
pyrroloindoles suitable for the development of medicines via the "magic bullet" concept. A strong
dependence of the antagonist relationship of the synthesized compounds towards histamine H1 and
serotonin 5-HT6 receptors with the nature of the substituent in the 4 position and the degree of
hydrogenation of the pyrrolo[3,4-b]indoles was demonstrated.
Keywords: antihistamine agents, Dimebon, pyrrolo[3,4-b]indoles.
Heterocyclic compounds containing a hydrogenated pyrrolo[3,4-b]indole fragment 1 can be considered as
structural analogs of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles 2 which have an exceptionally broad spectrum of
pharmacological activity and are licensed materials within a medico-pharmaceutical understanding of this term. An
excellent example of this series of compounds is Dimebon, i.e. 2,8-dimethyl-5-[2-(2-methylpyridin-5-yl)ethyl]-
Me
Me
H
N
N
NH
N
N
H
N
H
.
2HCl
1
2
3
N
Me
_______
* To whom correspondence should be addressed, e-mail: yai@chemdiv.com.
1Chemical Diversity Inc., San Diego, CA 92121, USA, e-mail: av@chemdiv.com.
2Chemical Diversity Research Institute, Khimki 141401, Moscow Region, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 209-220, February, 2010. Original
article submitted February 28, 2009.
170
0009-3122/10/4602-0170©2010 Springer Science+Business Media, Inc.

2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride (3). Dimebon was first synthesized in 1961 [1, 2], used
from 1983 in Russia as an antihistamine preparation [3, 4], and recently regarded as an effective agent in the
therapy of neurodegenerative illnesses, e.g. in particular Alzheimer's and Huntington's diseases [5, 6].
This statement allows one reliably to propose that a synthesis and study of the properties of novel
structural analogs of Dimebon in the little examined series of pyrrolo[3,4-b]indoles is undoubtedly of interest in
a search for novel, pharmacologically active molecules.
The first pyrrolo[3,4-b]indoles were prepared by cyclization of substituted 3-(phenylhydrazono)-
pyrrolidin-2-ones under Fischer reaction conditions and subsequent LiAlH4 reduction of the 1,4-dihydro-
2H-pyrrolo[3,4-b]indol-3-ones formed [7, 8]. A single stage synthesis was proposed later based on Fischer
cyclization of 2-ethoxycarbonyl-3-(phenylhydrazono)pyrrolidines [9-13]. One further synthesis of 2,4-di-
substituted tetrahydropyrrolo[3,4-b]indoles consists of the reaction of 2,3-di(bromomethyl)-1-phenyl-
sulfonylindole with primary amines [14, 15].
In continuation of our work [16-18] on the synthesis and study of the biological activity of structural
analogs of Dimebon 3 it appeared appropriate to prepare some hydrogenated 2,7-dimethylpyrrolo[3,4-b]indoles
and to study their pharmacological properties. For preparation of the needed pyrrolo[3,4-b]indoles we have used
well known reactions. Our task involved just a choice of necessary structures and optimal schemes for their
synthesis.
Starting from 1-ethoxycarbonylpyrrolidin-3-one and p-tolylhydrazine we have prepared 2-ethoxy-
carbonyl-7-methyl-3,4-dihydro-1H-pyrrolo[3,4-b]indole (4), reduced it with LiAlH4 to 2,7-dimethyl-3,4-dihydro-
1H-pyrrolo- [3,4-b]indole (5), and hydrogenated the latter in almost quantitative yield to 2,7-dimethyl-cis-
1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole (6) (the first representative of a novel heterocyclic system).
Me
Me
O
H3PO4
AcONa
+
CO2Et
30–35°C, 1 h
N
H2N
N
N
N
CO2Et
.
NHNH2 HCl
CO2Et
Me
Me
N
H
Me
N
LiAlH4
20°C, 2 h
Me
Me
H2 / Pt, EtOH
20°C, 24 h
N
H
N
N
H
H
H
4 33%
5 87%
6 95%
The 2,4,7-trimethyl-3,4-dihydro-1H-pyrrolo[3,4-b]indole (8) and its hydrogenated analog 9 were
prepared by successive methylation of compound 4, reduction of the 2-ethoxycarbony- 4,7-dimethyl derivative 7
formed to the trimethyl derivative 8, and hydrogenation of the latter using hydrogen on platinum.
