β-Carbolines: synthesis of harmane, harmine alkaloids and their structural analogs by thermolysis of 4-aryl-3-azidopyridines and investigation of their optical properties

Article abstract of DOI:10.1007/s10593-020-02625-4

[Figure not available: see fulltext.] Interest in β-carbolines is caused by the biological activity of these compounds and the use of their fluorescent properties in the study of their interaction with DNA and other biological targets, as well as with drug delivery vehicles. A new general method for the synthesis of harmane, harmine, and their structural analogs by thermolysis of substituted 4-aryl-3-azidopyridines was developed, and their optical properties were studied.

Full text of DOI:10.1007/s10593-020-02625-4

DOI 10.1007/s10593-020-02625-4
Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
β-Carbolines: synthesis of harmane, harmine alkaloids and
their structural analogs by thermolysis of 4-aryl-3-azidopyridines
and investigation of their optical properties
Vladislav Yu. Shuvalov1,2, Valeriya А. Elisheva1, Anastasiya S. Belousova1,
Evgenii V. Arshinov1, Larisa V. Glyzdinskaya1, Marina А. Vorontsova1,
Sergei А. Chernenko2, Aleksander S. Fisyuk2, Galina P. Sagitullina1*
1 F. M. Dostoevsky Omsk State University,
55a Mira Ave., Omsk 644077, Russia; е-mail: sagitullina@chemomsu.ru
2 Omsk State Technical University,
11 Mira Ave., Omsk 644050, Russia
Submitted October 2, 2019
Accepted October 21, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(1), 73–83
Interest in β-carbolines is caused by the biological activity of these compounds and the use of their fluorescent properties in the study of
their interaction with DNA and other biological targets, as well as with drug delivery vehicles. A new general method for the synthesis of
harmane, harmine, and their structural analogs by thermolysis of substituted 4-aryl-3-azidopyridines was developed, and their optical
properties were studied.
Keywords: alkaloids, 3-amino-4-arylpyridines, 4-aryl-3-azidopyridines, asymmetric Hantzsch pyridines, harmane, harmine, substituted
β-carbolines, fluorescence of β-carbolines.
One of the valuable gifts of nature to humanity is its
tireless synthesis of alkaloids, which have long been used
to treat various diseases. β-Carboline alkaloids are
produced by several plants, including Peganum harmala,
the main components of its extract being harmane, harmine,
harmaline, and harmalol. Peganum harmala extract has
been used since ancient times to treat syphilis, malaria,
hysteria, neuralgia, Parkinson's disease, rheumatism, as
well as for the preparation of hallucinogenic drinks and
tobacco. In China, Peganum harmala has been used to treat
cancer and malaria for more than 100 years.1
Harmane and harmine possess a wide spectrum of
biological activity.2 Harmine exhibits a high ability to
intercalate in DNA; it acts as a powerful and specific
inhibitor of tyrosine kinase DYRK1A, a promising target in
antitumor therapy; exhibits an affinity for neurotrans-
mitters, which makes this alkaloid a promising compound
for the development of drugs for the treatment of
neurodegenerative diseases, such as Alzheimer's disease. It
increases the induction of connective tissue growth factor
CCN2 in HCS-2/8 human chondrocyte cells and
osteoarthritic articular chondrocytes and, therefore, has a
chondrogenic and chondroprotective effect.3 Harmane
exhibits sedative, antidepressant, antiplatelet, antioxidant,
hypotensive, antidiabetic, antinociceptive, anti-parasite effect,
acts as acetylcholinesterase and myeloperoxidase inhibitor.4
β-Carboline alkaloids and their derivatives have a
pronounced antiviral activity. In particular, 9-methyl-
harmine disrupts the maturation and release of particles of
Dengue fever virus into the extracellular environment,
while harmane and its derivatives exhibit antiviral activity
against HIV.5
In 2014,
a piezochrome luminescent material, a
molecular donor–acceptor–donor triad, was synthesized on
0009-3122/20/56(1)-0073©2020 Springer Science+Business Media, LLC
73

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
Scheme 1
R
O
R
1. KMnO4
KOH, Py
, 10 min
CN
Me
EtONa
+
R
R
N
2. H2O
CN
Me
EtOH
rt, 20 h
H2N
90°C, 30 min
N
O
O
1 a R = H
b R = OMe
2a 82%
b 65%
CN
Me
CN
Me
200°C
1 h
HO2C
O
HO2C
N
CN
Me
t-BuOK
4a 85% (60% from 3a,b)
b 85% (61% from 3a,b)
5a 81%
b 84%
+
R
t-BuOH
40°C, 16 h
H2N
3a,b
the basis of harmane, which has acidochromic and
piezochromic fluorescence and is a promising molecular
switch.6
Harmane was used as a fluorescent molecular probe to
study transport proteins by stationary fluorimetry. Harmane,
harmine, and harmine derivatives are promising photo-
sensitizers for the photodynamic therapy of cancer.7
crotononitrile.13 Alternative synthesis of pyridine-6-carb-
oxylic acids 4a,b from compounds 1a,b using the single-
step Hantzsch reaction for the synthesis of pyridines 2a,b
with the subsequent oxidation of the furyl substituent of
pyridine turned out to be more efficient and better
reproducible (oxidation of the furyl substituent of pyridines
2a,b by KMnO4 in pyridine with KOH is more effective
than in Me2CO with KMnO4).14 Above methods provide
pyridines 4a,b in high yields (Scheme 1).
The known synthesis of 2-methylpyridines 5a,b
according to Katritzky et al. is multistage and time-
consuming.15 In our case, 4-aryl-3-cyano-2-methylpyri-
dines 5a,b were obtained by decarboxylation of pyridines
4a,b by heating without solvent (Scheme 1).
3-Cyano-2,6-dimethylpyridines 5c,d were obtained by
fusion of benzalacetone (1c) and anisalacetone (1d) with
3-aminocrotononitrile. The synthesis of amides 6a,c was
carried out by incomplete hydrolysis of the cyano group of
pyridines 5a,c by heating in concentrated H2SO4, and the
synthesis of amides 6b,d by the Radzishevsky hydrolysis
of the corresponding pyridines 5b,d.16 For the synthesis of
3-aminopyridines 8a–d, the classical (NaOCl, NaOH) and
modified (NBS, MeONa) Hoffmann reactions were
employed.17 Modified Hoffman reactions yielded 4-aryl-
2-methylpyridin-3-ylcarbamates 7a–l, from which 3-amino-
pyridines 8a–l were synthesized (Scheme 2).
The main methods for the synthesis of β-carbolines (9H-
pyrido[3,4-b]indoles) are the classic Pictet–Spengler and
Bischler–Napieralski reactions, as a result of which
tetrahydro- and dihydro-β-carbolines are obtained from
tryptamines and tryptophanes which then undergo
dehydrogenation of the pyridine ring. Both steps of these
reactions are constantly being improved.8 The Pictet–
Spengler reaction also uses gramines whose dialkylamino
group is substituted by the action of C-nucleophiles, either
with or without activation.9 Under similar conditions,
biomimetic synthesis of β-carbolines from tryptophan and
arylglycines was performed.10
Modern methods for the synthesis of β-carbolines are
represented by a number of reactions: the Ru-catalyzed
photoredox synthesis of 1-acyl-β-carbolines from trypt-
amines and terminal alkynes; Pd-catalyzed Buchwald–
Hartwig arylation of 2-chloroaniline with 3-bromopyridine
followed by the intramolecular Heck reaction; Pd-catalyzed
Ulmann cross coupling of 2-iodocyclohex-2-en-1-one with
4-iodo-3-nitropyridine to form 2-(3-nitropyridin-4-yl)cyclo-
hex-2-en-1-one, its reductive cyclization followed by dehydro-
genation of 6,7,8,9-tetrahydro-5H-pyrido[3,4-b]indole; Pd-
catalyzed annulation of 3-iodo-1H-indole-2-carboxaldehyde
imine with terminal and internal alkynes; Ru-catalyzed
[2+2+2] cycloaddition of O,N-dialkynylamides with nitriles;
Ru-catalyzed thermolysis of 2-(2-azidoaryl-1-methylpyridi-
nium triflate, which completes with the insertion of nitrene
into the С–Н bond of pyridine.11 Most of the above
methods for producing β-carbolines use expensive and
toxic catalysts, the use of which is less than ideal.12
Harmane, harmine, and their structural analogs 10a–l
were synthesized by thermolysis of 4-aryl-3-azidopyridines
9a–l in xylene. In turn, 4-aryl-3-azidopyridines 9a–l were
obtained from diazonium salts of 3-aminopyridines 8a–l.
Diazonium salts of 3-aminopyridines 8a,c,d were obtained
by treatment with NOBF4 in MeCN at –10°С, whereas
compounds 8b,e–l were accessed using NaNO2 in a
mixture of AcOH and HBF4 (diazonium salts were not
isolated). As a result of the substitution of the diazo group
in the pyridyldiazonium salts with the azide group by
nucleophilic substitution with NaN3, 3-azidopyridines 9a–l
were formed. 3-Azidopyridines 9a–d were obtained in
quantitative yields, isolated, and characterized, whereas the
unstable 3-azidopyridines 9e–l were isolated by extraction
with m-xylene and used without further purification
(Scheme 3).
We were able to implement a new method for the
synthesis of harmane, harmine alkaloids and their structural
analogs, in which 3-cyano-2-methylpyridines 5a,b were
used as starting compounds. In order to increase the yield,
the previously described synthesis of pyridines 4a,b from
4-aryl-2-oxobut-3-enoic acids 3a,b was optimized by
replacing MeCN with commercially available 3-amino-
β-Carbolines contain the acidic proton of the pyrrole
ring of indole and the nitrogen atom of the pyridine ring in
0009-3122/20/56(1)-0000©2020 Springer Science+Business Media, LLC
74

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
Scheme 2
their structure, which in the basic state have pKa 16 (pyrrole
NH) and pKa 7 (pyridine N). The electronic excitation of
carbolines to the first singlet excited state increases the
acidity and basicity of both centers by 4–7 pKa units. A
change in the acid-base properties of carbolines upon
excitation makes possible double proton transfer and the
implementation of the phototautomerization process.18
It is known that harmine, norharmane, and other
β-carboline alkaloids easily protonate and deprotonate
forming a cation, anion, and zwitterion,18 which have
different absorption and fluorescence spectra (Scheme 4).
