New route of benzyne cyclization for synthesis of 2,3,4,5-tetrahydro-1h-pyrido[4,3-b]indole derivatives avoiding highly toxic aryl hydrazines

Article abstract of DOI:10.1002/jhet.2150

A new route for the regioselective synthesis of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivatives was developed based on cyclization of 3-chlorophenylimine-N-alkyl-4-piperidones by "the complex bases" of NaNH₂ or KNH₂. The procedure was performed under variable reaction conditions in inert proton-free solvents, such as THF, dioxane, 1,2-dimethoxyethane, toluene, and xylene, at temperatures varying from 20C to boiling point of the solvent used. Toxic arylhydrazine intermediates occurring in the classical Fischer indole synthesis are avoided.

Full text of DOI:10.1002/jhet.2150

September 2014 New Route of Benzyne Cyclization for Synthesis of 2,3,4,5-Tetrahydro-
1H-pyrido[4,3-b]indole Derivatives Avoiding Highly Toxic Aryl Hydrazines
1257
*
Lucia Kovacikova and Milan Stefek
Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04
Bratislava, Slovakia
*
E-mail: Milan.Stefek@savba.sk
Received October 2, 2013
DOI 10.1002/jhet.2150
Published online 30 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
A new route for the regioselective synthesis of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivatives was
developed based on cyclization of 3-chlorophenylimine-N-alkyl-4-piperidones by “the complex bases” of
NaNH2 or KNH2. The procedure was performed under variable reaction conditions in inert proton-free
solvents, such as THF, dioxane, 1,2-dimethoxyethane, toluene, and xylene, at temperatures varying from
20°C to boiling point of the solvent used. Toxic arylhydrazine intermediates occurring in the classical
Fischer indole synthesis are avoided.
J. Heterocyclic Chem., 51, 1257 (2014).
INTRODUCTION
The Graebe-Ullmann method [7] retains the same
problems of regioselectivity and complexity of the Fischer
procedure. Its principle is thermic, photolytic or microwave
breakdown of 1-aryl-1H-1,2,3-triazolo(4,5-c)pyridines [8],
or of 1-pyridyl-1H-1,2,3-benzotriazoles [9].
Thermic cyclization of 3-(2-azidophenyl)pyridines [10]
or of 3-(2-nitrosophenyl)pyridines [11] represents an
analogous non-selective procedure. The same is true for
photochemical cyclizations of 4-aniline-pyridines [12] and
N-arylenamine-4-amine-piperidones [13].
Other methods employ cyclization of 2-(2-indolyl)ethyl-
aza-cumulenes [14], 2-(2-indolyl)ethylaldimines [15] or of
acylated 2-(2-indolyl)ethylamines [16]. Because of a high
number of reaction steps, they are just of laboratory
relevance.
Similar drawbacks are characteristic for synthetic procedures
based on thermic breakdown of 2-vinyl-3-azidomethylindoles
[17], derivatization of 1-metoxyindol-2-karbaldehyde [18,19],
Diels-Alder’s reactions of 3-formimidoyl- and 2-ethoxyindoles
[20,21], or for retro-Mannich reaction of tetrahydropyrimido
(1,6-a)indoles [22].
Substituted tetrahydropyridoindoles display a broad spec-
trum of biological and pharmacological activities. Of them,
mebhydrolin, 5-benzyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido
[4,3-b]indole, (I, Fig. 1) [1], dimebon, 2,8-dimethyl-5-[2-(6-
methyl-3-pyridinyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]
indole (II, Fig. 1) [2], and alosetron, 5-methyl-2-[(4-
methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indol-1-one (III, Fig. 1) [3] are clinically
used as antihistamine agents and serotonin antagonists.
Dimebon was clinically tested to treat Alzheimer and Hun-
tington diseases, yet owing to negative side effects, the drug
has remained unlicensed for any neurodegenerative diseases.