It is known that 2-alkyl--carbolines unsubstituted in the 5 and 8 positions readily take part in a Michael
reaction in the presence of metallic sodium and add 2- and 4-vinylpyridines to give 5-(pyridinylethyl)-
-carbolines [19]. It was found later that the use of DMSO as solvent in this reaction leads to a powerful
activation of the anions formed by the action of sodium or sodium hydride on 2-alkyl--carbolines. As a result of
this, reaction becomes possible with 3-vinylpyridines in which the vinyl bond is rather weakly polarized, none
the less, forming Dimebon 3 under these conditions [20].
171

Me
Me
H
CO2Et
MeI, DMF,
Cs2CO3
N
Me
N
N
Me
Me
H2 / Pt, EtOH
20°C, 24 h
LiAlH4
20°C, 2 h
4
N
H
N
N
Me
Me
Me
7 80%
8 85%
9 97%
We have used this reaction for preparing the 2,7-dimethyl-4-(pyridinylethyl)-3,4-dihydro-1H-
pyrrolo[3,4-b]indoles (11a-c). Reaction of the pyrrolo[3,4-b]indole 5 with the vinylazines 10a-c occurs more
smoothly to form the least amount of side and tarry products if it is carried out in the biphasic system of DMSO
and 60% KOH in the presence of (Bu4N)2SO4 as phase-transfer catalyst. It should be noted that reaction with
4-vinylpyridine (10c) occurs more readily (4-8 h, 40ºC) under these conditions than with 2-vinylpyridine (10a)
and, especially, with 6-methyl-3-vinylpyridine (10b), completion of which demands a higher temperature (80ºC)
and longer reaction time (12-24 h). The 4-pyridinylethyl derivatives 11b and 11c obtained were hydrogenated
on platinum in 90-95% yield to the hexahydro derivatives 12b,c.
Me
Me
H
DMSО, KOH,
H2O, (Bu4N)2SO4
N
H2 / Pt
EtOH
Me
N
R
Me
5
+ RCH=CH2
N
10a–c
80°C, 12–24 h
N
H
30°C, 24 h
R
11a–c 50–65%
10, 11 a R = 2-Py; 10–12 b R = 6-Me-3-Py, c R = 4-Py
12b,c 90–95%
From the 2,7-dimethyl-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole (6) under standard reaction
conditions we have prepared the corresponding 4-pyridin-3-ylmethyl, 4-benzoyl, 4-benzenesulfonyl, and
4-phenylamido derivatives 13-16 respectively.
Me
Me
PhCOCl,
THF, Et3N
NaBH(AcO)3,
3-PyCHO, CH2Cl2
H
H
N
H
N
6
PhOC
20°C, 20 min
60%
20°C, 24 h
65%
H
N
N
Me
N
Me
14
13
PhSO2Cl,
PhNCO, THF
Et3N, THF
20°C, 1 h
70%
20°C, 20 min
90%
Me
Me
H
H
Me
Me
N
N
N
H
SO2Ph
N
H
CONHPh
15
16
172

TABLE 1. Physicochemical Characteristics and Mass Spectra of
Compounds 4-9, 11-16
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
LC-MS,
m/z (M+H)
С
H
N
4
C14H16N2O2
68.63
68.83
64.55
64.72
55.37
55.18
69.27
69.47
65.68
65.95
56.48
56.73
62.44
62.64
63.27
63.49
62.42
62.64
57.37
57.63
56.72
56.66
61.09
61.37
69.19
69.40
59.45
59.25
66.58
66.37
6.42
6.60
6.58
6.79
6.75
6.95
7.22
7.38
7.08
7.24
7.17
7.32
6.27
6.36
6.28
6.66
6.18
6.36
6.56
6.77
6.65
6.51
6.37
6.58
6.68
6.44
5.99
5.80
6.23
6.45
11.57
11.47
12.36
12.58
10.93
10.73
10.96
10.80
11.72
11.83
10.42
10.18
11.66
11.53
18.77
18.74
11.39
11.53
10.27
10.08
10.28
10.43
12.07
11.93
8.73
8.52
7.73
7.68
12.47
12.22
246
187
189
259
201
203
292
306
292
308
294
280
293
329
308
5•HCl
C12H14N2•HCl
C12H16N2•2HCl
С15H19N2O2
6•2HCl
7
8•HCl
C13H16N2•HCl
C13H18N2•2HCl
C19H21N3•2HCl
С20H23N3•2HСl
C19H21N3•2HCl
C20H25N3•3HCl
C19H23N3•3HCl
C18H21N3•HCl
C19H20N2O•HCl
C18H20N2O2S•HCl
C19H21N3O•HCl
9•2HCl
11a•2HCl
11b•2HCl
11c•2HCl
12b•3HCl
12c•3HCl
13•2HCl
14•HCl
15•HCl
16•HCl
The free bases were purified by crystallization, column chromatography, or HPLC. Most of the
hydrogenated pyrrolo[3,4-b]indoles prepared in this study are unstable as the base or the hydrochlorides
containing water and rapidly tar upon storage. On the other hand, the anhydrous hydrochlorides are crystalline,
white or cream powders which are stable with prolonged storage under normal conditions.
