Synthesis of 4-Ethoxycarbonyl(cyano)-β-Carbolines via Thermolysis of 4-Aryl-3(5)-Azidopyridine Derivatives and the Study of their Optical and Hypoglycemic Properties

Article abstract of DOI:10.1007/s10593-021-02892-9

[Figure not available: see fulltext.] 4-Ethoxycarbonyl(cyano)-1,3-dimethyl-β-carbolines were synthesized via thermolysis of 4-aryl-3(5)-azidopyridines and their optical and hypoglycemic properties were studied. For the first time, the accessible Hantzsch nitropyridines were used as the starting materials. Diazotization of 3-aminopyridines having a trimethoxyaryl substituent at the C-4 position of the pyridine ring by intramolecular azo coupling afforded 7,8,9-trimethoxy-2,4-dimethylpyrido[3,4-c]cinnolines. When evaluating the hypoglycemic properties of the four obtained β-carbolines, it was found that ethyl 7-fluoro-1,3-dimethyl-9H-pyrido[3,4-b]indole-4-carboxylate, the structure of which contains the fluorine atom, has the highest glucose-lowering action.

Full text of DOI:10.1007/s10593-021-02892-9

DOI 10.1007/s10593-021-02892-9
Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
Synthesis of 4-ethoxycarbonyl(cyano)-β-carbolines
via thermolysis of 4-aryl-3(5)-azidopyridine derivatives
and the study of their optical and hypoglycemic properties
Viktoriya А. Proshchenkova1, Vladislav Yu. Shuvalov2, Larisa V. Glyzdinskaya1,
Alexander S. Fisyuk2, Sergei A. Chernenko1, Mikhail V. Khvostov3,
Tatyana G. Tolstikova3, Marina А. Vorontsova1, Galina P. Sagitullina1*
1 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; е-mail: v.y.shuvalov@chemomsu.ru
3 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 Akademika Lavrentieva Ave., Novosibirsk 630090, Russia; е-mail: m.khvostov@g.nsu.ru
Submitted August 31, 2020
Accepted September 24, 2020
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(2), 187–198
4-Ethoxycarbonyl(cyano)-1,3-dimethyl-β-carbolines were synthesized via thermolysis of 4-aryl-3(5)-azidopyridines and their optical and
hypoglycemic properties were studied. For the first time, the accessible Hantzsch nitropyridines were used as the starting materials.
Diazotization of 3-aminopyridines having a trimethoxyaryl substituent at the C-4 position of the pyridine ring by intramolecular azo
coupling afforded 7,8,9-trimethoxy-2,4-dimethylpyrido[3,4-c]cinnolines. When evaluating the hypoglycemic properties of the four
obtained β-carbolines, it was found that ethyl 7-fluoro-1,3-dimethyl-9H-pyrido[3,4-b]indole-4-carboxylate, the structure of which
contains the fluorine atom, has the highest glucose-lowering action.
Keywords: azidopyridine, Hantzsch nitropyridines, pyrido[3,4-c]cinnoline, 9H-pyrido[3,4-b]indole, azo coupling, Cadogan reaction,
cyclization.
The alkaloid norharmane, the simplest β-carboline,
exhibits a wide spectrum of biological activity.1 This
makes the norharmane molecule (9H-pyrido[3,4-b]indole)
a pharmacophore. According to P. Gund's definition, a
pharmacophore is ''a set of structural features in a molecule
that is recognized at a receptor site and is responsible for
that molecule's biological activity''.2a The type of biological
activity depends on the presence of various substituents in
the structure of β-carboline. Harmane and harmine differ
from norharmane by the presence of methyl and methoxy
groups in their structure. This implies the possibility of a
directed change of the biological activity of β-carbolines by
introducing various groups into their structures. Biological
activity is exhibited not only by natural β-carbolines, but
also by their synthetic structural analogs (Fig. 1).2
There are three main ways of introducing various groups
into the molecule of an organic compound: selecting the
synthesis route, transformation of functional groups present
in the structure, and the functionalization of the C–H bonds
of aromatic rings. Direct functionalization of the C–H
bonds of β-carboline by electrophilic substitution reactions
is easily accomplished only in the benzene ring, whereas
0009-3122/21/57(2)-0187©2021 Springer Science+Business Media, LLC
187

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
Scheme 1
Figure 1. β-Carbolines norharmane and its derivatives harmane and
harmine.
the electron-deficient pyridine ring is inert with respect to
these reactions. In this regard, methods for the synthesis of
β-carbolines with a given set of substituents in the pyridine
ring are of great importance.