One of the most elaborated methods to prepare 2,3,4,5-
tetrahydro-1H-pyrido[4,3-b] indoles is Fischer indole
synthesis [4] based on the reaction of arylhydrazines and
4-piperidones in acid environment. The disadvantage of
this method is the use of arylhydrazines, which are
instable, highly toxic, and mutagenic. In the technological
process, their use puts great demand on working security
and environment protection. The method yields uniform
products only for symmetrically substituted arylhydrazines
and 4-piperidones. The use of non-symmetric 3-substituted
arylhydrazines leads to a non-selective reaction and to the
production of regioizomers [5]. In the case of 2-substituted
derivatives, transposition and elimination of functional
groups occurs on the aromatic skeleton in position 2,
relative to hydrazine function [6]. These facts often complicate
product isolation and decrease the yield.
Disadvantages of the aforementioned procedures employed
for the synthesis of tetrahydropyridoindoles are par-
tially eliminated by Heck’s reaction of 2-iodine aniline
with N-ethoxycarbonyl-4-piperidones under catalysis
of Pd(OAc)2 in dimethylformamide. However, this
approach was used only in a particular case [23] and
moreover, isolation of the product required chromato-
graphic separation.
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L. Kovacikova and M. Stefek
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bases [24,25]. The bases most frequently used include
amides of alkali metals in the liquid ammonia or inert
aprotic solvents [26,27] . Mixtures of amides of alkali
metals with appropriate alcoholates of alkali metals (e.g.,
t-BuONa ), which react together and give rise to so-called
complex bases in inert aprotic solvents, mostly in ethers,
are also used [28]. Organolithium compounds, such as lith-
ium diisopropylamide [29] or t-butyllithium (t-BuLi) [30,31]
can be used as alternative basis for aryne generation.
The cyclization 3-chlorophenylimine-N-alkyl-4-piperidones,
described in this paper, represents a highly efficient method
of the regioselective synthesis of 2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indoles, with minimum damage to environ-
ment because the procedure avoids toxic arylhydrazine
intermediates.
Figure 1. Chemical structure of mebhydrolin (I), dimebon (II) and
alosetron (III).
The method of aryne cyclization plays an important role
in the synthesis of indoles and other heterocyclic
compounds. Intramolecular C-nucleophil aryne coupling
gives rise to condensed cyclic and heterocyclic systems.
This synthetic strategy, also called benzyne cyclization,
has a broad use in the preparation of four-member, five-
member, and six-member rings or higher ones. The most
frequently used methods of dehydroarene preparation
comprise the reaction of arylhalogenides with strong
RESULTS AND DISCUSSION
In the present paper, we describe the synthesis of 2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole derivatives based on
cyclization of 3-chlorophenylimine-N-alkyl-4-piperidones
with NaNH2 or KNH2, under variable reaction conditions
in inert proton-free solvents, such as THF, dioxane, 1,2-
dimethoxyethane, toluene, or xylene (Scheme 1). The
starting imines (Schiff bases) 3a–j were prepared according
to the literature with good yields by interaction of appropri-
ately substituted 3-chloroanilines (1a–e) and N-alkyl-
piperidones (2a–c) under catalysis of p-toluenesulfonic acid.
The solvents used, yields, and final purities of the precursor
imines 3a–j are summarized in Table 1.
Scheme 1. Synthetic route of substituted 2,3,4,5-tetrahydro-1H-pyrido
[4,3-b]indole derivatives.
Generally, on synthesizing indole derivatives from
imines, complex bases are used, e.g., prepared by interaction
of sodium amide with sodium t-butanolate. Addition of
alcoholate helps dissolution of sodium amide in aprotic
Table 1
Synthesis of the imine precursors 3a–j.
Comp
R2
R6
R8
Solvent
Purity (%) (GC–MS)
Boiling point
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH3
CH3
CH3
CH3
CH3
CH2Ph
CH2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
H
H
H
CH3
CH3O
H
H
H
H
Cyclohexane
Cyclohexane
Benzene
Cyclohexane
Toluene
Toluene
Toluene
Toluene
Toluene
88.3
94.6
87.5
86.4
50.3 (crude)
56.4 (crude)
51.4 (crude)
35.2 (crude)
33.4 (crude)
38.2 (crude)
125–130°C/1 mmHg
133–136°C/1 mmHg
148–153°C/1 mmHg
132–136°C/1 mmHg
69.8
74.8
72.5
65.3
—
—
—
—
—
CH3
CH3O
H
H
H
CH3
H
CH3
CH3O
—
—
—
—
—
—
H
H
3j
Toluene
—
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Benzyne Cyclization in Synthesis of 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indoles
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Precursor imines (3a–j): general procedure.