1
The structure of the pyrrolo[3,4-b]indoles obtained was confirmed by H NMR spectroscopic and
LC-MS data. The values of the molecular ions correspond to their molecular weights and the proton chemical
1
shifts in the H NMR spectra unambiguously characterize the structure of the products and are identical to
literature data and the authors opinion (Tables 1 and 2). Elemental analytical data (Table 1) is also in agreement.
We have studied the ability of the synthesized hydrogenated pyrrolo[3,4-b]indoles 8, 9, 11a-c, 12b,c to
block calcium currents induced by the H1 histamine receptor in SK-N-SH cells and also the ability of these
compounds, depending on concentration, to block the functional response to serotonin stimulation of HEK293
cells, stably expressed the recombinant human 5-HT6 receptor (Table 3).
In order to evaluate the effects of the synthesized -carboline derivatives on calcium currents induced by
the H1 histamine receptors we carried out two variants of the experiments. In a) the investigated compounds
were added to the mixture before addition of histamine and the intensity measured as stage 1 and in b) the
compound was introduced after addition of histamine and the rate of lowering of cytosolic calcium measured as
stage 2. Data for the compounds activity, expressed as the concentration of half effect (IC50), is summarized in
Table 3.
173

TABLE 2. 1H NMR Spectra of the Pyrrolo[3,4-b]indoles
Com-
pound
Chemical shifts, , ppm (J, Hz)
4
5•HCl
2.35 (3H, s, 7-CH3); 2.57 (3H, s, 2-CH3); 3.82-3.86 (3H, m, 1-CH2, 3-CH2);
3.90 (1H, m, 1-CH2); 6.89 (1H, m, H-6); 7.10 (1H, s, H-8); 7.26 (1H, m, H-5);
10.87 (1H, br. s, 4-NH)
6•2HCl
2.14 (3H, s, 7-CH3); 2.16 (3H, s, 2-CH3); 2.30 (1H, m, H-3); 2.46 (1H, m, 3-CH2);
2.67 (2H, m, H-1); 3.71 (1H, m, H-8b); 4.21 (1H, m, H-3a); 5.42 (1H, br. s, 4-NH);
6.25 (1H, d, J = 7.8, H-5); 6.68 (1H, d, J = 7.8, H-6); 6.75 (1H, s, H-8)
7
8•HCl
2.40 (3H, s, 7-CH3); 2.63 (3H, s, 2-CH3); 3.67 (3H, s, 4-CH3); 3.90 (2H, br. s, 3-CH2);
3.96 (2H, br. s, 1-CH2); 6.93-6.97 (1H, m, H-6); 7.16 (1H, s, H-8);
7.28-7.31 (1H, m, H-5)
11a•2HCl 2.30 (3H, s, 7-CH3); 2.45 (3H, s, 2-CH3); 3.07 (2H, m, PyCH2CH2);
3.58 (2H, br. s, PyCH2CH2); 3.74 (2H, br. s, 3-CH2); 4.36 (2H, m, 1-CH2);
6.82 (1H, m, H-6); 7.01 (1H, s, H-8); 7.05 (1H, m, H-5 Py); 7.18 (1H, m, H-5);
7.22 (1H, m, H-3 Py); 7.57 (1H, m, H-4 Py); 8.48 (1H, m, H-6 Py)