β-Carboline synthesis from tryptophan by the Pictet–
Spengler reaction allows access to 1,2,3,4-tetrahydro-
β-carbolines which are easily oxidized to aromatic
compounds. The presence of a carboxyl group in the
structure of β-carboline at the C-3 position of the pyridine
ring makes it possible to synthesize a number of
compounds by transformation of the carboxyl group.3
β-Carbolines containing substituents at the C-4 position are
synthesized by other methods: 1) by the reaction of indole-
2-carbaldehydes and substituted propargylamines with the
formation of Schiff bases followed by isomerization of the
acetylene group leading to allenes and 6π-azacyclization of
the latter to β-carbolines;4a 2) by palladium-catalyzed
reactions of N-substituted indole-2-carbaldehyde tert-
butylimines with internal alkynes;4b 3) by one-pot Ag(I)-,
Bi(III)-, and Pd(II)-catalyzed (triple-relay catalysis)
cascade of reactions of 5-exo-dig cyclization of 3-[2-(tosyl-
amino)phenyl]hex-5-en-1-yn-3-ol into indoline, nucleophilic
azidation of the double bond of indoline, and thermolysis
of azide to nitrene with cyclization to β-carboline;4c 4) by
the reaction of tryptamine hydrochloride with ethyl
glyoxylate followed by acylation at the nitrogen atom of
tetrahydro-β-carboline, oxidation by DDQ to 4-oxo-
carboline, conversion of the carbonyl group into a methoxy
group by reaction with dimethoxypropane in the presence
of p-TsOH, and aromatization with chloranil (Scheme 1).4d
This work describes a new method for the synthesis of
β-carbolines with the ethoxycarbonyl group and the cyano
group at the C-4 position of the pyridine ring and
investigation of the relationship of the optical and
biological properties of the obtained β-carbolines with their
structure.
The simplicity of the Hantzsch synthesis of nitro-
pyridines was for us an incentive to use them as starting
compounds for the preparation of β-carbolines. The
Cadogan reaction as a one-step method for the synthesis of
β-carbolines appeared to be the most attractive, but did not
meet the expectations. When carrying out the Cadogan
reaction by fusing nitropyridine 1а with DPPE as a
reducing agent without a solvent, the formation of
β-carboline did not occur even in trace amounts.5
β-Carboline was also not found in the reaction mixture of
the catalytic reaction with PPh3 and MoO2Cl2(dmf)2.6 In the
reaction with smaller in volume P(OEt)3, β-carboline 4а is
formed with a low yield (Table 1).
approach of P(OEt)3 to the nitro group shielded by two
substituents (Scheme 2). The low yield of β-carbolines 4a‒c
led us to abandon the Cadogan reaction as a route for the
synthesis of β-carbolines.
Later, we decided upon thermolysis of 5-azidopyridines
3, 7 a‒h in m-xylene as the method for the synthesis
β-carbolines. The starting nitropyridines 1, 5 a‒i were
synthesized by the Hantzsch reaction in two steps
(Supplementary information). The reduction of the nitro
Table 1. Optimization of the reaction conditions for
the Cadogan reaction for compound 1a*
Reducing
agent
(amount)
Tempe-
Solvent rature,
°С
Catalyst,
5 mol %
Time, Yield,
Entry
h
%
DPPE
(1.1 mmol)
1
2
3
4
5
–
150
–
10
0
PPh3
(1.2 mmol)
PhMe
110 MoO2Cl2(dmf)2 24
0
PPh3
(1.2 mmol)
p-Cymene 177 MoO2Cl2(dmf)2 15
0
P(OEt)3
–
–
165
165
–
–
50
72
6**
21**
P(OEt)3***
* The reactions were carried out with 1 mmol of compound 1a under an
N2 atmosphere.