The stirred
solvents (e.g., THF, toluene) so that the reaction is carried on
in a homogenous medium. Relative to the precursor imine,
five equivalents of NaNH2 (KNH2) are optimally used with
two equivalents of t-BuONa (t-BuOK). According to our
results, the reaction can be performed with profoundly
decreased molar ratios of the basic components relative
to the imine precursor, yet with still reasonably high
yields, when using crown ether (4b-16, 18-crown6),
polyethyleneglycol (4b-17, PEG-500; 4b-18, PEG-6000),
or the catalyst of phase transfer tetrabutyl ammonium
chloride (4b-19, TBACH), as shown in Table 2. Prolonga-
tion of the reaction time from 24 to 48 h, on using THF,
dioxane, or dimethoxyethane solvents, may significantly
increase the yield even with decreased content of the
complex bases. Similar yields were obtained when
organolithium compounds (4a-2, 4b-5, 4b-6, t-BuLi; 4b-7,
lithium di-isopropyl amide) were used to cyclize the imine.
The reaction performed with NaNH2 alone in THF (4b-22,
4b-23) gave significantly lower yields in comparison with
reactions performed with NaNH2 in the presence of the afore-
mentioned catalysts (Table 2). The synthesis employing a high
excess of the Grignards reagent (4b-8) failed completely.
To conclude, a new route for the regioselective synthe-
sis of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole deriva-
tives was developed on the basis of cyclization of
3-chlorophenylimine-N-alkyl-4-piperidones by “the com-
plex bases” of NaNH2 or KNH2. The procedure was
performed under variable reaction conditions avoiding toxic
arylhydrazines as intermediates of the classical Fischer indole
synthesis and as such represents an example of contempo-
rary chemistry friendly to the environment.
mixture of appropriately substituted 3-chloroanilines (1a–e, 1.2mol)
and N-alkyl-4-piperidones (2a–c, 1 mol) in a corresponding solvent
(500 mL) was refluxed under catalysis by p-toluenesulfonic acid
monohydrate (PTSA. H2O, 2g). Water generated during the
reaction was continuously removed by azeotropic distillation.
After completion of the reaction, the solvent was evaporated
under reduced pressure, and the crude reaction product (3a–j) was
further purified by vacuum distillation or used for the next
reaction step without purification. Reaction conditions, yields, and
purity of the products 3a–j are shown in Table 1.
Substituted 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indoles (4a–j).
Procedure 1.
Solid sodium t-butanolate was added to the
stirred suspension of sodium amide NaNH2 in 15 mL dry
solvent, and the reaction mixture was heated to 55–60°C for
2 h, followed by cooling to 0–5°C under argon atmosphere. A
solution of an appropriately substituted imine (3, 10 mmol) in
10 mL of dry solvent was added dropwise, and then the reaction
mixture was heated again for the reaction time indicated. The
solvent was evaporated under reduced pressure to dryness. The
crude product was dissolved in toluene, washed with water,
dried (MgSO4), and concentrated in vacuum. The residue was
dissolved in the mixture of toluene: triethylamine (10:1), filtered
through a short column of silica gel (6 g, 40–63 μm), and
evaporated again to dryness in vacuum to afford crude product
4a–j crystallized from appropriate solvent. Molar ratios of the
bases employed, solvent used, reaction temperature and time,
yield, purity, solvent used for crystallization, and melting points
are summarized in Table 2.