11b•2HCl 2.40 (3H, s, 7-CH3); 2.44 (3H, s, 6-CH3Py); 2.51 (3H, s, 2-CH3);
2.98 (2H, m, PyCH2CH2); 3.59 (2H, m, PyCH2CH2); 3.81 (2H, m, 3-CH2);
4.28 (2H, m, 1-CH2); 6.93 (1H, m, H-6); 7.15 (2H, m, H-5,8);
7.37 (2H, m, H-4 Py, H-5 Py); 8.16 (1H, m, H-2 Py)
11c•2HCl 2.39 (3H, s, 7-CH3); 2.54 (3H, s, 2-CH3); 3.04 (2H, m, PyCH2CH2);
3.67 (2H, br. s, PyCH2CH2); 3.84 (2H, br. s, 3-CH2); 4.35 (2H, m, 1-CH2);
6.93 (1H, m, H-6); 7.15 (3H, m, H-8, H-3 Py, H-5 Py); 7.38 (1H, m, H-5);
8.45 (2H, m, H-2 Py, H-6 Py)
12b•3HCl 2.14 (3H, s, 7-CH3); 2.17 (3H, s, 6-CH3Py); 2.28 (1H, m, 1-CH2);
2.42 (3H, s, 2-CH3); 2.64-2.80 (4H, m, PyCH2CH2); 3.32-3.21 (3H, m, 1-CH2, 3-CH2);
3.74 (1H, m, 8b-CH); 4.14 (1H, m, 3a-CH); 6.24 (1H, m, H-6);
6.74 (2H, m, H-5, H-5 Py); 7.16 (1H, s, 8-H); 7.58 (1H, m, H-4 Py);
8.33 (1H, m, H-2 Py)
13•2HCl
2.13 (3H, s, 7-CH3); 2.17 (3H, s, 2-CH3); 2.45 (2H, m, 1-CH2); 2.72 (2H, m, 3-CH2);
3.77 (1H, m, 8b-CH); 4.17 (1H, m, 3a-CH); 4.40 (2H, m, PyCH2);
6.18 (1H, d, J = 8.0, H-5); 6.71 (1H, d, J = 8.0, H-6); 6.79 (1H, s, H-8);
7.33 (1H, m, H-5 Py); 7.67 (1H, d, J = 7.7, H-4 Py); 8.45 (1H, d, J = 4.1, H-6 Py);
8.51 (1H, s, H-2 Py)
14•HCl
15•HCl
2.25 (3H, s, 7-CH3); 2.76 (3H, s, 2-CH3); 3.25-3.51 (3Н, br. m, 1-CH2, 3-CH2, 8b-CH);
3.77 (1Н, br. s, 1-CH2); 4.25 (1Н, br. s, 3-CH2); 5.19 (1Н, br. s, 3a-CH);
6.94 (1Н, br. m, H-6); 7.20 (1H, s, H-8); 7.54 (6H, br. m, H-5, Ph);
10.05 (1Н, br. s, NH)
2.24 (3H, s, 7-CH3); 2.82 (3H, s, 2-CH3); 3.45 (4Н, br. m, 1-CH2, 3-CH2);
4.07 (1Н, br. s, 8b-CH); 4.97 (1Н, br. s, 3a-CH); 7.04 (1Н, s, H-8);
7.07 (1H, d, J = 8.6, H-6); 7.36 (1H, d, J = 8.6, H-5);
7.58 (2H, t, J = 7.9, H-3 Ph, H-5 Ph); 7.70 (1H, t, J = 7.5, H-4 Ph);
7.84 (2H, d, J = 7.9, H-2 Ph, H-6 Ph); 10.15 (1Н, br. s, NH)
16•HCl
2.19 (3H, s, 7-CH3); 2.24 (3H, s, 2-CH3); 2.58 (2Н, m, 1-CH2, 3-CH2);
2.82 (1H, d, J = 8.8, 3-CH2); 2.91 (1H, d, J = 10.0, 1-CH2); 3.93 (1Н, m, 8b-CH);
5.07 (1Н, m, 3a-CH); 6.92 (1H, d, J = 8.0, H-6); 6.99 (1H, s, H-8);
7.01 (1H, m, H-4 Ph); 7.28 (2H, m, H-3,5 Ph); 7.52 (2H, m, H-2 Ph, H-6 Ph);
7.70 (1H, d, J = 8.0, H-5); 8.38 (1Н, s, CONH)
As is evident in Table 3 the nature of the substituent in position 4 of the heterocycle and the degree of
hydrogenation strongly influence its ability of the compound to block calcium currents induced by histamine
receptors in stage 1. Hence the 4-methyl derivatives 8·HCl and 9·HCl are 30-50 times less active than Dimebon.