** Yields after isolation by chromatography.
*** Sealed vial.
The inefficiency of the reduction of the nitro group of
pyridines 1а‒с to nitrene and the closure of the pyrrole ring
of β-carboline can be explained by steric obstacles to the
188

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
Scheme 2
in high yields and characterized. Heating compounds 3, 7 а‒h
in m-xylene made it possible to obtain β-carbolines 4, 8 а‒h.
Thermolysis of 5-azidopyridines 3h, 7h with an
asymmetric arrangement of two methoxy groups resulted in
the formation of isomeric β-carbolines 4h, 4h' and 8h, 8h'
in 94 and 92% combined yields, respectively (Scheme 3).
Hantzsch nitropyridines were used as starting materials
for the synthesis of 3-methylharmane 13a and 3-methyl-
harmine 13b (Schemes 4, 5). Hydrolysis of the ester group
of pyridines 1а,b yielded compounds 9а,b, which were
transformed into nitropyridines 10а,b by decarboxylation.
Reduction of the nitro group of pyridines 10а,b yielded
3-aminopyridines 11а,b.
The use of NOBF4 was effective as a diazotizing agent
in the synthesis of diazonium salts from 3-aminopyridines
11а,b. Nucleophilic substitution of the diazo group with
NaN3 gave 3-azidopyridines 12а,b. Thermolysis of 3-azido-
pyridines 12а,b in m-xylene afforded 3-methylharmane
13а and 3-methylharmine 13b.7
R
Method I
Cadogan reaction
P(OEt)3
EtO2C
Me
N
R
165°C, 72 h
O2N
Me
CO2Et
Me
N
H
4a–c
Me
N
1a–c
EtO2C
EtO2C
EtO2C
Me
Me
Me
N
N
N
Me
MeO
N
H
N
H
N
H
Me
Me
Me
4a (21%)
4b (25%)
4c (30%)
group of pyridines was carried out with SnCl2 in EtOH
(Scheme 3).
Diazotization of the amino group of pyridines 2, 6 a‒i
by NaNO2 in AcOH and HBF4 mixture at 0°С gave
pyridines with a diazo group, which were not isolated but
immediately converted into 5-azidopyridines 3, 7 а‒h by
the action of NaN3. 5-Azidopyridines 3, 7 а‒h were isolated
Diazotation of 5-aminopyridines 2i, 6i with NaNO2 at
0°C is followed by an electrophilic substitution reaction
with the formation of pyrido[3,4-c]cinnolines 14a,b
(Scheme 6). The formation of cinnolines 14a,b takes place
as a result of intramolecular azo coupling of the
Scheme 3
R
R
R
X
Me
R
Method II
SnCl2 2H2O
EtOH
1. 48% HBF4, NaNO2
AcOH, H2O, 0°C, 1 h
O2N
Me
X
H2N
Me
X
N3
Me
X
m-Xylene
N
N
6 h
2. NaN3, 30 min
63 90%
, 3 h
60 92%
N
Me
Me
N
Me
N
Me
H
1, 5 a–i
2, 6 a–i
3, 7 a–h
4, 8 a–h
1 3 X = CO2Et, 5 7 X = CN
a R = H, b R = 4-Me, c R = 4-MeO, d R = 4-Ph, e R = 2-MeO, f R = 4-Cl, g R = 4-F, h R = 3,4-(MeO)2, i R = 3,4,5-(MeO)3
MeO
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
Me
Me
Me
Me
Me
N
N
N
N
N
Me
MeO
Ph
N
H
N
H
N
H
N
H
N
H
Me
Me
Me
Me
Me
4a (70%)
4b (88%)
4c (79%)
4d (73%)
4e (60%)
EtO2C
EtO2C
EtO2C
EtO2C
Me
Me
Me
Me
MeO
MeO
+
N
N
N
N
MeO
Cl
F
N
H
N
H
N
N
H
Me
Me
Me
Me
H
MeO
4f (72%)
4g (89%)
4h (63%)
4h' (31%)
NC
NC
NC
NC
MeO
NC
Me
Me
Me
N
Me
N
Me
N
N
N
Me
NC
MeO
Ph
N
N
H
N
N
H
N
H
Me
Me
Me
Me
H
Me
H
8e (60%)
8b (80%)
8c (73%)
8d (86%)
8a (77%)
NC
NC
NC
Me
Me
Me
Me
MeO
MeO
N
N
N
N
+
MeO
Cl
F
N
N
H
N
N
H
Me
Me
Me
Me
H
H
MeO
8h' (71%)
8f (70%)
8g (75%)
8h (21%)
189

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
Scheme 4
Scheme 5
Scheme 6
R
N
R
1. NOBF4
MeCN, –10°C
m-Xylene
H2N
Me
2. NaN3
6 h
N3
Me
Me
N
Me
11a,b
12a,b
Me
N
was found that compound 4g has a statistically significant
glucose-lowering effect, comparable to that of vildagliptin
(Fig. 2).