Procedure 2. The solution of 3-chlorophenylimine-N-methyl-
4-piperidone (3a, 10mmol) or 3-chloro-4-methylphenylimine-N-
methyl-4-piperidone (3b, 10mmol) in 10mL of dry THF was
added dropwise to the stirred solution prepared by mixing 20 mL
t-butyllithium in pentane (30 mmol) and 20mL of dry THF at
À80°C, and then the reaction mixture was heated under argon
atmosphere to 20–25°C for the indicated reaction time. The
solvent was evaporated under reduced pressure to dryness. The
crude product was dissolved in toluene, washed with water, dried
(MgSO4), and concentrated in vacuum. The residue was dissolved
in the mixture of toluene: triethylamine (10:1), filtered through a
short column of silica gel (6g, 40–63 μm), and evaporated again
to dryness in vacuum to afford crude product (4a,b) crystallized
from the appropriate solvent. Molar ratios of the bases employed,
solvent used, reaction temperature and time, yield, purity,
solvent used for crystallization, and melting points are
summarized in Table 2.
EXPERIMENTAL
Nuclear magnetic resonance spectra were recorded on Bruker
Avance DPX 300 spectrometer (Bruker Biospin SA, Wissenbourg,
1
France) operating at 300.13 MHz for H and 75.46 MHz for 13C.
1H-NMR and 13C-NMR spectra were acquired using internal ace-
tone (1H δ = 2.225; 13C δ = 31.07) as a reference standard in CDCl3
or D2O used as solvents. To assign the signals, the COSY, HSQC,
TOCSY, NOESY, and DEPT techniques were used. Elemental
analyses were performed on EA 1108 Carlo Erba. Melting points
were determined on a Kofler melting point apparatus (Franz Küstner,
Dresden, Germany) with digital thermometer (DT012C) and are
uncorrected. Mass spectra were recorded on mass detector HP
5970B MSD (Hewlett-Packard, Palo Alto, CA, USA) at 70 eV
ionization. The purity of the intermediate products was deter-
mined by GC–MS on HP 5890/5970B GC-MS System (Hewlett-
Packard, Palo Alto, CA, USA) using the column HP-5 (12 m × 0.22
mm × 0.33 μm). The precursor 3-chloroanilines (3-chloroaniline
1a, 3-chloro-4-methylaniline 1b, 3-chloro-4-methoxylaniline 1c,
3-chloro-6-methylaniline 1d, and 3-chloro-6-methoxylaniline 1e)
and N-alkyl-4-piperidones (N-methyl-4-piperidone 2a, N-benzyl-4-
piperidone 2b, and N-fenethyl-4-piperidone 2c) were purchased
from Sigma-Aldrich. Other chemicals were purchased from local
commercial sources. All solvents and reactants were purified before
use according to standard procedures [32].
Procedure 3. The solution of 3-chloro-4-methylphenylimine-
N-methyl-4-piperidone (3b, 10mmol) in 10mL of dry THF was
added dropwise to the stirred solution prepared by mixing 15 mL
of lithium diisopropylamide in THF (30 mmol) and 20 mL of
dry THF at À80°C, and then the reaction mixture was heated to
20–25°C for 24h under argon atmosphere. The solvent was
evaporated under reduced pressure to dryness. The crude product
was dissolved in toluene, washed with water, dried (MgSO4), and
concentrated in vacuum. The residue was dissolved in the mixture
of toluene: triethylamine (10:1), filtered through a short column of
silica gel (6g, 40–63 μm), and evaporated again to dryness in
vacuum to afford crude product (4b) crystallized from toluene.
The yield, purity, and melting point are summarized in Table 2.
Procedure 4. The solution of 3-chloro-4-methylphenylimine-
N-methyl-4-piperidone (3b, 10mmol) in 10mL of dry THF was
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Benzyne Cyclization in Synthesis of 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indoles
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added dropwise to the stirred solution prepared by mixing 15 mL of
t-BuMgCl in THF (80 mmol) and 20mL of dry THF at À80°C, and
then the reaction mixture was heated to 60°C for 48h under argon
atmosphere. The solvent was evaporated under reduced pressure
to dryness. The crude product was dissolved in toluene, washed
with water, dried (MgSO4), and concentrated in vacuum. The
residue was dissolved in the mixture of toluene: triethylamine
(10:1), filtered through a short column of silica gel (6g, 40–63 μm
), and evaporated again to dryness in vacuum to afford crude
product (4b). The yield, purity, and melting point are summarized
in Table 2.