Within the series of 2,7-dimethyl-4-(2-pyridinylethyl)-3,4-dihydro-1H-pyrrolo[3,4-b]indoles 11a-c a transition
from the 4-[2-(pyridin-2-yl)ethyl] derivative 11a to 4-[6-methyl-2-(pyridin-3-yl)ethyl]- and to 4-[2-(pyridin-4-
yl)ethyl] derivatives 11b and 11c respectively is accompanied by an increase in activity from IC50 = 0.32 in
compound 11a to 0.20 in 11b and to 0.08 mol/l for 11c and the activity of the latter is more than twice that of
Dimebon (for which IC50 = 0.16 mol/l). The change from tetrahydro derivatives 11b,c to the corresponding
174

TABLE 3. Ability of Dimebon and Hydrogenated Pyrrolo[3,4-b]indoles to
Block H1 Histamine and Serotonin 5-HT6 Receptors in Cell Function
Experimental Conditions
IC50, mol/l
Compound
H1
5-HT6
Stage 1
Stage 2
Dimebon
8·HCl
0.16
3.16
5.01
0.32
0.20
0.08
5.01
0.79
1.58
1.26
3.16
1.00
0.63
0.79
3.16
1.58
2.14
>50
>50
12.7
26.1
16.1
>50
>50
7.0
9·2HCl
11a·2HCl
11b·2HCl
11c·2HCl
12b·3HCl
12c·3HCl
15·HCl
hexahydropyrrolo[3,4-b]indoles 12b,c causes a 10-25-fold lowering of antihistamine activity. However, the
4-[2-(pyridin-4-yl)ethyl] derivative 12c is 7 times more active than the 4-[2-(6-methylpyridin-3-yl)ethyl analog
12b. It should be noted that changing from stage 1 to stage 2 for the pyrrolo[3,4-b]indoles 11a-c and 12c is
accompanied, as in the case of Dimebon, by a 2-10-fold lowering of the IC50 value while compounds 8, 9 and
12b show a 1.5-3-fold increase in activity.
Fig. 1. Profile of the interactions of compounds 3 (a) and 11b (b) with different receptors and ion
channels. The interactions were calculated from the displacement of radiolabelled ligands from their
complex with the corresponding receptors. Dimebon 3 and the pyrrolo[3,4-b]indole 11b were at a
concentration of 10 M.
175

As noted above, Dimebon 3 efficiently binds to 5-HT6 receptors which are potential targets for the
development of medicines against illnesses connected with memory disorders. In this connection we have
studied the ability of the hydrogenated pyrrolo[3,4-b]indoles 8, 9, 11a-c, 12b,c, 15 to interact with serotonin
5-HT6 receptors (Table 3). We studied the concentration dependent ability of these compounds to block the
functional response to serotonin stimulation of HEK293 cells stably expressed the recombinant human 5-HT6
receptor. With serotonin stimulation of these cells there was observed an increased synthesis of intracellular
cyclic AMP as calculated using LANCE technology [21].
Studies have shown that, by contrast with Dimebon, the synthesized pyrrolo[3,4-b]indoles either weakly
block 5-HT6 receptors (11a-c, IC50 from 12.7 to 26.1 mol/l) or are overall inactive (IC50 greater than 50 mol/l
for 8, 9, 12b,c) and this agrees with data for the displacement of radiolabelled ligands from their complex with
5-HT6 receptors by the pyrrolo[3,4-b]indole 11b (Figure 1). An exception is the 2,7-dimethyl-4-phenylsulfonyl-
cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole (15) with a marked antagonist activity towards 5-HT6 receptors
(IC50 = 7.0 mol/l) and this is a general characteristic of heterocyclic compounds containing a phenylsulfonyl
substituent [22-24].