R
N
Me
H
13a,b
Fluorescence spectroscopy is often used to study the
mechanisms of the biological activity of β-carbolines.10
The electronic spectra of 9H-pyrido[3,4-b]indoles are well
studied.11 However, little is known about the photophysical
properties of substituted derivatives. We recently reported
that in EtOH solution 1,3-dimethyl-9H-pyrido[3,4-b]-
indoles 13а,b exist in two forms, neutral and protonated,
and their fluorescence spectra represent a superposition of
the spectra of these two forms.7 The introduction of an
acceptor group into the pyridine ring leads to a decrease in
its basicity. The signals of the protonated form appear in
the absorption and fluorescence spectra of compounds
4, 8 a‒h' only upon addition of an acid (Fig. 3).
The shape of the peaks in the absorption and
fluorescence spectra does not change significantly. The
introduction of a carbethoxy group (compound 4a) and a
cyano group (compound 8a) at the C-4 position of the
1,3-dimethyl-9H-pyrido[3,4-b]indole predictably leads to
an insignificant increase in the fluorescence quantum yield
Me
Me
N
N
MeO
N
H
N
Me
Me
H
3-Methylharmane
3-Methylharmine
13a (59%)
13b (42%)
pyridyldiazonium salt with the electron-rich trimethoxy-
benzene ring.
As noted earlier, β-carboline derivatives are promising
in the search for new biologically active agents. Thus, it
has been established that compounds of this class can be
effective stimulators of insulin secretion8 which can be
used in the treatment of type 2 diabetes mellitus. Based on
the preliminary computer screening with the PASS
(Prediction of Activity Spectra for Substances)9 program,
we selected compounds 4c,g and 8e,h for hypoglycemic
activity evaluation by the glucose tolerance test in mice. It
Figure 2. Efficacy of β-carbolines 4c,g and 8e,h in the oral glucose tolerance test. The graph shows the effect of compounds 4c,g and
8e,h on a decrease in blood glucose level over time in CD-1 mice.
190

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
EtOH in such a way that the concentration of the resulting
solutions was below 10–5 mol/dm3. The molar extinction
coefficient was determined according to the described
method.12 The quantum yield of the studied compounds
was determined using the comparison method relative to
9,10-diphenylanthracene.13 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. Silica gel (60–120 μm) was used for
column chromatography.
3-Aminocrotononitrile was supplied by Acros Organics
and used without additional purification. The synthesis of
ethyl 3-aminobut-2-enoate,14 nitroenones,15 5-nitropyri-
dines 1а and 5a,16 1-nitropropan-2-one,17 1-(diethoxy-
methyl)-4-methylbenzene,18 N-(4-fluorobenzylidene)butan-
1-amine19 was done according to published methods.