For example, the maxima in the luminescence spectra
for various acid-base forms of harmine 10b are at 420
(cation H2CB+), 372 (neutral form HCB), 435 (anion CB–),
and 482 nm (zwitterion HCB+–),19 which makes it possible
to use it as a fluorescent probe for biological research,7
responsive to changes in the pH of the medium and the
external environment.20
The absorption spectra of compounds 10a–d in EtOH
solution are a superposition of neutral and protonated form
signals. Therefore, treatment of these solutions with
radiation with different wavelengths leads to different
Scheme 3
Method I
1. For 8a,c,d
R
R
Method I
NOBF4, MeCN, 0°C, 30 min
For 8b,e–l
NaNO2, 48% HBF4
AcOH, H2O, 0°C, 45 min
R1
For 9e–l
m-Xylene
, 6–10 h
4
3
5
8
4a
N2
1
4b
6
N3
NH2
9a
2. NaN3, AcOH
0–2°C, 30 min
Method II
For 9a–d
m-Xylene
, 10 h
8a
Me
9
N
7
R
R1
N
9a–l
Me
R1
N
8a–l
Me
H
10a–l
OMe
Br
Me
N
Me
N
N
N
N
N
Me
NH
Me
Me
Me
NH
NH
Me
NH
Me
NH
NH
10e (68%)
MeO
MeO
Harmane
10a (45%)
3-Methylharmine
3-Methylharmane
Harmine
10b (51%)
MeO
10f (51%)
10d (42%)
10c (59%)
Me
Br
OMe
Me
N
N
N
N
N
N
Me
Me
Me
NH
Me
Me
Me
NH
NH
10g (60%)
NH
10k (57%)
NH
10h (65%)
NH
10i (66%)
Cl
MeO
MeO
Cl
Me
10l (62%)
10j (78%)
75

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
Scheme 4
excitations in each of these forms and, as a result, to a
change in the fluorescence spectra. For example, when
compound 10d is irradiated with a 300 nm light, the signals
of the neutral form with maxima of 361 and 374 nm, as
well as of protonated forms with a maximum of 407 nm are
observed in the fluorescence spectrum (Fig. 1). At the same
time, when the solution is irradiated with light with a
wavelength of 325 nm, the broadened signal with a
maximum at 414 nm corresponding to the protonated form
is the main one (Fig. 1).
Only the neutral form signals are observed in the
fluorescence spectra of compounds 10a–d recorded in
aprotic solvents such as DMSO and CH2Cl2. When acid
(СF3CO2H) is added to the β-carboline 10d solution, only
the protonated signal is observed (Figs. S26 and S27, see
the Supplementary information file). A similar picture is
observed for all alkyl-substituted β-carbolines 10a–d. At
the same time, in the fluorescence spectra of solutions of
aryl-substituted β-carbolines 10e–l (recorded in EtOH), the
signal of the neutral form with a maximum at 370–390 nm
is the main signal (Fig. S13, see the Supplementary
information file). When these compounds are irradiated
with radiation with different wavelengths, it practically
does not change. In the short-wavelength region of the
absorption spectra, there are two intense peaks related to
the π–π and n–π transitions.19 For example, for compound
10k (Fig. 1), the maxima of these transitions are at 257 and
279 nm, respectively.
Signals of various acid-base forms are registered in the
absorption and fluorescence spectra of aqueous ethanol
solutions (H2O–EtOH, 9:1) of compound 10k recorded at
various pH values (Figs. S28 – S31, see the Supplementary
information file). When acidifying a solution of compound
10k by 2 N H2SO4 in the absorption spectra, a transition
from the form HCB to the form H2CB+ is noticeable.
However, the absorption spectrum changes slightly with
increasing pH of the medium. At the same time, at pH up to
4.5, only the H2CB+ form exists in the solution with a
maximum emission at 425 nm. At pH 4.5–6.6, the protonated
form H2CB+ transforms into the neutral form HCB, and at
pH 6.6–9.5 only the neutral form HCB with maximum
emission at 374 nm is present in solution. At pH 9.5, the
neutral form HCB begins to transform into the deprotonated
form CB– with a maximum emission at 485 nm.
Figure 1. Absorption and fluorescence spectra of EtOH solutions
of compounds 10d,k.
We determined the values of pKa 5.53 (H2CB+/HCB)
and pKa 11.56 (HCB/CB–) for compound 10k (Figs. S32
and S33, see the Supplementary information file). The pKa
value (H2CB+/HCB) was determined graphically19 from the
absorption (λ 373 nm) and fluorescence (λ 374 nm) spectra,
whereas pKa (HCB/CB–) was determined only from the
fluorescence spectra (λ 374 nm), since the absorption
spectrum did not change for this transition (Fig. 2; Figs.
S32 and S33, see the Supplementary information file).
A comparison of these data with the known values for
harmine 10b19 (pKa 7.75 (H2CB+/HCB), pKa 12.5 (HCB/CB–))
shows that the introduction of any substituent at position
C-3 has a significant effect on the acid-base properties of
the molecule and can be used to tune fluorescent probes
based on these compounds.
To conclude, we have developed a general method for
the synthesis of harmane, harmine alkaloids and their
structural analogs from available precursors. It was found
that thermolysis of 4-aryl-3-azidopyridines completes with
the formation of β-carbolines by the insertion of nitrene in
the C–H bond of the aryl substituent.
Experimental
IR spectra were registered on a Simex FT-801 FT-IR
spectrometer in KBr pellets. 1H and 13C NMR spectra were
acquired on a Bruker DRX-400 spectrometer (400 and
100 MHz, respectively) in CDCl3 or DMSO-d6, using
76

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
2949, 2764, 1729 (C=O), 1594, 1535, 1262, 1236, 1192,
1
1064, 835, 759, 700, 620, 579. H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 2.57 (3H, s, 2-CH3); 3.66 (3Н, br. s,
NHCOOCH3); 6.36 (1Н, br. s, NHCOOCH3); 7.12 (1Н, d,
J = 5.0, H-5); 7.33–7.35 (2Н, m, H Ph); 7.39–7.47 (3Н, m,
H Ph); 8.43 (1Н, d, J = 5.0, H-6). 13C NMR spectrum
(CDCl3), δ, ppm: 21.4; 52.6; 122.5; 125.7; 128.3 (2C); 128.4;
128.6 (2C); 137.0; 147.1; 147.4; 155.0; 157.4. Found, %: C
69.47; H 5.79; N 11.59. C14H14N2O2. Calculated, %:
C 69.41; H 5.82; N 11.56.
Methyl [4-(4-methoxyphenyl)-2-methylpyridin-3-yl]-
carbamate (7b). Yield 0.25 g (90%), colorless crystals, mp
137–138°С (petroleum ether). IR spectrum, ν, cm–1: 3266
(NH), 2955, 2839, 1703 (C=O), 1610, 1514, 1306, 1264,
1
1248, 1184, 1071, 1028, 823. H NMR spectrum (CDCl3),
Figure 2. Dependence of the fluorescence spectrum of compound
10k on the pH of the solution in H2O–EtOH, 9:1, concentration
5.8 µМ , excitation wavelength 278 nm.
δ, ppm (J, Hz): 2.55 (3H, s, 2-CH3); 3.67 (3H, br. s,
NHCOOCH3); 3.83 (3Н, s, ОCH3); 6.42 (1Н, br. s,
NHCOOCH3); 6.93–6.97 (2Н, m, H Ar); 7.11 (1Н, d,
J = 5.1, H-5); 7.25–7.28 (2Н, m, H Ar); 8.37 (1Н, d, J = 5.1,
H-6). 13C NMR spectrum (CDCl3), δ, ppm: 21.1; 52.7; 55.3;
114.2 (2C); 122.7; 128.9 (2C); 129.6 (2C); 146.7; 147.3;
155.0; 157.0; 159.9. Found, %: C 66.22; H 5.95; N 10.31.
C15H16N2O3. Calculated, %: C 66.16; H 5.92; N 10.29.
Methyl (2,6-dimethyl-4-phenylpyridin-3-yl)carbamate
(7c). Yield 0.24 g (94%), colorless crystals, mp 132–133°С
(petroleum ether). IR spectrum, ν, cm–1: 3164 (NH), 2953,
2773, 1720 (C=O), 1593, 1530, 1388, 1264, 1248, 1202,
1098, 877, 752, 699, 599. 1H NMR spectrum (CDCl3),
δ, ppm: 2.52 (3H, s, 2-CH3); 2.54 (3H, s, 6-CH3); 3.62 (3Н,
br. s, NHCOOCH3); 6.03 (1Н, br. s, NHCOOCH3); 6.97
(1Н, s, H-5); 7.28–7.32 (2Н, m, Н Ph); 7.35–7.43 (3Н, m,
Н Ph). 13C NMR spectrum (CDCl3), δ, ppm: 21.1; 23.9; 52.6;
122.2; 126.2; 128.3 (2C); 128.4; 128.6 (2C); 137.2; 147.8;
155.2; 156.2; 156.4. Found, %: C 70.22; H 6.33; N 10.95.
C15H16N2O2. Calculated, %: C 70.29; H 6.29; N 10.93.