Procedure 5. Potassium t-butanolate (20 mmol) was added
to the stirred suspension of potassium amide KNH2 (50 mmol)
in 30 mL of dry THF, and the reaction mixture was heated to
55–60°C for 2 h, followed by cooling to around 20°C under
argon atmosphere. A solution of 3-chloro-4-methylphenylimine-
N-methyl-4-piperidone 3b (10 mmol) in 10 mL dry THF was
added dropwise, and then the reaction mixture was heated again
to 55–60°C for 24 h. The solvent was evaporated under reduced
pressure to dryness. The crude product was dissolved in
toluene, washed with water, dried (MgSO4), and concentrated in
vacuum. The residue was dissolved in the mixture of toluene:
triethylamine (10:1), filtered through a short column of silica gel
(6 g, 40–63 μm), and evaporated again to dryness in vacuum to
afford crude product (4b) crystallized from toluene The yield,
purity, and melting point are summarized in Table 2.
Procedure 6. The 18-Crown-6 (0.5 mmol) was added to the
stirred suspension of potassium amide (KNH2, 30 mmol) in
15 mL dry THF. The reaction mixture was heated to 55–60°C
for 0.5 h, followed by cooling to around 20°C under argon
atmosphere. A solution of 3-chloro-4-methylphenylimine-N-
methyl-4-piperidone 3b (10 mmol) in 10 mL dry THF was
added dropwise, and then the reaction mixture was heated again
to 55–60°C for 48 h. The solvent was evaporated under reduced
pressure to dryness. The crude product was dissolved in
toluene, washed with water, dried (MgSO4), and concentrated in
vacuum. The residue was dissolved in the mixture of toluene:
triethylamine (10:1), filtered through a short column of silica gel
(6 g, 40–63 μm), and evaporated again to dryness in vacuum to
afford crude product (4b) crystallized from toluene. The yield,
purity, and melting point are summarized in Table 2.
Procedure 7. PEG 500 or PEG 6000 (0.5 mmol) was added
to the stirred suspension of sodium amide NaNH2 (30 mmol) in
15 mL dry THF, and the reaction mixture was heated to 55–60°
C for 0.5 h, followed by cooling to around 20°C under argon
atmosphere. A solution of 3-chloro-4-methylphenylimine-N-
methyl-4-piperidone 3b (10 mmol) in 10 mL dry THF was
added dropwise, and then the reaction mixture was heated again
to 55–60°C for 48 h. The solvent was evaporated under reduced
pressure to dryness. The crude product was dissolved in
toluene, washed with water, dried (MgSO4), and concentrated in
vacuum. The residue was dissolved in the mixture of toluene:
triethylamine (10:1), filtered through a short column of silica gel
(6 g, 40–63 μm), and evaporated again to dryness in vacuum to
afford crude product (4b) crystallized from toluene. The yield,
purity, and melting point are summarized in Table 2.
dropwise, and then the reaction mixture was heated again to
55–60°C for 48 h. The solvent was evaporated under reduced
pressure to dryness. The crude product was dissolved in
toluene, washed with water, dried (MgSO4), and concentrated
in vacuum. The residue was dissolved in the mixture of
toluene: triethylamine (10:1), filtered through a short column of
silica gel (6 g, 40–63 μm), and evaporated again to dryness in
vacuum to afford crude product (4b) crystallized from toluene.
The yield, purity, and melting point are summarized in Table 2.