Compounds 11–13 а,b were described by us earlier.7
Synthesis of compounds 2, 6 a‒i (General method). A
mixture of nitropyridine 1a‒i or 5a‒i (2 mmol),
SnCl2·2H2O (2.03 g, 9 mmol), and EtOH (2 ml) was heated
under reflux for 3 h. The reaction mixture was cooled to
room temperature and the solvent was evaporated under
reduced pressure. The residue was cooled, and H2O (52 ml)
was added. The resulting mixture was thoroughly triturated
until a homogeneous suspension formed, then made alkaline
with 10% aqueous NaOH (4.5 ml). Aminopyridine crystals
were filtered off or extracted with EtOAc (3×50 ml). The
organic layer was dried over MgSO4, and the solvent was
evaporated under reduced pressure. The resulting residue
was recrystallized from an appropriate solvent.
Figure 3. Normalized absorption and fluorescence spectra of solu-
tions of compound 4a in EtOH (black line) and EtOH + 2 drops of
HClO4 (red line).
(by 0.13 and 0.12, respectively) and also to the
bathochromic shift in the fluorescence spectra (57–86 nm)
(Table S1, Supplementary information file). The
introduction of substituents into the benzene ring does not
significantly affect the position of the maxima in the
absorption and fluorescence spectra of compounds 4b, 4e‒g,
8h,h' (Table S1, Supplementary information file). For
compounds 8b‒g, the presence of such substituents leads to
a hypsochromic shift of the fluorescence maximum by 27‒
51 nm as compared to 9H-pyrido[3,4-b]indoles 4a and 8a,
with the exception of dimethoxy-substituted 9H-pyrido-
[3,4-b]indoles 4h,h'. For these compounds, a redshift of the
fluorescence maxima by 46–61 nm and a Stokes shift of
113–120 nm are observed. It should be noted that the
introduction of a substituent into the benzene ring, as a
rule, leads to a drop in the quantum yield for all
compounds 4b‒h', 8b‒g,h' except for compound 8h; in
this case, a slight increase in the quantum yield is observed
(Table S1, Supplementary information file).
To conclude, a new series of β-carboline derivatives was
developed and their optical and hypoglycemic properties
were studied. 4-Ethoxycarbonyl- and 4-cyano-β-carbolines
are excellent base compounds for modeling biological
activity by transforming ester and cyano groups into other
groups. It was found that ethyl 7-fluoro-1,3-dimethyl-9H-
pyrido[3,4-b]indole-4-carboxylate with a fluorine atom in
the pyrido[3,4-b]indole ring at a dose of 10 mg/kg has a
statistically significant glucose-lowering effect comparable
to that of vildagliptin.
Ethyl 5-amino-2,6-dimethyl-4-phenylnicotinate (2a).
Yield 0.32 g (60%), colorless crystals, mp 122‒123°С
(n-heptane). IR spectrum, ν, cm–1: 3433, 3319 (NH2), 1722
1
(C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.87
(3H, t, J = 7.0, CH2CH3); 2.48 (3H, s, 6-CH3); 2.49 (3H, s,
2-CH3); 3.56 (1H, br. s, NH2); 3.94 (2H, q, J = 7.0,
CH2CH3); 7.25–7.27 (2H, m, H Ar); 7.36–7.45 (3H, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 13.5; 20.3;
21.2; 61.0; 127.7; 128.5; 128.8 (2С); 129.0 (2С); 132.5;
134.9; 135.9; 142.8; 143.7; 168.1. Found, %: C 71.14;
H 6.75; N 10.41. C16H18N2O2. Calculated, %: C 71.09;
H 6.71; N 10.36.
Ethyl 5-amino-2,6-dimethyl-4-(4-methylphenyl)nico-
tinate (2b). Yield 0.42 g (74%), colorless crystals, mp 105‒
106°С (n-heptane). IR spectrum, ν, cm–1: 3294, 3179
Experimental
1
IR spectra were registered on a Simex FT-801 Fourier
(NH2), 1721 (C=O). H NMR spectrum (CDCl3), δ, ppm
1
transform spectrometer in KBr pellets. H and 13C NMR
(J, Hz): 0.92 (3H, t, J = 7.0, CH2CH3); 2.38 (3H, s, CH3);
2.51 (3H, s, 6-CH3); 2.52 (3H, s, 2-CH3); 3.63 (2H, br. s,
NH2); 3.98 (2H, q, J = 7.0, CH2CH3); 7.14–7.16 (2H, m,
H Ar); 7.24–7.26 (2H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 13.6; 19.8; 20.8; 21.3; 61.1; 128.2; 128.5
(2С); 129.7 (2С); 131.4; 133.2; 136.5; 138.6; 142.3; 143.0;
167.9. Found, %: C 71.87; H 7.13; N 9.81. C17H20N2O2.
Calculated, %: C 71.81; H 7.09; N 9.85.