Methyl [4-(4-methoxyphenyl)-2,6-dimethylpyridin-
3-yl]carbamate (7d). Yield 0.27 g (95%), colorless
crystals, mp 102–103°С (petroleum ether). IR spectrum,
ν, cm–1: 3271 (NH), 3001, 2958, 2839, 1704 (C=O), 1610,
1515, 1386, 1268, 1189, 1076, 1032, 864, 841, 777, 711,
1
residual solvent signals (CDCl3: 7.26 ppm for H nuclei
1
and 77.0 ppm for 13C nuclei; DMSO-d6: 2.50 ppm for H
nuclei and 39.5 ppm for 13C nuclei) to assign chemical
shifts. Elemental analysis was performed on a Carlo Erba
EA 1106 CHN-analyzer. Absorption spectra were recorded
on a PerkinElmer Lambda 750 diode-array spectrophoto-
meter, photoluminescence spectra were recorded on a Cary
Eclipse fluorescence spectrophotometer. In both cases, the
concentration of the solutions of the studied compounds in
the corresponding solvents was below 10–5 mol/dm–3. The
molar coefficient of absorption was determined by a
literature method.21,22 The quantum yield of the
luminescence of the studied compounds was determined
relative to quinine sulfate using the comparison
method.23,24 Melting points were determined on a Boetius
heating bench and are uncorrected. Monitoring of the
reaction progress and assessment of the purity of
synthesized compounds were done by TLC on Silufol
UV-254 plates. 60–120 μ silica gel was used for column
chromatography.
Chalcones 1a,b,25a 1c,d,25b 1e,g,h,k,25c 1f,j,25d 1i,25e 1l25f
synthesized by the Claisen–Schmidt condensation of the
corresponding acetophenones and aromatic aldehydes.
Synthesis of compounds 3а,b26 and 5a,15,27a,b 5b,27a 5c,27b
5f–k,27d was done in accordance with published methods.
Synthesis of methyl (4-aryl-2-methylpyridin-3-yl)-
carbamates 7a–l (General method). Amide 6a–l (1.00 mmol)
and NBS (0.19 g (1.05 mmol) were added to a solution of
MeONa, obtained from Na (0.31 g) and anhydrous MeOH
(16 ml). The reaction mixture was stirred and heated (70°С)
for 6 min, then NBS (0.09 g, 0.53 mmol) was added, and
heating was continued for 10 min. After the completion of
the reaction, the solvent was evaporated under reduced
pressure, the residue was diluted with H2O and, with
cooling, neutralized with 50% AcOH. The resulting oil was
triturated with cooling, and, if necessary, left in the
refrigerator overnight. The resulting crystals were filtered
off, washed with H2O, and purified by recrystallization.
Methyl (2-methyl-4-phenylpyridin-3-yl)carbamate (7a).
Yield 0.18 g (76%), colorless crystals, mp 161–162°С
(petroleum ether). IR spectrum, ν, cm–1: 3161 (NH), 2989,
1
600, 548, 515. H NMR spectrum (CDCl3), δ, ppm: 2.52
(3H, s, 2-CH3); 2.53 (3H, s, 6-CH3); 3.64 (3Н, br. s,
NHCOOCH3); 3.82 (3H, s, ОCH3); 6.05 (1Н, br. s,
NHCOOCH3); 6.91–6.95 (3Н, m, H Ar, H-5); 7.22–7.26
(2Н, m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.0;
23.8; 52.6; 55.3; 114.1 (2C); 122.2; 126.3; 129.4; 129.6
(2C); 147.5; 155.3; 156.1; 156.4; 159.8. Found, %:
C 67.17; H 6.30; N 9.81. C16H18N2O3. Calculated, %:
C 67.12; H 6.34; N 9.78.
Methyl [6-(4-bromophenyl)-2-methyl-4-phenylpyri-
din-3-yl]carbamate (7e). Yield 0.33 g (83%), colorless
crystals, mp 175–176°С (EtOH). IR spectrum, ν, cm–1: 3204
(NH), 3008, 2959, 1736 (C=O), 1591, 1527, 1455, 1408,
1371, 1251, 1093, 1064, 1007, 915, 837, 757, 697.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.68 (3Н, s,
2-СН3); 3.65 (3Н, br. s, NHCOOCH3); 6.21 (1Н, br. s,
NHCOOCH3); 7.36–7.41 (2Н, m, Н Ph); 7.41–7.48 (3Н, m,
Н Ph); 7.51 (1Н, s, Н-5); 7.57 (2H, d, J = 8.4, Н Ar); 7.88
(2H, d, J = 8.4, Н Ar). 13C NMR spectrum (CDCl3),
δ, ppm: 21.2; 52.8; 119.8; 122.1; 123.9; 128.1; 128.3 (2C);
77

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
128.8 (4C); 131.9 (2C); 136.9 (2С); 147.8; 153.5; 154.9;
157.1. Found, %: C 60.53; H 4.33; N 7.09. C20H17BrN2O2.
Calculated, %: C 60.47; H 4.31; N 7.05.
colorless crystals, mp 167–168°С (EtOH). IR spectrum, ν, cm
–1: 3172 (NH), 3001, 2951, 2834, 1721 (C=O), 1608, 1516,
1
1458, 1376, 1255, 1174, 1067, 1038, 841, 770, 696. H
Methyl [4,6-bis(4-methoxyphenyl)-2-methylpyridin-
3-yl]carbamate (7f). Yield 0.34 g (89%), colorless
crystals, mp 148–149°С (EtOH). IR spectrum, ν, cm–1: 3295
(NH), 2959, 2841, 1700 (C=O), 1611, 1512, 1457, 1374,
NMR spectrum (CDCl3), δ, ppm: 2.61 (3Н, s, 2-СН3); 3.66
(3Н, br. s, NHCOOCH3); 3.85 (3Н, s, ОCH3); 5.98 (1Н, br.
s, NHCOOCH3); 6.95–7.01 (2Н, m, Н Ar); 7.36–7.47 (6Н,
m, Н Ph, Н-5); 7.93–7.97 (2Н, m, Н Ar). 13C NMR
spectrum (CDCl3), δ, ppm: 21.7; 52.7; 55.3; 114.1 (2C);
118.7; 126.6; 128.3 (2C); 128.4 (3C); 128.7 (2C); 131.7;
137.6; 147.6; 155.1; 155.2; 156.9; 160.5. Found, %:
C 72.43; H 5.77; N 8.07. C21H20N2O3. Calculated, %:
C 72.40; H 5.79; N 8.04.
1
1290, 1257, 1240, 1064, 1027, 840. H NMR spectrum
(CDCl3), δ, ppm: 2.59 (3Н, s, 2-СН3); 3.69 (3Н, br. s,
NHCOOCH3); 3.84 (3Н, s, ОCH3); 3.85 (3Н, s, ОCH3);
6.04 (1Н, br. s, NHCOOCH3); 6.95–6.99 (4Н, m, Н Ar);
7.30–7.32 (2Н, m, Н Ar); 7.43 (1Н, s, Н-5); 7.92–7.95 (2Н,
m, Н Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.7; 52.7;
55.3; 114.0 (2C); 114.1 (2C); 118.8; 126.6; 128.3 (2C);
129.6 (2C); 129.7; 131.7; 147.2; 155.0; 155.2; 156.9;
159.7; 160.4. Found, %: C 69.89; H 5.90; N 7.37.
C22H22N2O4. Calculated, %: C 69.83; H 5.86; N 7.40.
Methyl [4-(4-methoxyphenyl)-2-methyl-6-phenyl-
pyridin-3-yl]carbamate (7k). Yield 0.33 g (95%),
colorless crystals, mp 167–168°С (EtOH). IR spectrum, ν, cm
–1: 3288 (NH), 3033, 2747, 2842, 1698 (C=O), 1609, 1616,
1446, 1254, 1064, 10223, 833, 770, 701. 1H NMR
spectrum (CDCl3), δ, ppm: 2.62 (3Н, s, 2-СН3); 3.69 (3Н,
br. s, NHCOOCH3); 3.85 (3Н, s, ОCH3); 6.04 (1Н, br. s,
NHCOOCH3); 6.96–7.00 (2Н, m, Н Ar); 7.30–7.34 (2Н, m,
Н Ph); 7.36–7.46 (3Н, m, Н Ph); 7.50 (1Н, s, Н-5); 7.97–7.99
(2Н, m, Н Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.7;
52.7; 55.3; 114.2 (2C); 119.6; 127.0 (2C); 127.3; 128.7
(2C); 128.8; 129.6; 129.7 (2C); 133.5; 139.1; 147.2; 155.3;
157.1; 159.8. Found, %: C 72.43; H 5.76; N 8.08.
C21H20N2O3. Calculated, %: C 72.40; H 5.79; N 8.04.
Methyl
[6-(4-bromophenyl)-4-(4-methoxyphenyl)-
2-methylpyridin-3-yl]carbamate (7g). Yield 0.38
g
(90%), colorless crystals, mp 143–144°С (EtOH). IR spect-
rum, ν, cm–1: 3400 (NH), 2952, 2838, 1729 (C=O), 1601,
1
1493, 1408, 1242, 1064, 1015, 837, 768. H NMR spectrum
(CDCl3), δ, ppm: 2.64 (3Н, s, 2-СН3); 3.62 (3Н, br. s,
NHCOOCH3); 3.85 (3Н, s, ОCH3); 6.61 (1Н, br. s,
NHCOOCH3); 7.02–7.10 (2Н, m, Н Ar); 7.25–7.28 (2Н, m,
Н Ar); 7.45 (1Н, s, Н-5); 7.55–7.57 (2Н, m, Н Ar); 7.86–
7.88 (2Н, m, Н Ar). 13C NMR spectrum (CDCl3), δ, ppm:
21.8; 52.5; 55.9; 111.3 (2C); 119.9 (2C); 121.5; 123.2;
126.3; 128.6 (2C); 130.4; 131.2 (2C); 131.8; 137.8; 144.5;
153.6; 155.7; 156.6. Found, %: C 58.97; H 4.51; N 6.53.
C21H19BrN2O3. Calculated, %: C 59.03; H 4.48; N 6.56.