Studies of the pharmacological activity of the synthesized compounds are continuing and the results will
be published in a specific report.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian-400 (400 MHz, 27ºC) spectrometer using DMSO-d6 with
TMS as internal standard. Chromato-mass spectra were obtained on a Shimadzu HPLC chromatograph fitted
with a Waters XBridge C18 column (4.6×150 mm), PE SCIEX API 150 (chemical ionization) mass detector, and
Shimadzu spectrophotometric detector (max 220 and 254 nm). According to the chromato-mass spectrometric
data the purity of all of the synthesized compounds was greater than 98.0%. Preparative HPLC used a Shimadzu
LC-8A system with a Dr Masch Reprosil-Pur C18-AQ chromatographic column (20×250 mm) with a flow rate of
25 ml/min in gradient mode with a MeCN–water +0.05% CF3COOH eluent.
Reagents were used from the companies Acros, Sigma-Aldrich, Lancaster, and ChemDiv, solvents were
imported or native products of "chemically pure" or "pure" grade. Just before use, all of the reagents used were
purified by crystallization from a suitable solvent or fractionally distilled. Solvents were purified and dried by
reported methods.
In all cases monitoring of the reaction course and conversion of the substrate was carried out using
chromato-mass spectrometry. The concentration of solutions and drying of solid materials were only carried out
in vacuo with the exception of specified examples.
Ethyl 7-Methylpyrrolo[3,4-b]indole-2(1H,3H,4H)carboxylate (4). A solution of 1-ethoxycarbonyl-
pyrrolidin-3-one (5.50 g, 35 mmol) was added with vigorous stirring to a solution of p-tolylhydrazine
hydrochloride (5.56 g, 35 mmol) and AcONa (2.87 g, 35 mmol) in water (200 ml) and stirred for a further
15-30 min. The hydrazone precipitate formed was filtered off, washed three times with water, dried, ground up,
washed with ether (2×100 ml), and dried in air. The hydrazone (11.3 g) was mixed with H3PO4 (85%, 40 ml),
stirred for 1 h at 25-30ºC to full homogenization and solidification. A mixture of ice and water (350 ml) was added
and the precipitate formed was filtered off, washed with water to pH 7 of the water washings, drained, dried, and
crystallized from a mixture of acetonitrile and water (1:1) to give the pyrrolo[3,4-b]indole 4 (3.3 g, 33%).
2,7-Dimethyl-3,4-dihydro-1H-pyrrolo[3,4-b]indole (5). Compound 4 (2.44 g, 10 mmol) was stirred
over 2 h at 20ºC with LiAlH4 (50 mg, 13 mmol) in dry ether (15 ml) under an argon atmosphere. An aqueous
solution of NaOH (10%, 50 l) was added and the product was stirred until hydrogen evolution ceases. The
reaction mixture was filtered off and the organic layer was separated, dried over K2CO3, and evaporated to
dryness to give the pyrrolo[3,4-b]indole 5 (1.64 g, 87%).
176

2,7-Dimethyl-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole (6). A mixture of the pyrrolo[3,4-b]indole
5 (0.5 g, 2.7 mmol) and PtO2 (150 mg) in ethanol (20 ml) was stirred under a hydrogen atmosphere for 24 h at
20ºC. The reaction product was filtered off, evaporated, and chromatographed on silica gel impregnated with
Et3N using hexane–CHCl3–Et3N (4:2:1) as eluent. The yield of compound 6 was 0.48 g (95%).
Ethyl 4,7-Dimethylpyrrolo[3,4-b]indole-2(1H,3H,4H)carboxylate (7). A mixture of the indole 4 (0.37
g, 2.0 mmol), MeI (0.36 g, 2.5 mmol), and Cs2CO3 (750 mg) in N-methylpyrrolidone (10 ml) was stirred for 6 h
at 50ºC. The reaction product was diluted with water and extracted with CH2Cl2 and the organic layer was dried
(Na2SO4), filtered through a thin layer of silica gel, and evaporated to dryness to give the pyrrolo-[3,4-b]indole 7
(0.41 g, 80%).