spectra were acquired on a Bruker DRX-400 spectrometer
(400 and 100 MHz, respectively) in CDCl3 or DMSO-d6
with the residual solvent signals (CDCl3: 7.26 ppm for
1H nuclei and 77.0 ppm for 13C nuclei; DMSO-d6: 2.50 ppm
1
for H nuclei and 39.5 ppm for 13C nuclei) as internal
standard. Elemental analysis was performed on a Carlo
Erba EA 1106 CHN-analyzer. Absorption spectra were
recorded on a PerkinElmer Lambda 750 diode array
spectrophotometer, photoluminescence spectra were
recorded on a Cary Eclipse fluorescence spectrophoto-
meter. In both cases, the test compounds were dissolved in
Ethyl
5-amino-4-(4-methoxyphenyl)-2,6-dimethyl-
nicotinate (2c). Yield 0.54 g (90%), colorless crystals,
mp 65‒66°С (n-heptane). IR spectrum, ν, cm–1: 3299, 3207
1
(NH2), 1702 (C=O). H NMR spectrum (CDCl3), δ, ppm
191

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
(J, Hz): 0.95 (3H, t, J = 7.0, CH2CH3); 2.47 (3H, s, 6-CH3);
Ethyl 5-amino-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-
nicotinate (2h). Yield 0.57 g (87%), colorless crystals,
mp 96‒97°С (n-heptane). IR spectrum, ν, cm–1: 3483, 3392
2.48 (3H, s, 2-CH3); 3.57 (2H, br. s, NH2); 3.82 (3H, s,
OCH3); 3.98 (2H, q, J = 7.0, CH2CH3); 6.94–6.97 (2H, m,
H Ar); 7.17–7.21 (2H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 13.7; 20.2; 21.1; 55.3; 61.0; 114.4 (2С);
126.7; 128.1; 130.0 (2С); 132.3; 136.3; 142.6; 143.4;
159.7; 168.3. Found, %: C 67.91; H 6.67; N 9.31.
C17H20N2O3. Calculated, %: C 67.98; H 6.71; N 9.33.
1
(NH2), 1727 (C=O). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 0.97 (3H, t, J = 7.0, CH2CH3); 2.42 (3H, s, 6-CH3);
2.44 (3H, s, 2-CH3); 3.50 (2H, br. s, NH2); 3.84 (3H, s,
OCH3); 3.89 (3H, s, OCH3); 3.99 (2H, q, J = 7.0, CH2CH3);
6.80–6.84 (2H, m, H Ar); 6.92 (1H, s, H Ar). 13C NMR
spectrum (CDCl3), δ, ppm: 13.8; 20.8; 21.7; 56.0; 56.0;
60.9; 111.7; 112.3; 121.4; 127.5; 127.6; 131.6; 135.7;
143.2; 144.2; 149.1; 149.4; 168.8. Found, %: C 65.48;
H 6.66; N 8.50. C18H22N2O4. Calculated, %: C 65.44;
H 6.71; N 8.48.
Ethyl 5-amino-4-(biphenyl-4-yl)-2,6-dimethylnicoti-
nate (2d). Yield 0.54 g (78%), colorless crystals, mp 132‒
133°С (PhMe). IR spectrum, ν, cm–1: 3488, 3395 (NH2),
1
1724 (C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
0.90 (3H, t, J = 7.0, CH2CH3); 2.50 (3H, s, 6-CH3); 2.52
(3H, s, 2-CH3); 3.65 (2H, br. s, NH2); 3.98 (2H, q, J = 7.0,
CH2CH3); 7.34–7.39 (3H, m, H Ar); 7.44–7.47 (2H, m,
H Ar); 7.59–7.62 (2H, m, H Ar); 7.66–7.70 (2H, m, H Ar).