Methyl [4-(4-chlorophenyl)-2-methyl-6-phenylpyridin-
3-yl]carbamate (7h). Yield 0.31 g (87%), colorless
crystals, mp 161–162°С (EtOH). IR spectrum, ν, cm–1: 3203
(NH), 3135, 2955, 1715 (C=O), 1601, 1548, 1488, 1447,
1339, 1067, 1016, 883, 834, 774, 692, 594. 1H NMR
spectrum (CDCl3), δ, ppm: 2.62 (3Н, s, 2-СН3); 3.67 (3Н,
br. s, NHCOOCH3); 6.06 (1Н, br. s, NHCOOCH3); 7.30–7.33
(2Н, s, Н Ar); 7.37–7.47 (5Н, m, Н Ph); 7.48 (1Н, s, Н-5);
7.96–7.98 (2Н, m, Н Ar). 13C NMR spectrum (CDCl3),
δ, ppm: 21.7; 52.8; 119.3; 127.0 (2C); 127.9; 128.7 (2C);
128.9 (2C); 129.0; 129.7 (2C); 130.1; 134.6; 135.9; 138.8;
146.7; 155.0; 155.6. Found, %: C 68.02; H 4.83; N 7.91.
C20H17ClN2O2. Calculated, %: C 68.09; H 4.86; N 7.94.
Methyl [2-methyl-4,6-bis(4-methylphenyl)pyridin-
3-yl]carbamate (7i). Yield 0.29 g (83%), colorless
crystals, mp 158–159°С (EtOH). IR spectrum, ν, cm–1: 3231
(NH), 3031, 2922, 1694 (C=O), 1592, 1524, 1457, 1379,
1266, 1189, 1059, 827. 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.34 (3Н, s, CH3); 2.35 (3Н, s, CH3); 2.47 (3Н, s,
2-СН3); 3.54 (3Н, br. s, NHCOOCH3); 7.26–7.28 (4Н, m,
Н Ar); 7.37–7.39 (2Н, m, Н Ar); 7.65 (1Н, s, Н-5); 7.99–
8.01 (2Н, m, Н Ar); 8.88 (1Н, br. s, NHCOOCH3).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.7; 20.8; 21.3
(2-CH3); 51.8; 118.6; 126.5 (2C); 127.8; 128.3 (2C); 128.8
(2C); 129.2 (2C); 134.5; 135.5; 137.5; 138.4; 148.2; 153.7;
155.2; 157.2. Found, %: C 76.32; H 6.42; N 8.12.
C22H22N2O2. Calculated, %: C 76.28; H 6.40; N 8.09.
Methyl
[4-(4-chlorophenyl)-2-methyl-6-(4-methyl-
phenyl)pyridin-3-yl]carbamate (7l). Yield 0.31 g (84%),
colorless crystals, mp 166–167°С (EtOH). IR spectrum,
ν, cm–1: 3219 (NH), 3140, 2953, 1714 (C=O), 1601, 1488,
1446, 1337, 1234, 1069, 1016, 818, 589. 1H NMR
spectrum (CDCl3), δ, ppm: 2.39 (3Н, s, CH3); 2.62 (3Н, s,
2-СН3); 3.67 (3Н, br. s, NHCOOCH3); 6.01 (1Н, br. s,
NHCOOCH3); 7.24–7.26 (2Н, m, Н Ar); 7.30–7.33 (2Н, m,
Н Ar); 7.40–7.44 (2Н, m, Н Ar); 7.46 (1Н, s, Н-5); 7.87–7.89
(2Н, m, Н Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.3;
21.6; 52.8; 119.0; 126.8; 126.9 (2C); 128.9 (2C); 129.5
(2C); 129.7 (2C); 129.9; 134.6; 135.9; 136.0; 139.1; 146.8;
155.1; 155.6. Found, %: C 68.69; H 5.25; N 7.60.
C21H19ClN2O2. Calculated, %: C 68.76; H 5.22; N 7.64.
Synthesis of 3-amino-4-arylpyridines 8a–l (General
procedure). Method I. 2 М Aqueous NaOH (3.7 ml) was
added to a solution of amide 6a–d (1 mmol) in i-PrOH
(10 ml). Then 12% aqueous NaOCl (2.5 ml) was added in
portions over 5 h (0.5 ml every hour). The resulting
mixture was heated at 60°С for 1 h. After the completion of
the reaction, i-PrOH was evaporated under reduced
pressure, the residue was diluted with H2O, and the formed
oil was extracted with EtOAc. The organic layer was dried
over MgSO4, evaporated under reduced pressure, and the
residue was purified by recrystallization.
Method II. Carbamate 7a–l (1.00 mmol) was added to a
solution of NaOH (0.30 g) in Н2О (0.8 ml) and EtOH
(2.2 ml). The reaction mixture was stirred for 24 h at 70°С,
then cooled to room temperature, and diluted with H2O.
The precipitated crystals were filtered off and purified by
recrystallization. Compound 8j was isolated as hydro-
chloride salt. This was done by dissolving the residue in the
form of an oil in EtOH (2 ml) and adding 36% HCl
(0.2 ml) with cooling.
Methyl [6-(4-methoxyphenyl)-2-methyl-4-phenyl-
pyridin-3-yl]carbamate (7j). Yield 0.28 g (79%),
78

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
2-Methyl-4-phenylpyridin-3-amine (8a). Yield 0.16 g
4,6-Bis(4-methoxyphenyl)-2-methylpyridin-3-amine
(8f). Yield 0.22 g (70%, method II), colorless crystals,
mp 87–88°С (EtOH). IR spectrum, ν, cm–1: 3465, 3376
(NH2), 2963, 2837, 1610, 1512, 1293, 1249, 1029, 840.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.43 (3Н, s,
2-СН3); 3.76 (3Н, s, ОCH3); 3.80 (3Н, s, ОCH3); 4.62 (2Н,
br. s, NH2); 6.91–6.94 (2Н, m, Н Ar); 7.05–7.07 (2Н, m,
Н Ar); 7.31 (1Н, s, Н-5); 7.42–7.45 (2Н, m, Н Ar); 7.88–
7.91 (2Н, m, Н Ar). 13C NMR spectrum (DMSO-d6),
δ, ppm: 21.4; 55.1; 55.2; 113.8 (2C); 114.4 (2C); 118.1;
126.5 (2C); 129.7 (2C); 129.8; 132.1; 132.3; 137.2; 143.2;
143.7; 158.7; 158.9. Found, %: C 75.00; H 6.30; N 8.76.
C20H20N2O2. Calculated, %: C 74.98; H 6.29; N 8.74.
(84%, method I), 0.15 g (80%, method II), yellow crystals,
mp 66–67°С (petroleum ether). IR spectrum, ν, cm–1: 3417,
3311 (NH2), 3216, 2912, 1639, 1591, 195, 1474, 1417,
1258, 1228, 1076, 1026, 984, 828, 780, 752, 709, 600, 544.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.37 (3H, s,
2-CH3); 3.63 (2Н, br. s, NH2); 6.82 (1Н, d, J = 4.9, H-5);
7.28–7.39 (5Н, m, H Ph); 7.89 (1Н, d, J = 4.9, H-6).
13C NMR spectrum (CDCl3), δ, ppm: 20.7; 122.6; 128.1;
128.5 (2C); 129.0 (2C); 133.3; 137.3; 137.5; 138.7; 143.9.
Found, %: C 78.19; H 6.55; N 15.25. C12H12N2. Calculated,
%: C 78.23; H 6.57; N 15.21.
4-(4-Methoxyphenyl)-2-methylpyridin-3-amine (8b).
Yield 0.15 g (72%, method I), 0.15 g (72%, method II),
colorless crystals, mp 138–139°С (petroleum ether).
IR spectrum, ν, cm–1: 3424, 3310 (NH2), 3198, 2834, 1629,
1517, 1250, 1180, 1029, 823, 568. 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 2.47 (3H, s, 2-CH3); 3.76 (2Н,
br. s, NH2); 3.84 (3H, s, ОCH3); 6.91 (1Н, d, J = 5.0, H-5);
6.97–7.01 (2Н, m, H Ar); 7.34–7.37 (2Н, m, H Ar); 7.94
(1Н, d, J = 5.0, H-6). 13C NMR spectrum (CDCl3), δ, ppm:
20.4; 55.3; 114.5 (2C); 122.9; 129.2; 129.7 (2C); 133.6;
138.0 (2С); 143.4; 159.5. Found, %: C 72.90; H 6.54;
N 13.04. C13H14N2O. Calculated, %: C 72.87; H 6.59; N 13.07.
2,6-Dimethyl-4-phenylpyridin-3-amine (8c). Yield
0.17 g (84%, method I), 0.15 g (76%, method II), colorless
crystals, mp 80–81°С (petroleum ether). IR spectrum,
ν, cm–1: 3432, 3319 (NH2), 3216, 3061, 2916, 1625, 1552,
1463, 1270, 1236, 1019, 956, 868, 744, 698, 592, 552.
1H NMR spectrum (CDCl3), δ, ppm: 2.47 (3H, s, 2-CH3);
2.48 (3H, s, 6-CH3); 3.63 (2Н, br. s, NH2); 6.81 (1Н, s,
H-5); 7.36–7.48 (5Н, m, Н Ph). 13C NMR spectrum
(CDCl3), δ, ppm: 20.2; 22.8; 122.3; 128.2; 128.5 (2C);
129.1 (2C); 135.1; 135.4; 137.3; 142.8; 146.2. Found, %:
C 78.70; H 7.16; N 14.10. C13H14N2. Calculated, %: C 78.75;
H 7.12; N 14.13.
6-(4-Bromophenyl)-4-(4-methoxyphenyl)-2-methyl-
pyridin-3-amine (8g). Yield 0.36 g (97%, method II),
colorless crystals, mp 185–186°С (EtOH). IR spectrum,
ν, cm–1: 3450, 3381 (NH2), 3005, 2957, 2834, 1622, 1551,
1
1491, 1462, 1243, 1177, 1117, 1020, 831, 757. H NMR
spectrum (DMSO-d6), δ, ppm: 2.43 (3Н, s, 2-СН3); 3.75
(3Н, s, ОCH3); 4.58 (2Н, br. s, NH2); 7.14–7.16 (2Н, m,
Н Ar); 7.20–7.23 (2Н, m, Н Ar); 7.37 (1Н, s, Н-5); 7.52–7.54
(2Н, m, Н Ar); 7.90–7.92 (2Н, m, Н Ar). 13C NMR spectrum
(DMSO-d6), δ, ppm: 21.3; 55.4; 119.7 (2C); 119.8; 120.1
(2C); 120.9; 125.9; 127.2 (2C); 130.2; 131.3 (2C); 138.6;
139.2; 141.5; 143.1; 156.3. Found, %: C 61.85; H 4.61; N 7.61.