Procedure 9. Sodium t-butanolate (6.33 mmol) was added
to the stirred suspension of sodium amide NaNH2 (126.6 mmol)
in 100 mL dry 1,2-dimethoxyethane, and the reaction mixture
was heated to 55–60°C for 2 h, followed by cooling to around
20°C under argon atmosphere. A solution of 3-chloro-4-
methylphenylimine-N-methyl-4-piperidone 3b (42.2 mmol) in
40 mL dry 1,2-dimethoxyethane was added dropwise, and then
the reaction mixture was heated again to 55–60°C for 48 h. The
solvent was evaporated under reduced pressure to dryness. The
crude product was dissolved in toluene, washed with water,
dried (MgSO4), and concentrated in vacuum. The residue was
dissolved in the mixture of toluene: triethylamine (10:1), filtered
through a short column of silica gel (6 g, 40–63 μm), and
evaporated again to dryness in vacuum to afford crude product
(4b) crystallized from toluene. The yield, purity, and melting
point are summarized in Table 2.
Procedure 10. A solution of 3-chloro-4-methylphenylimine-
N-methyl-4-piperidone 3b (10mmol) in 10mL dry THF was
added dropwise to the stirred suspension of sodium amide NaNH2
(30 or 50 mmol) in 15mL dry solvent, and then the reaction
mixture was heated to 55–60°C for 48 h. The solvent was
evaporated under reduced pressure to dryness. The crude product
was dissolved in toluene, washed with water, dried (MgSO4), and
concentrated in vacuum. The residue was dissolved in the mixture
of toluene: triethylamine (10:1), filtered through a short column of
silica gel (6g, 40–63 μm), and evaporated again to dryness in
vacuum to afford crude product 4b crystallized from toluene. The
yield, purity, and melting point are summarized in Table 2.
2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4a). White
solid; mp 168–170°C (Benzene); 1H-NMR (CDCl3): δ 2.54
(s, 3H, N–CH3), 2.54 (t, 2H, H-4), 2.73 (t, 2H, H-3), 3.66
(s, 2H, H-1), 7.05–7.37 (m, 4H, H–Ar), 8.74 (bs, NH); 13C-
NMR (CDCl3): 23.40 (C-4), 45.70 (N–CH3) 51.70 (C-1), 52.40
(C-3), 108.15 (C-9b), 110.60 (C-6), 117.30 (C-7), 119.00
(C-8), 120.90 (C-9), 125.93 (C-4a), 131.91 (C-9a), 136.15 (C-5a).
MS m/z (%): 186 (M+, 24), 143 (100), 115 (11), 93 (4), 77 (6). Anal.
Calcd for C12H14N2 (186.25): C, 77.38; H, 7.57; N, 15.04. Found:
C, 77.13; H, 7.73; N, 15.14.
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
(4b).
White solid; mp 153–155°C (Toluene); 1H-NMR (CDCl3):
δ 2.41 (s, 3H, CH3-8), 2.54 (s, 3H, N–CH3), 2.68 (t, 2H, H-3), 2.76
(t, 2H, H-4), 3.63 (s, 2H, H-1), 6.90–7.17 (m, 3H, H–Ar), 8.23
(bs, NH); 13C-NMR (CDCl3): 21.55 (CH3-8), 23.76 (C-4), 45.87
(N–CH3), 51.84 (C-3), 52.56 (C-1), 108.10 (C-9b), 110.34 (C-6),
117.34 (C-9), 122.53 (C-7), 126.37 (C-4a), 128.33 (C-9a), 132.05
(C-5a), 134.53 (C-8). MS m/z (%): 200 (M+, 21), 157 (100), 128
(4), 115 (4), 99 (5). Anal. Calcd for C13H16N2 (200.28): C, 77.96;
H, 8.05; N, 13.98. Found: C, 77.77; H, 8.28; N, 13.87.
Procedure 8. Tetrabutylammonium chloride (0.5 mmol) was
added to the stirred suspension of sodium amide NaNH2
(30mmol) in 15mL dry THF, and the reaction mixture was heated
to 55–60°C for 0.5 h, followed by cooling to around 20°C under
argon atmosphere. A solution of 3-chloro-4-methylphenylimine-N-
methyl-4-piperidone 3b (10 mmol) in 10 mL dry THF was added
2-Methyl-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]in-
dole (4c).