13C NMR spectrum (CDCl3), δ, ppm: 13.6; 20.3; 21.2;
61.1; 127.0 (2С); 127.6; 127.7 (2С); 128.9 (2С); 129.2
(2С); 132.2; 133.7; 136.0; 140.2 (2C); 141.4; 142.8; 143.7;
168.1. Found, %: C 76.33; H 6.44; N 8.11. C22H22N2O2.
Calculated, %: C 76.28; H 6.40; N 8.09.
Ethyl
5-amino-4-(3,4,5-trimethoxyphenyl)-2,6-di-
methylnicotinate (2i). Yield 0.48 g (67%), colorless
crystals, mp 140‒141°С (n-heptane). IR spectrum, ν, cm–1:
3488, 3392 (NH2), 1711 (C=O). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 0.95 (3H, t, J = 6.8, CH2CH3);
2.50 (6H, s, 2,6-CH3); 3.67 (2H, br. s, NH2); 3.82 (6H, s,
OCH3); 3.86 (3H, s, OCH3); 4.00‒4.04 (2H, m, CH2CH3);
6.50 (2H, s, H Ar). 13C NMR spectrum (CDCl3), δ, ppm:
13.7; 20.2; 21.1; 56.2 (2С); 60.9; 61.1; 105.9 (2С); 127.7;
130.1; 132.5; 136.0; 138.1; 142.7; 143.6; 153.8 (2С);
168.2. Found, %: C 63.38; H 6.73; N 7.75. C19H24N2O5.
Calculated, %: C 63.32; H 6.71; N 7.77.
Ethyl
5-amino-4-(2-methoxyphenyl)-2,6-dimethyl-
nicotinate (2e). Yield 0.37 g (62%), colorless crystals,
mp 119‒120°С (n-heptane). IR spectrum, ν, cm–1: 3317,
3314 (NH2), 1720 (C=O). 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 0.87 (3H, t, J = 7.0, CH2CH3); 2.47 (3H, s, 6-CH3);
2.51 (3H, s, 2-CH3); 3.48 (2H, br. s, NH2); 3.77 (3H, s,
OCH3); 3.93 (2H, q, J =7.0, CH2CH3); 6.97–7.02 (2H, m,
H Ar); 7.08–7.10 (1H, m, H Ar); 7.35–7.39 (1H, m, H Ar).
13C NMR spectrum (CDCl3), δ, ppm: 13.6; 20.4; 21.7;
55.9; 60.7; 111.3; 121.2; 123.9; 127.7; 130.2 (2С); 130.5;
136.5; 143.4; 143.9; 156.7; 168.1. Found, %: C 67.92;
H 6.68; N 9.31. C17H20N2O3. Calculated, %: C 67.98;
H 6.71; N 9.33.
5-Amino-2,6-dimethyl-4-phenylnicotinonitrile (6a).
Yield 0.27 g (60%), colorless crystals, mp 170‒171°С
(n-heptane). IR spectrum, ν, cm–1: 3482, 3384 (NH2), 2228
1
(CN). H NMR spectrum (CDCl3), δ, ppm: 2.48 (3H, s,
6-CH3); 2.67 (3H, s, 2-CH3); 3.63 (2H, br. s, NH2); 7.36–
7.38 (2H, m, H Ar); 7.45–7.56 (3H, m, H Ar). 13C NMR
spectrum (CDCl3), δ, ppm: 21.2; 22.8; 107.2; 117.0; 128.8
(2С); 129.5 (3С); 133.6; 135.9; 136.0; 147.2; 150.2. Found,
%: C 75.34; H 5.85; N 18.79. C14H13N3. Calculated, %:
C 75.31; H 5.87; N 18.82.