C19H17BrN2O. Calculated, %: C 61.80; H 4.64; N 7.59.
4-(4-Chlorophenyl)-2-methyl-6-phenylpyridin-3-amine
(8h). Yield 0.27 g (92%, method II), colorless crystals,
mp 127–128°С (EtOH). IR spectrum, ν, cm–1: 3442, 3363
(NH2), 3035, 2938, 1598, 1489, 1386, 1232, 1088, 1014,
1
757, 694, 594. H NMR spectrum (DMSO-d6), δ, ppm:
2.45 (3Н, s, 2-СН3); 4.86 (2Н, br. s, NH2); 7.24–7.28 (1Н,
m, Н Ar); 7.35–7.41 (3Н, m, Н-5, Н Ar); 7.52–7.57 (4Н, m,
Н Ar); 7.95–7.97 (2Н, m, Н Ar). 13C NMR spectrum
(DMSO-d6), δ, ppm: 21.5; 118.8; 125.3 (2C); 127.1; 128.4
(2C); 128.9 (2C); 130.5 (2C); 130.8; 132.5; 136.6; 137.9;
139.2; 143.4; 143.7. Found, %: C 73.27; H 5.15; N 9.53.
C18H15ClN2. Calculated, %: C 73.34; H 5.13; N 9.50.
2-Methyl-4,6-bis(4-methylphenyl)pyridin-3-amine (8i).
Yield 0.25 g (85%, method II), colorless crystals, mp 106–
107°С (EtOH). IR spectrum, ν, cm–1: 3465, 3376 (NH2), 2963,
2837, 1610, 1512, 1293, 1249, 1029, 840. 1H NMR
spectrum (DMSO-d6), δ, ppm: 2.30 (3Н, s, 2-СН3); 2.36 (3Н,
s, CH3); 2.44 (3Н, s, CH3); 4.68 (2Н, br. s, NH2); 7.17–7.19
(2Н, m, Н Ar); 7.30–7.32 (2Н, m, Н Ar); 7.34 (1Н, s, H-5);
7.38–7.40 (2Н, m, Н Ar); 7.84–7.86 (2Н, m, Н Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.7; 20.8; 21.4;
118.5; 125.2 (2C); 128.3 (2C); 129.0 (2C); 129.6 (2C);
132.3; 134.7; 136.2; 136.6; 137.1; 137.6; 143.3; 143.7.
Found, %: C 83.26; H 6.95; N 9.74. C20H20N2. Calculated,
%: C 83.30; H 6.99; N 9.71.
4-(4-Methoxyphenyl)-2,6-dimethylpyridin-3-amine (8d).
Yield 0.15 g (66%, method I), 0.18 g (81%, method II),
colorless crystals, mp 115–116°С (petroleum ether).
IR spectrum, ν, cm–1: 3423, 3336 (NH2), 3220, 2835, 1613,
1
1511, 1460, 1290, 1246, 1173, 1035, 833, 558. H NMR
spectrum (CDCl3), δ, ppm: 2.44 (3H, s, 2-СН3); 2.45 (3H,
s, 6-СН3); 3.56 (2Н, br. s, NH2); 3.84 (3H, s, ОCH3); 6.76
(1Н, s, Н-5); 6.96–6.99 (2Н, m, H Ar); 7.33–7.36 (2Н, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 20.5; 23.1;
55.3; 114.5 (2C); 122.2; 129.7 (2C); 134.6; 135.3; 143.0;
146.6; 159.5. Found, %: C 73.59; H 7.03; N 12.30.
C14H16N2O. Calculated, %: C 73.66; H 7.06; N 12.27.
6-(4-Bromophenyl)-2-methyl-4-phenylpyridin-3-amine
(8e). Yield 0.31 g (91%, method II), colorless crystals,
mp 122–123°С (EtOH). IR spectrum, ν, cm–1: 3464, 3375
(NH2), 3212, 2935, 1616, 1551, 1491, 1454, 1425, 1376,
1349, 1233, 1178, 1069, 1008, 885, 829, 746, 701.
1H NMR spectrum (CDCl3), δ, ppm: 2.62 (3Н, s, 2-СН3);
3.94 (2Н, br. s, NH2); 7.36 (1Н, s, Н-5); 7.41–7.54 (7Н, m,
Н Ar, Н Ph); 7.81–7.83 (2Н, m, Н Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 20.3; 120.2; 122.2; 127.9 (2C); 128.5
(2C); 128.6; 129.3 (2C); 131.7 (2C); 135.0; 137.0; 137.5;
143.4; 144.7. Found, %: C 63.77; H 4.42; N 8.30.
C18H15BrN2. Calculated, %: C 63.73; H 4.46; N 8.26.
6-(4-Methoxyphenyl)-2-methyl-4-phenylpyridin-3-amine
hydrochloride (8j). Yield 0.25 g (86%, method II), yellow
crystals, mp 201–202°С (EtOH). IR spectrum, ν, cm–1: 3459,
3297 (NH2), 3215, 1625, 1513, 1439, 1291, 1262, 1187,
1
1088, 1026, 835, 781, 738, 705, 602. H NMR spectrum
(DMSO-d6), δ, ppm: 2.73 (3Н, s, 2-СН3); 3.43 (2H, br. s,
NH2); 3.82 (3Н, s, ОCH3); 7.07–7.10 (2Н, m, Н Ar); 7.51–
7.61 (5Н, m, Н Ar); 7.66 (1Н, s, Н-5); 7.88–7.91 (2Н, m,
Н Ar). 13C NMR spectrum (DMSO-d6), δ, ppm: 16.3; 55.5;
79

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
114.3 (2C); 123.4; 124.0; 128.4 (2C); 129.3 (2C); 129.4
was added for 30 min. The reaction mixture was warmed to
0°С and stirred for 30 min, diluted with H2O, and extracted
with Et2O. The extract was dried over MgSO4,
concentrated, and the product was purified by column
chromatography on silica gel, eluent CHCl3–EtOAc, 9:1,
and recrystallized from petroleum ether.
3-Azido-2-methyl-4-phenylpyridine (9a). Yield 0.17 g
(80%), colorless crystals, mp 35–36°С (petroleum ether).
IR spectrum, ν, cm–1: 3060, 3025, 3010, 2971, 2922, 2135
(N3), 1584, 1537, 1464, 1437, 1296, 1219, 1152, 1096,
1073, 880, 847, 828, 752, 696. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 2.63 (3H, s, 2-СН3); 7.09 (1Н, d, J = 4.9, Н
-5); 7.43–7.52 (5Н, m, Н Ph); 8.33 (1Н, d, J = 4.9, Н-6).
13C NMR spectrum (CDCl3), δ, ppm: 21.2; 123.4; 128.6
(2C); 128.7 (2C); 128.9; 132.4; 135.7; 143.4; 145.2; 152.6.
Found, %: C 68.59; H 4.76; N 26.61. C12H10N4. Calculated,
%: C 68.56; H 4.79; N 26.65.
3-Azido-2,6-dimethyl-4-phenylpyridine (9c). Yield
0.21 g (94%), colorless crystals, mp 41–42°С (petroleum
ether). IR spectrum, ν, cm–1: 2930, 2920, 2116 (N3), 1606,
1513, 1296, 1248, 1150, 1095, 1070, 878, 844, 755, 699.
1H NMR spectrum (CDCl3), δ, ppm: 2.54 (3Н, s, 2-СН3);
2.60 (3Н, s, 6-СН3); 6.95 (1Н, s, Н-5); 7.41–7.49 (5Н, m,
Н Ph). 13C NMR spectrum (CDCl3), δ, ppm: 21.0; 23.6;
123.0; 128.6 (2C); 128.7 (2C); 128.8; 129.8; 135.9; 143.8;
151.7; 154.2. Found, %: C 69.58; H 5.38; N 24.95.
C13H12N4. Calculated, %: C 69.62; H 5.39; N 24.98.
(2C); 129.5; 135.0; 138.6; 138.8 (2С); 140.8; 160.8. Found,
%: C 69.88; H 5.81; N 8.59. C19H19ClN2O. Calculated, %:
C 69.83; H 5.86; N 8.57.
4-(4-Methoxyphenyl)-2-methyl-6-phenylpyridin-3-amine
(8k). Yield 0.23 g (80%, method II), colorless crystals,
mp 134–135°С (EtOH). IR spectrum, ν, cm–1: 3459, 3372
(NH2), 2961, 2837, 1611, 1510, 1444, 1349, 1286, 1247,
1
1170, 1104, 1025, 976, 873, 830, 775, 688, 593. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.34 (3Н, s, 2-СН3);
3.70 (3Н, s, ОCH3); 4.63 (2Н, br. s, NH2); 6.95–6.98 (2Н,
m, Н Ar); 7.16 (1Н, t, J = 7.2, Н Ar); 7.27–7.29 (3Н, m,
Н Ar, Н-5); 7.33–7.35 (2Н, m, Н Ar); 7.84–7.86 (2Н, m,
Н Ar). 13C NMR spectrum (DMSO-d6), δ, ppm: 21.4; 55.2;
114.4 (2C); 118.9; 125.2 (2C); 127.0; 128.4 (2C); 129.7
(2C); 130.1; 132.1; 137.9; 139.3; 143.4; 143.5; 158.9.
Found, %: C 78.61; H 6.27; N 9.68. C19H18N2O. Calculated,
%: C 78.59; H 6.25; N 9.65.