White solid; mp 170–171°C (Methanol); 1H-NMR
(CDCl3): δ 2.80 (t, 4H, H-3, H-4), 3.58 (s, 3H, N-CH3), 3.66
(s, 2H, H-1), 3.85 (s, 3H, CH3O-8) 6.75–7.10 (m, 3H, H–Ar),
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8.05 (bs, NH); 13C-NMR (CDCl3): 23.85 (C-4), 45.80 (N–CH3),
51.75 (C-1), 52.44 (C-3), 55.90 (CH3O-8), 100.03 (C-9), 108.54
(C-9b), 110.60 (C-7), 111.17 (C-6), 126.42 (C-4a), 131.19
(C-9a), 132.72 (C-5a), 153.85 (C-8). MS m/z (%): 216 (M+, 23),
187 (3), 173 (100), 158 (55), 142 (4), 130 (8), 103 (5), 77 (6). Anal.
Calcd for C13H16N2O (216.28): C, 72.19; H, 7.45; N, 12.95. Found:
C, 72.34; H, 7.21; N, 13.22.
156 (100), 143 (30), 115 (8), 91 (9), 77 (8). Anal. Calcd for
C19H20N2 (276.38): C, 82.57; H, 7.29; N, 10.13. Found: C,
82.42; H, 7.55; N, 10.01.
2-(2-Fenethyl)-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-
b]indole (4i).
White solid; mp 155–157°C (Toluene); 1H-
NMR (CDCl3): δ 2.43 (s, 3H, CH3-8), 2.78 (t, 2H, H-4), 2.90
(m, 2H, H-3), 2.91 (m, 2H, N–CH2), 2.93 (m, 2H, CH2–C6H5),
3.78 (s, 2H, H-1), 6.92–7.20 (m, 3H, H–Ar), 7.15–7.40 (m, 5H,
H–Ph), 7.83 (bs, NH); 13C-NMR (CDCl3): 21.45 (CH3-8),
23.73 (C-4), 34.27 (N–CH2), 49.46 (C-1), 50.78 (C-3), 60.00
(CH2–Ph), 108.03 (C-9b), 110.20 (C-6), 117.30 (C-9), 122.55
(C-7), 126.39 (C-4a), 128.39 (C-9a), 132.13 (C-5a), 134.36
(C-8), 128.39, 128.71, 140.34 (C–Ph). MS m/z (%): 290 (M+, 44),
199 (80), 170 (100), 157 (35), 91 (7), 65 (4). Anal. Calcd for
C20H22N2 (290.41): C, 82.71; H, 7.63; N, 9.64. Found: C, 82.35;
H, 7.94; N, 9.70.
2,6-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
(4d).
White solid; mp 127–129°C (Ethanol); 1H-NMR (CDCl3):
δ 2.46 (s, 3H, CH3-6), 2.58 (s, 3H, N–CH3), 2.85 (t, 2H, H-4), 2.89
(t, 2H, H-3), 3.71 (s, 2H, H-1), 6.96–7.28 (m, 3H, H–Ar), 7.96
(bs, NH); 13C-NMR (CDCl3): 23.67 (C-4), 45.65 (N–CH3),
51.87 (C-1), 52.42 (C-3), 55.32 (CH3O-6), 101.67 (C-7),
108.91 (C-9b), 110.59 (C-9), 119.54 (C-8), 126.34 (C-5a),
127.32 (C-4a), 131.21 (C-9a), 145.78 (C-6). MS m/z (%): 200
(M+, 22), 157 (100), 128 (4), 115 (6), 77 (4), 63 (3). Anal. Calcd
for C13H16N2 (200.28): C, 77.96; H, 8.05; N, 13.98. Found: C,
77.78; H, 8.41, N, 13.81.
2-(2-Fenethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]
indole (4j).