2,4,7-Trimethyl-3,4-dihydro-1H-pyrrolo[3,4-b]indole (8) was prepared in 85% yield by the method
reported before for compound 5.
2,4,7-Trimethyl-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole (9) was prepared in 97% yield by
analogy with the method for compound 6.
2,7-Dimethyl-4-(2-pyridinylethyl)-3,4-dihydro-1H-pyrrolo[3,4-b]indoles 11a-c (General Method). An
50% aqueous solution of Bu4N)2SO4 (100 l), the vinylpyridine 10a-c (3-4 mmol) and a 60% aqueous solution
of KOH (8-12 ml) were added to a solution of the pyrrolo[3,4-b]indole 5 (0.372 g, 2.0 mmol) in DMSO (2 ml).
The reaction mixture was purged with argon and stirred for 12-24 h at 80ºC, treated with CH2Cl2, washed with
water, and the organic layer was dried over K2CO3. Solvent was evaporated to dryness and the residue was
chromatographed on silica gel impregnated with Et3N using hexane–CHCl3–Et3N (5:4:1) as eluent.
2,7-Dimethyl-4-(2-pyridinylethyl)-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indoles 12b,c were
prepared in 90-95% yield using the method reported for compound 6.
2,7-Dimethyl-4-(pyridin-3-ylmethyl)-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole
(13).
A
solution of indole 6 (98 mg, 0.52 mmol) in CH2Cl2 (2 ml), pyridine-3-carbaldehyde (60 l, 0.60 mmol), and
NaBH(AcO)3 (120 mg, 0.60 mmol) was stirred at room temperature for 2 h. Solvent was evaporated to dryness
and the residue was separated using column chromatography as reported for compounds 10a-c using hexane–
CHCl3–Et3N (5:3:2) as eluent to give the pyrrolo[3,4-b]indole 13 (94 mg, 65%).
4-Benzoyl-2,7-dimethyl-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole (14). Benzoyl chloride
(28 mg, 0.20 mmol) was added with stirring to a solution of the indole 6 (30 mg, 0.16 mmol) and Et3N (20 mg,
0.20 mmol) in THF (3 ml) and stirred for a further 20 min at 20ºC. The precipitate was filtered off, washed with
THF (10 ml), solvent evaporated, and the compound was separated column chromatographically as reported for
compounds 10a-c to give the pyrrolo[3,4-b]indole 14 (28 mg, 60%).
4-Benzenesulfonyl-2,7-dimethyl-cis-1,2,3,3a,4,8b-hexahydropyrrolo[3,4-b]indole (15). Benzene-
sulfonyl chloride (35 mg, 0.20 mmol) was added to a stirred solution of indole 6 (30 mg, 0.16 mmol) and Et3N
(20 mg, 0.20 mmol) in THF (3 ml) and stirred for 20 min at 20ºC. Separation by the method for compound 14
gave the pyrrolo[3,4-b]indole 15 (59 mg, 90%).
N-Phenyl-2,7-dimethyl-1,2,3,3a-tetrahydropyrrolo[3,4-b]indole-4(8bH)-carboxamide (16). Phenyl-
isocyanate (24 mg, 0.20 mmol) was added with stirring to a solution of the indole 6 (30 mg, 0.16 mmol) in THF
(3 ml) and stirred for 4 h at 20ºC. Separation by the method reported for compound 14 gave the pyrrolo-
[3,4-b]indole 16 (43 mg, 70%).
Hydrochlorides of the Pyrrolo[3,4-b]indoles 5, 6, 8, 9, 11a-c, 12b,c, 13-16. A test tube containing a
solution of the pyrrolo[3,4-b]indole (2 mmol) in a mixture of dry ether–THF (9:1) was centrifuged, the solution
of the indole carefully decanted off, and anhydrous HCl (6-8 mmol) in dry ether was added to it. The tube was
held for 10 min at 20ºC in an ultrasonic bath, centrifuged, solvent poured off, and the procedure was repeated.
The precipitate was dried in vacuo to give the pyrrolo[3,4-b]indole hydrochloride (white or cream colored
crystals) in 93-97% yield. Analytical results are given in Table 1.
177

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