4-(4-Chlorophenyl)-2-methyl-6-(4-methylphenyl)pyridin-
3-amine (8l). Yield 0.24 g (78%, method II), colorless
crystals, mp 114–115°С (EtOH). IR spectrum, ν, cm–1:
3490, 3403 (NH2), 3084, 2931, 1615, 1491, 1454, 1429,
1
1396, 1379, 1233, 1180, 1089, 823. H NMR spectrum
(DMSO-d6), δ, ppm: 2.30 (3Н, s, CH3); 2.44 (3Н, s,
2-СН3); 4.80 (2Н, br. s, NH2); 7.17–7.19 (2Н, m, Н Ar);
7.36 (1Н, s, Н-5); 7.51–7.56 (4Н, m, Н Ar); 7.84–7.86 (2Н,
m, Н Ar). 13C NMR spectrum (DMSO-d6), δ, ppm: 20.7;
21.4; 118.4; 125.1 (2C); 128.9 (2C); 129.0 (2C); 129.7;
130.5 (2C); 130.9; 132.5; 136.2; 136.5; 136.6; 137.6;
143.6. Found, %: C 73.93; H 5.57; N 9.03. C19H17ClN2.
Calculated, %: C 73.90; H 5.55; N 9.07.
3-Azido-4-(4-methoxyphenyl)-2,6-dimethylpyridine
(9d). Yield 0.24 g (96%), colorless crystals, mp 34–35°С
(petroleum ether). IR spectrum, ν, cm–1: 2932, 2839, 2119
1
(N3), 1609, 1514, 1291, 1251. H NMR spectrum (CDCl3),
3-Azido-4-(4-methoxyphenyl)-2-methylpyridine (9b).
A cooled solution of 48% HBF4 (3.5 ml) was added
dropwise with cooling to 0°С to a solution of 3-amino-
pyridine 8b (1.0 mmol) in AcOH (5 ml) and H2O (2 ml).
The reaction mixture was stirred for 30 min, then a cooled
solution of NaNO2 (83 mg, 1.2 mmol) in H2O (1 ml) was
added dropwise. The reaction mixture was kept at 0°С for
45 min, then NaN3 (78 mg, 1.2 mmol) was added in
portions at the same temperature. The reaction mixture was
stirred for 30 min, diluted with H2O, and neutralized with
ammonia. The precipitated crystals were filtered off,
washed with H2O, and purified by recrystallization. Yield
0.23 g (96%), colorless crystals, mp 65–66°С (petroleum
ether). IR spectrum, ν, cm–1: 3012, 2966, 2838, 2134 (N3),
δ, ppm: 2.52 (3H, s, 2-СН3); 2.58 (3H, s, 6-СН3); 3.85 (3H,
s, ОCH3); 6.92 (1Н, s, Н-5); 6.97–7.00 (2Н, m, Н Ar); 7.38–
7.42 (2Н, m, Н Ar). 13C NMR spectrum (CDCl3), δ, ppm:
21.0; 23.6; 55.3; 114.1 (2C); 122.9; 128.1; 129.9 (3C); 143.4;
151.7; 154.2; 160.0. Found, %: C 66.08; H 5.59; N 22.07.
C14H14N4O. Calculated, %: C 66.13; H 5.55; N 22.03.
Synthesis of 1-methyl-β-carbolines 10a–l (General
procedure). Method I. 48% HBF4 (3.5 ml) was added
dropwise to a solution of aminopyridine 8e–l (1.0 mmol) in
a mixture of AcOH (5 ml) and H2O (2.1 ml). The reaction
mixture was stirred for 30 min, then a cooled solution of
NaNO2 (83 mg, 1.2 mmol) in H2O (3 ml) was added
dropwise. The reaction mixture was stirred at 0°С for
45 min, and the precipitated crystals of diazonium
tetrafluoroborate were filtered off. The diazonium salt was
suspended in AcOH (10 ml), and NaN3 (78 mg, 1.2 mmol)
was added in portions at 0–2°С. The reaction mixture was
stirred for additional 30 min and then diluted with H2O.
The oily azidopyridine 9a–l was extracted with m-xylene
(27 ml), and the extract was dried over MgSO4. The drying
agent was filtered off, and the filtrate was heated under
reflux for 6–10 h (TLC control). The solvent was
evaporated under reduced pressure, and β-carboline was
purified by recrystallization from EtOH.
1
1607, 1464, 1269, 1174, 1096, 1035, 834, 548. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 2.61 (3H, s, 2-СН3);
3.85 (3H, s, ОCH3); 6.99–7.01 (2Н, m, Н Ar); 7.06 (1Н, d,
J = 5.1, Н-5); 7.40–7.42 (2Н, m, Н Ar); 8.29 (1Н, d, J = 5.1,
Н-6). 13C NMR spectrum (CDCl3), δ, ppm: 21.2; 55.3;
114.2 (2C); 123.4; 128.0; 130.0 (2C); 132.4; 143.1; 145.3;
152.6; 160.2. Found, %: C 65.04; H 5.07; N 23.35.
C13H12N4O. Calculated, %: C 64.99; H 5.03; N 23.32.
Synthesis of 4-aryl-3-azido-2-methylpyridines 9a,с,d
(General method). A solution of amine 8a,c,d (1.0 mmol)
in MeCN (0.5 ml) was added dropwise to a stirred solution
of NOBF4 (129 mg, 1.1 mmol) in MeCN (2 ml) at –10°С
for 15 min. The reaction mixture was warmed to 0°С and
stirred for 30 min. The mixture was again cooled to –10°С,
and a solution of NaN3 (76 mg, 1.1 mmol) in H2O (1 ml)
Method II. A solution of 4-aryl-3-azidopyridine 9a–d
(1 mmol) in m-xylene (27 ml) was heated under reflux for
10 h. After the completion of the reaction, m-xylene was
evaporated under reduced pressure. The residue was
dissolved in EtOH (2 ml), and 36% HCl (0.2 ml) was
80

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
added. The formed carbolinium hydrochloride was filtered
mp 235–236°С (EtOH). IR spectrum, ν, cm–1: 3157 (NH),
off, dissolved in H2O, and the solution was neutralized with
aqueous ammonia. The formed crystals were filtered off
and recrystallized from MeCN.
3087, 1623, 1561, 1492, 1449, 1348, 1244, 1080, 1006,
1
891, 831, 738. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.83 (3Н, s, СН3); 7.23–7.27 (1Н, m, Н-6); 7.51–
7.55 (1Н, m, Н-7); 7.59–7.61 (1Н, m, Н-8); 7.63–7.66 (2Н,
m, Н Ar); 8.13–8.16 (2Н, m, Н Ar); 8.27 (1Н, d, J = 7.8,
Н-5); 8.59 (1Н, s, Н-4); 11.64 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 20.7; 109.1; 112.1; 119.4;
120.6; 121.4; 121.9; 128.0 (3C); 128.2; 131.4 (2C); 134.1;
139.3; 140.9; 141.7; 143.6. Found, %: C 64.17; H 3.87;
N 8.36. C18H13BrN2. Calculated, %: C 64.11; H 3.89;
N 8.31.
1-Methyl-9H-pyrido[3,4-b]indole (harmane) (10a).
Yield 82 mg (45%, method II), colorless crystals, mp 236–
237°С (МеCN) (mp 233–235°С,11c mp 235–236°С28).
IR spectrum, ν, cm–1: 3131 (NH), 3064, 2971, 2883, 1625,
1
1568, 1504, 1322, 1236, 882, 820, 750. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.74 (3H, s, СН3); 7.21 (1Н,
ddd, J = 7.9, J = 6.9, J = 1.0, Н-6); 7.52 (1H, ddd, J = 8.2,
J = 6.9, J = 1.3, Н-7); 7.58 (1H, dt, J = 8.2, J = 0.9, Н-8);
7.91 (1H, dd, J = 5.4, J = 0.5, Н-4); 8.15–8.18 (2Н, m,
Н-3,5). 13C NMR spectrum (DMSO-d6), δ, ppm: 20.5;
112.1; 112.9; 119.4; 121.2; 121.9; 127.1; 128.1; 134.5;
137.6; 140.4; 142.2. Found, %: C 79.07; H 5.50; N 15.39.
C12H10N2. Calculated, %: C 79.10; H 5.53; N 15.37.
7-Methoxy-3-(4-methoxyphenyl)-1-methyl-9H-pyrido-
[3,4-b]indole (10f). Yield 0.16 g (51%, method I),
colorless crystals, mp 190–191°С (EtOH). IR spectrum,
ν, cm–1: 3363 (NH), 2937, 2838, 1633, 1518, 1469, 1344,
1
1161, 1108, 1031, 920, 817, 610, 557. H NMR spectrum
7-Methoxy-1-methyl-9H-pyrido[3,4-b]indole (harmine)
(10b). Yield 0.11 g (51%, method II), colorless crystals,
mp 253–254°С (MeCN) (mp 262–264°С,29a mp 252°С
(MeOH, CHCl3)29b). IR spectrum, ν, cm–1: 3150 (NH),
2967, 2887, 1627, 1566, 1453, 1327, 1281, 1201, 1164,
1025, 816. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
2.70 (3H, s, СН3); 3.84 (3H, s, ОСН3); 6.83 (1Н, dd,
J = 8.7, J = 2.3, Н-6); 7.02 (1Н, d, J = 2.2, Н-8); 7.78 (1Н,
d, J = 5.3, Н-4); 8.03 (1Н, d, J = 8.8, Н-5); 8.12 (1H, d,
J = 5.3, Н-3); 11.45 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 20.3; 55.5; 94.8; 109.3; 112.2; 114.9;
122.8; 127.5; 134.6; 137.9; 141.4; 142.0; 160.3. Found, %:
C 73.49; H 5.68; N 13.25. C13H12N2O. Calculated, %:
C 73.56; H 5.70; N 13.20.
(DMSO-d6), δ, ppm (J, Hz): 2.76 (3Н, s, СН3); 3.78 (3Н, s,
ОCH3 Ar); 3.85 (3Н, s, ОСН3); 6.83 (1Н, dd, J = 8.6,
J = 2.0, Н-6); 6.99–7.01 (3Н, m, Н-8, Н Ar); 8.05–8.11
(3Н, m, Н-5, Н Ar); 8.30 (1Н, s, Н-4). 13C NMR spectrum
(DMSO-d6), δ, ppm: 20.7; 55.3; 55.5; 94.9; 107.6; 109.2;
114.1 (2C); 115.4; 122.9; 127.5 (2C); 128.9; 133.1; 133.7;
140.7; 142.5; 145.5; 159.0; 160.4. Found, %: C 75.48;
H 5.72; N 8.85. C20H18N2O2. Calculated, %: C 75.45;
H 5.70; N 8.80.