White solid; mp 133–135°C (Ethanol); 1H-NMR
(CDCl3): δ 2.61 (t, 2H, H-4), 2.89 (t, 2H, H-3), 2.95 (m, 2H,
CH2-C6H5), 2.98 (m, 2H, N–CH2), 3.83 (s, 2H, H-1), 3.88
(s, 3H, CH3O-8), 6.77–7.01 (m, 3H, H–Ar), 7.15–7.38 (m, 5H,
H–Ph), 8.42 (bs, NH); 13C-NMR (CDCl3): 23.43 (C-4), 34.00
(N-CH2), 49.33 (C-1), 50.85 (C-3), 55.79 (CH3O-8), 60.00
(CH2–Ph), 99.75 (C-9), 107.77 (C-9b), 110.43 (C-7), 111.23
(C-6), 126.31 (C-4a), 131.19 (C-5a), 133.00 (C-9a), 132.65
(C-8), 126.00, 128.33, 128.60, 140.11 (C–Ph). MS m/z (%):
306 (M+, 15), 215 (70), 186 (100), 173 (26), 158 (25), 108 (7),
77 (9). Anal. Calcd for C20H22N2O (306.40): C, 78.40; H, 7.23;
N, 9.14. Found: C, 78.35; H, 7.34; N, 9.07.
2-Methyl-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]
indole(4e).
White solid; mp 170–171°C (Methanol); 1H-NMR
(CDCl3): δ 2.58 (s, 3H, N-CH3), 2.86 (t, 4H, H-3, H-4), 3.70 (s,
2H, H-1), 3.95 (s, 3H, CH3O-6), 6.63–7.03 (m, 3H, H–Ar),
8.20 (bs, NH); 13C-NMR (CDCl3): 23.67 (C-4), 45.65 (N–
CH3), 51.87 (C-1), 52.42 (C-3), 55.32 (CH3O-6), 101.67 (C-7),
108.91 (C-9b), 110.59 (C-9), 119.54 (C-8), 126.34 (C-5a),
127.32 (C-4a), 131.21 (C-9a), 145.78 (C-6). MS m/z (%): 216
(M+, 30), 173 (100), 158 (38), 130 (7), 108 (8), 77 (5), 63 (3).
Anal. Calcd for C13H16N2O (216.28): C, 72.19; H, 7.45; N,
12.95. Found: C, 72.42; H, 7.18; N, 13.05.
2-Benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4f).
White
solid; mp 154–155°C (Ethanol); 1H-NMR (CDCl3): δ 2.70
(t, 2H, H-3), 2.84 (t, 2H, H-4), 3.71 (s, 2H, H-1), 3.78 (s,
2H, CH2–C6H5), 7.00–7.20 (m, 4H, H–Ar), 7.20–7.55 (m, 5H,
H–Ph), 7.89 (bs, NH). 13C-NMR (CDCl3): 23.73 (C-4), 49.86
(C-1), 50.21 (C-3), 62.47 (CH2–Ph), 108.75 (C-9b), 110.70
(C-6), 117.61 (C-9), 119.29 (C-8), 121.19 (C-7), 126.22 (C-4a),
132.25 (C-9a), 136.12 (C-5a), 127.23, 128.50, 129.26, 138.63,
138.63 (C–Ph). MS m/z (%): 262 (M+, 24), 143 (100), 115 (7), 91
(22), 65 (6). Anal. Calcd for C18H18N2 (262.35): C, 82.40; H,
6.91; N, 10.67. Found: C, 82.64; H, 7.11; N, 10.25.
Acknowledgements. To the memory of Dr Vladimir Snirc PhD,
who suddenly passed away in the middle of this study. Financial
support by grant VEGA 2/0067/11 is gratefully acknowledged.
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2-Benzyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]in-
dole (4g).
White solid; mp 178–179°C (Ethanol); 1H-NMR
(CDCl3): δ 2.39 (s, 3H, CH3-8), 2.68 (t, 2H, H-3), 2.83 (t, 2H,
H-4), 3.67 (s, 2H, H-1), 3.77 (s, 2H, CH2–C6H5), 6.89–7.13
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White solid; mp 161–162°C (Ethanol); 1H-NMR
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(C-4a), 132.00 (C-9a), 136.15 (C-5a), 126.30, 128.51,
128.58, 140.35 (C–Ph). MS m/z (%): 276 (M+, 11), 185 (82),
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