3-(4-Bromophenyl)-1-methyl-7-methoxy-9H-pyrido-
[3,4-b]indole (10g). Yield 0.22 g (60%, method I), colorless
crystals, mp 257–258°С (EtOH). IR spectrum, ν, cm–1:
3220 (NH), 3164, 2836, 1624, 1514, 1464, 1344, 1266,
1
1107, 1007, 882, 827, 785, 733, 627. H NMR spectrum
1,3-Dimethyl-9H-pyrido[3,4-b]indole (3-methylharmane)
(10c). Yield 0.12 g (59%, method II), colorless crystals,
mp 186–187°С (MeCN) (mp 182–184°С,30a mp 179°С
(petroleum ether, CHCl3)30b). IR spectrum, ν, cm–1: 3129
(NH), 3071, 2964, 1626, 1573, 1505, 1454, 1336, 1250,
(DMSO-d6), δ, ppm (J, Hz): 2.80 (3Н, s, СН3); 4.04 (3Н, s,
ОСН3); 6.76 (1Н, d, J = 8.2, Н-6); 7.17 (1Н, d, J = 8.2,
Н-8); 7.44–7.48 (1Н, m, Н-5); 7.62–7.64 (2Н, m, Н Ar);
8.04–8.06 (2Н, m, Н Ar); 8.36 (1Н, s, Н-4). 13C NMR
spectrum (DMSO-d6), δ, ppm: 20.7; 55.7; 100.6; 104.8;
110.7; 110.8; 120.8; 127.5; 128.3 (2C); 129.5; 131.6 (2C);
133.4; 139.5; 141.4; 142.2; 144.1; 156.7. Found, %:
C 62.10; H 4.15; N 7.67. C19H15BrN2O. Calculated, %:
C 62.14; H 4.12; N 7.63.
7-Chloro-1-methyl-3-phenyl-9H-pyrido[3,4-b]indole
(10h). Yield 0.19 g (65%, method I), colorless crystals,
mp 184–185°С (EtOH). IR spectrum, ν, cm–1: 3410 (NH),
3161, 3057, 1625, 1467, 1066, 907, 806, 762, 700.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.83 (3Н,
s, СН3); 7.26 (1Н, dd, J = 8.4, J = 1.8, Н-6); 7.34 (1Н, t,
J = 7.3, Н Ph); 7.47 (2Н, t, J = 7.6, Н Ph); 7.59 (1Н, d,
J = 1.6, Н-8); 8.15–8.17 (2Н, m, Н Ph); 8.29 (1Н, d,
J = 8.4, Н-5); 8.55 (1Н, s, Н-4); 11.70 (1H, br. s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.6; 108.9;
111.5; 119.5; 120.3; 123.3; 126.0 (2C); 127.3; 127.7; 128.4
(2C); 132.2; 134.2; 139.9; 141.3; 141.7; 145.5. Found, %:
C 73.80; H 4.44; N 9.60. C18H13ClN2. Calculated, %:
C 73.85; H 4.48; N 9.57.
1
1150, 1012, 968, 903, 749, 646, 587. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.55 (3H, s, 3-СН3); 2.71 (3H,
s, 1-СН3); 7.17 (1Н, t, J = 6.9, Н-6); 7.46–7.55 (2Н, m,
Н-7,8); 7.72 (1Н, s, Н-4); 8.11 (1Н, d, J = 7.4, Н-5); 11.37
(1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 20.3;
23.8; 110.9; 111.8; 118.9; 121.0; 121.6; 127.6; 128.0;
132.8; 140.7; 140.9; 145.2. Found, %: C 79.52; H 6.18; N
14.25. C13H12N2. Calculated, %: C 79.56; H 6.16; N 14.27.
7-Methoxy-1,3-dimethyl-9H-pyrido[3,4-b]indole
(3-methylharmine) (10d). Yield 95 mg (42%, method II),
colorless crystals, mp 207–208°С (СH3CN). IR spectrum,
ν, cm–1: 3316 (NH), 2957, 2919, 1628, 1572, 1480, 1460,
1377, 1331, 1281, 1165, 1134, 1102, 1026, 949, 872, 823,
1
569. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.51
(3H, s, 3-СН3); 2.65 (3H, s, 1-СН3); 3.83 (3H, s, ОСН3);
6.78 (1Н, dd, J = 8.6, J = 2.2, Н-6); 6.98 (1Н, d, J = 2.2,
Н-8); 7.60 (1Н, s, Н-4); 7.96 (1Н, d, J = 8.6, Н-5); 11.24
(1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
20.1; 23.8; 55.5; 94.7; 108.9; 110.5; 114.8; 122.7; 128.6;
132.9; 140.2; 142.4; 145.6; 160.2. Found, %: C 74.24;
H 6.28; N 12.41. C14H14N2O. Calculated, %: C 74.31;
H 6.24; N 12.38.
1,7-Dimethyl-3-(4-methylphenyl)-9H-pyrido[3,4-b]-
indole (10i). Yield 0.19 g (66%, method I), yellow crystals,
mp 167–168°С (EtOH). IR spectrum, ν, cm–1: 3425 (NH),
3270, 2918, 2856, 1631, 1565, 1508, 1462, 1344, 1154,
1034, 869, 816. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 2.40 (3Н, s, CH3 Ar); 2.53 (3Н, s, 7-СН3); 2.79
3-(4-Bromophenyl)-1-methyl-9H-pyrido[3,4-b]indole
(10е). Yield 0.23 g (68%, method I), colorless crystals,
81

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
(3Н, s, 1-СН3); 7.10 (1Н, d, J = 8.0, Н-6); 7.25–7.28 (3Н,
References
m, Н-8, Н Ar); 7.96–8.00 (3Н, m, Н-5, Н Ar); 8.13 (1Н, s,
Н-4); 8.22 (1H, br. s, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 20.4; 21.2; 22.2; 109.1; 111.6; 120.1; 121.4; 121.8;
126.7 (2C); 129.3 (2C); 129.5; 133.7; 137.2; 138.1; 138.6;
140.9; 141.0; 147.7. Found, %: C 83.84; H 6.32; N 9.76.
C20H18N2. Calculated, %: C 83.88; H 6.34; N 9.78.
1. (а) Nenaah, G. Fitoterapia 2010, 81, 779. (b) Mahmoudian, M.;
Jalilpour, H.; Salehian, P. Iran. J. Pharmacol. Ther. 2002, 1, 1.
2. (a) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem.
2007, 14, 479. (b) Rao, R. N.; Maiti, B.; Chanda, K. ACS
Comb. Sci. 2017, 19, 199. (c) Dai, J.; Dan, W.; Schneider, U.;
Wang, J. Eur. J. Med. Chem. 2018, 157, 622.
3-(4-Methoxyphenyl)-1-methyl-9H-pyrido[3,4-b]indole
(10j). Yield 0.23 g (78%, method I), colorless crystals,
mp 256–257°С (EtOH). IR spectrum, ν, cm–1: 3144 (NH),
2837, 1622, 1605, 1500, 1463, 1344, 1292, 1240, 1173,
1114, 1027, 886, 832, 736. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.82 (3Н, s, СН3); 3.80 (3Н, s, ОCH3);
7.00–7.04 (2Н, m, Н Ar); 7.20–7.24 (1Н, m, Н-6); 7.50–
7.54 (1Н, m, Н-7); 7.57–7.59 (1Н, m, Н-8); 8.09–8.13 (2Н,
m, Н Ar); 8.26 (1Н, d, J = 7.8, Н-5); 8.45 (1Н, s, Н-4);
11.53 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 20.7; 55.1; 108.0; 112.0; 113.9 (2C); 119.1; 121.5;
121.9; 127.3 (2C); 127.8; 128.4; 132.9; 133.6; 140.9;
141.3; 145.0; 158.9. Found, %: C 79.11; H 5.56; N 9.74.
C19H16N2O. Calculated, %: C 79.14; H 5.59; N 9.72.
3. (a) Cao, R.; Peng, W.; Chen, H.; Ma, Y.; Liu, X.; Hou, X.;
Guan, H.; Xu, A. Biochem. Biophys. Res. Commun. 2005,
338, 1557. (b) Bain, J.; Plater, L.; Elliott, M.; Shpiro, N.;
Hastie, C. J.; Mclauchlan, H.; Klevernic, I.; Arthur, J. S. C.;
Alessi, D. R.; Cohen, P. Biochem. J. 2007, 408, 297. (c) Li, S.-P.;
Wang, Y.-W.; Qi, S.-L.; Zhang, Y.-P.; Deng, G.; Ding, W.-Z.;
Ma, C.; Lin, Q.-Y.; Guan, H.-D.; Liu, W.; Cheng, X.-M.;
Wang, C.-H. Front. Pharmacol. 2018, 9, 346. (d) Hara, E. S.;
Ono, M.; Kubota, S.; Sonoyama, W.; Oida, Y.; Hattori, T.;
Nishida, T.; Furumatsu, T.; Ozaki, T.; Takigawa, M.; Kuboki, T.
Biochimie 2013, 95, 374. (e) Pagano, B.; Caterino, M.; Filosa, R.;
Giancola, C. Molecules 2017, 22, 1831.
4. Khan, H.; Patel, S.; Kamal, M. A. Curr. Drug Metab. 2017,
18, 853.
5. (a) Quintana, V. M.; Piccini, L. E.; Zenere, J. D. P.;
Damonte, E. B.; Ponce, M. A.; Castilla, V. Antiviral Res.
2016, 134, 26. (b) Ishida, J.; Wang, H.-K.; Oyama, M.;
Cosentino, M. L.; Hu, C.-Q.; Lee, K.-H. J. Nat. Prod. 2001,
64, 958.
6. Kwon, M. S.; Gierschner, J.; Seo, J.; Park, S. Y. J. Mater.
Chem. 2014, 2, 2552.
7. (a) Paul, B. K.; Guchhait, N. J. Phys. Chem. B 2011, 115,
10322. (b) Paul, B. K.; Guchhait, N. J. Phys. Chem. B 2011,
115, 11938. (c) Guan, H.; Liu, X.; Peng, W.; Cao, R.; Ma, Y.;
Chen, H.; Xu, A. Biochem. Biophys. Res. Commun. 2006, 342,
894. (d) Garcia-Zubiri, I. X.; Burrows, H. D.; de Melo, J. S. S.;
Pina, J.; Monteserin, M.; Tapia, M. J. Photochem. Photobiol.
2007, 83, 1455.
8. (a) Love, B. E. Org. Prep. Proced. Int. 1996, 28, 1.
(b) Galvis, C. E. P.; Kouznetsov, V. V. Synthesis 2017, 4535.
9. (a) Rao, A. V. R.; Chavan, S. P.; Sivadasan, L. Tetrahedron
1986, 42, 5065. (b) Fujita, H.; Nishikawa, R.; Sasamoto, O.;
Kitamura, M.; Kunishima, M. J. Org. Chem. 2019, 84, 8380.
10. Wang, Z.-X.; Xiang, J.-C.; Cheng, Y.; Ma, J.-T.; Wu, Y.-D.;
Wu, A.-X. J. Org. Chem. 2018, 83, 12247.
11. (a) Chalotra, N.; Ahmed, A.; Rizvi, M. A.; Hussain, Z.;
Ahmed, Q. N.; Shah, B. A. J. Org. Chem. 2018, 83, 14443.
(b) Namjoshi, O. A.; Gryboski, A.; Fonseca, G. O.; Linn, M. L. V.;
Wang, Z.-J. Deschamps, J. R.; Cook, J. M. J. Org. Chem. 2011,
76, 4721. (c) Yan, Q.; Gin, E.; Banwell, M. G.; Willis, A. C.;
Carr, P. D. J. Org. Chem. 2017, 82, 4328. (d) Zhang, H.;
Larock, R. C. J. Org. Chem. 2002, 67, 9318.
(e) Dassonneville, B.; Witulski, B.; Detert, H. Eur. J. Org.
Chem. 2011, 2836. (h) Pumphrey, A. L.; Dong, H.; Driver, T. G.
Angew. Chem., Int. Ed. 2012, 51, 5920.
12. Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657.
13. Kaczanowska, K.; Eickhoff, H.; Albert, K.; Wiesmuller, K.-H.;
Schaffner, A.-P. J. Heterocycl. Chem. 2011, 48, 792.
14. (a) Krinochkin, A. P.; Kopchuk, D. S.; Chepchugov, N. V.;
Kim, G. A.; Kovalev, I. S.; Rahman, M.; Zyryanov, G. V.;
Majee, A.; Rusinov, V. L.; Chupakhin, O. N. Chin. Chem.
Lett. 2017, 28, 1099. (b) Weller, D. D.; Luellen, G. R.;
Weller, D. L. J. Org. Chem. 1982, 47, 4803.
7-Methoxy-1-methyl-3-phenyl-9H-pyrido[3,4-b]indole
(10k). Yield 0.16 g (57%, method I), colorless crystals,
mp 242–243°С (EtOH). IR spectrum, ν, cm–1: 3169 (NH),
1
2951, 2836, 1628, 1461, 1161, 820, 741, 702. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.78 (3Н, s, СН3);
3.85 (3Н, s, ОСН3); 6.85 (1Н, dd, J = 8.6, J = 2.2, Н-6);
7.03 (1Н, s, Н-8); 7.32 (1Н, t, J = 7.3, Н Ph); 7.45 (2Н, t,
J = 7.6, Н Ph); 8.11–8.14 (3Н, m, H-5, Н Ph); 8.40 (1Н, s,
Н-4); 11.48 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6)
δ, ppm: 20.7; 55.5; 94.9; 108.6; 109.3; 115.4; 123.0; 126.3
(2C); 127.5; 128.7 (2C); 128.8; 134.0; 140.4; 140.9; 142.5;
145.4; 160.4. Found, %: C 79.12; H 5.57; N 9.74.
C19H16N2O. Calculated, %: C 79.14; H 5.59; N 9.72.
7-Chloro-1-methyl-3-(4-methylphenyl)-9H-pyrido[3,4-b]-
indole (10l). Yield 0.17 g (55%, method I), colorless
crystals, mp 191–192°С (EtOH–MeCN, 1:1). IR spectrum,
ν, cm–1: 3434 (NH), 1626, 1571, 1467, 1311, 1252, 1062,
932, 907, 904, 601. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.33 (3Н, s, CH3 Ar); 2.42 (3Н, s, СН3); 7.18–7.23
(3H, m, H-6, Н Ar); 7.46 (1H, s, H-8); 7.87 (2H, d, J = 8.0,
Н Ar); 7.97 (1H, d, J = 8.4, H-5); 8.05 (1H, s, H-4); 10.23
(1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
19.8; 21.2; 109.8; 111.4; 120.3; 120.3; 122.6; 126.7 (2C);
128.5; 129.4 (2C); 133.5; 133.9; 137.4; 137.5; 141.0;
141.5; 147.5. Found, %: C 74.35; H 4.96; N 9.16.
C19H15ClN2. Calculated, %: C 74.39; H 4.93; N 9.13.
Supplementary information file containing the
description of synthesis and physicochemical characte-
ristics of compounds 2a,b, 4a,b, 5a–e,l, and 6a–l, as well
as absorption and fluorescence spectra of compounds 10а–l
can be accessed at http://link.springer.com/journal/10593.
This work was financially supported by the Russian
Foundation for Basic Research and the Ministry of
Education of the Omsk Region (grant 16-43-550144p_a)
and the Ministry of Education and Science of the Russian
Federation (project 4.1657.2017 / 4.6).
15. Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem.
1999, 64, 6076.
16. Nesnow, S.; Miyazaki, T.; Khwaja, T.; Meyer, R. B.;
Heidelberger, C. J. Med. Chem. 1973, 16, 524.
82

Chemistry of Heterocyclic Compounds 2020, 56(1), 73–83
17. (a) Huang, X.; Keillor, J. W. Tetrahedron Lett. 1997, 38, 313.
J. Med. Chem. 1988, 23, 379. (c) Szmant, H. H.; Basso, A. J.
J. Am. Chem. Soc. 1952, 74, 4397. (d) Bai, X.-G.; Xu, C.-L.;
Zhao, S.-S.; He, H.-W.;Wang, Y.-C.; Wang, J.-X. Molecules
2014, 19, 17256. (e) Yang, J.-X.; Tao, X.-T.; Yuan, C. X.;
Yan, Y. X.; Wang, L.; Liu, Z.; Ren, Y.; Jiang, M. H. J. Am.
Chem. Soc. 2005, 127, 3278. (f) Garg, S.; Raghav, N. RSC
Adv. 2015, 5, 72937.
(b) Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997,
62, 7495.
18. (a) Perez, M. A. M.; Guzman, M. C. C.; Toledo, J. H.;
Almeida, M. B. J. Chem. Soc., Perkin Trans. 2 1986, 1573.
(b) Reyman, D.; Vinas, M. H.; Poyato, J. M. L.; Pardo, A. J.
Phys. Chem. A 1997, 101, 768. (c) Tarzi, O. I.; Erra-Balsells, R. J.
Photochem. Photobiol. B 2006, 82, 79. (d) Pardo, A.;
Reyman, D.; Martin, E.; Poyato, J. M. L.; Camacho, J. J.;
Hidalgo, J.; Sanchez, M. J. Lumin. 1988, 42, 163.
19. Wolfbeis, O. S.; Furlinger, E. Z. Phys. Chem. 1982, 129, 171.
20. Vignoni, M.; Rasse-Suriani, F. A. O.; Butzbach, K.; Erra-
Balsells, R.; Epe, B.; Cabrerizo, F. M. Org. Biomol. Chem.
2013, 11, 5300.
21. Kumar, A.; Singh, S.; Mudahar, G. S.; Thind, K. S. Radiat.
Phys. Chem. 2006, 75, 737.
22. Williams, A. T. R.; Winfield, S. A.; Miller, J. N. Analyst
1983, 108, 1067.
23. Allen, M. W. Measurement of Fluorescence Quantum Yields;
Thermo Fisher Scientific: Madison. Technical note: 52019.
24. Brouwer, A. M. Pure Appl. Chem. 2011, 83, 2213.
25. (a) Demir, A. S.; Sesenoglu, O.; UIku, D.; Arici, C. Helv.
Chim. Acta. 2004, 87, 106. (b) Elias, G.; Rao, M. N. A. Eur.
26. Stecher, E. D.; Ryder, H. F. J. Am. Chem. Soc. 1952, 74, 4392.
27. (a) Hassanien, A. Z. A.; Ghozlan, S. A. S.; Elnagdi, M. H. J.
Heterocycl. Chem. 2003, 40, 225. (b) Shibata, K.; Urano, K.;
Matsui, M. Bull. Chem. Soc. Jpn. 1988, 61, 2199. (c) Sizova, E. E.;
Arshinov, E. E.; Kotsareva, Y. A.; Glizdinskaya, L. V.;
Sagitullina, G. P. Chem. Heterocycl. Compd. 2017, 53, 1026.
[Khim. Geterotsikl. Soedin. 2017, 53, 1026.]
28. Dong, J.; Shi, X.-X.; Yan, J.-J.; Xing, J.; Zhang Q.; Xiao, S.
Eur. J. Org. Chem. 2010, 36, 6987.
29. (a) Huang, Y.-Q.; Song, H.-J.; Liu, Y.-X.; Wang, Q.-M.
Chem.–Eur. J. 2018, 24, 2065. (b) Mukhamedova, S.;
Maekh, C. Kh.; Yunusov, S. Yu. Chem. Nat. Compd. 1983,
19, 376. [Khim. Prirod. Soedin. 1983, 19, 394.]
30. (a) Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 45, 5411.
(b) Dorofeenko, G. N.; Dulenko, L. V. Chem. Heterocycl. Compd.
1969, 5, 313. [Khim. Geterotsikl. Soedin. 1969, 417.]
83