Ethyl 5-amino-4-(4-chlorophenyl)-2,6-dimethylnicoti-
nate (2f). Yield 0.50 g (82%), colorless crystals, mp 132‒
133°С (n-heptane). IR spectrum, ν, cm–1: 3311, 3211
5-Amino-2,6-dimethyl-4-(4-methylphenyl)nicotino-
nitrile (6b). Yield 0.30 g (63%), colorless crystals, mp 178‒
179°С (CCl4). IR spectrum, ν, cm–1: 3468, 3374 (NH2),
1
(NH2), 1722 (C=O). H NMR spectrum (CDCl3), δ, ppm
1
(J, Hz): 0.95 (3H, t, J = 7.0, CH2CH3); 2.48 (3H, s, 6-CH3);
2.49 (3H, s, 2-CH3); 3.56 (2H, br. s, NH2); 3.99 (2H, q,
J = 7.0, CH2CH3); 7.21–7.23 (2H, m, H Ar); 7.41–7.43
(2H, m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 13.7;
20.2; 21.2; 61.2; 127.6; 129.3 (2С); 130.3 (2С); 131.2;
133.2; 134.7; 135.9; 142.8; 143.8; 167.8. Found, %: 62.99;
H 5.65; N 9.14. C16H17ClN2O2. Calculated, %: C 63.05;
H 5.62; N 9.19.
2229 (CN). H NMR spectrum (CDCl3), δ, ppm: 2.44 (3H,
s, CH3); 2.49 (3H, s, 6-CH3); 2.68 (3H, s, 2-CH3); 3.65
(2H, br. s, NH2); 7.29–7.35 (4H, m, H Ar). 13C NMR
spectrum (CDCl3), δ, ppm: 21.2; 21.3; 22.8; 107.2; 117.1;
128.6 (2С); 130.2 (2С); 130.6; 135.9; 136.1; 139.4; 147.2;
150.2. Found, %: C 75.86; H 6.35; N 17.69. C15H15N3.
Calculated, %: C 75.92; H 6.37; N 17.71.
5-Amino-4-(4-methoxyphenyl)-2,6-dimethylnicotino-
nitrile (6c). Yield 0.44 g (86%), colorless crystals, mp 170‒
171°С (CH3CN). IR spectrum, ν, cm–1: 3431, 3350 (NH2),
Ethyl 5-amino-4-(4-fluorophenyl)-2,6-dimethylnicoti-
nate (2g). Yield 0.49 g (85%), colorless crystals, mp 150‒
151°С (petroleum ether). IR spectrum, ν, cm–1: 3308, 3212
1
2225 (CN). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
1
(NH2), 1729 (C=O). H NMR spectrum (CDCl3), δ, ppm
2.46 (3H, s, 6-CH3); 2.64 (3H, s, 2-CH3); 3.63 (2H, br. s,
NH2); 3.85 (3H, s, OCH3); 7.04 (2H, d, J = 8.4, H Ar); 7.30
(2H, d, J = 8.4, H Ar). 13C NMR spectrum (CDCl3), δ, ppm:
21.2; 22.8; 55.3; 107.4; 115.0 (2С); 117.2; 125.6; 130.2
(2С); 135.9; 136.1; 147.1; 150.2; 160.4. Found, %:
C 71.20; H 6.01; N 16.52. C15H15N3O. Calculated, %:
C 71.13; H 5.97; N 16.59.
5-Amino-4-(4-biphenyl)-2,6-dimethylnicotinonitrile
(6d). Yield 0.50 g (84%), colorless crystals, mp 230‒231°С
(PhMe). IR spectrum, ν, cm–1: 3471, 3375 (NH2), 2228
(J, Hz): 0.92 (3H, t, J = 7.0, CH2CH3); 2.40 (3H, s, 6-CH3);
2.42 (3H, s, 2-CH3); 3.42 (2H, br. s, NH2); 3.95 (2H, q,
J = 7.0, CH2CH3); 7.07–7.13 (2H, m, H Ar); 7.21–7.26
(2H, m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm
(J, Hz): 13.7; 20.9; 21.8; 60.9; 116.0 (2С, d, J = 21.7);
127.4; 130.7; 130.8 (2С, d, J = 7.8); 131.0 (d, J = 3.5);
135.5; 143.3; 144.3; 162.7 (d, J = 248.0); 168.5. Found, %:
C 66.72; H 5.96; N 9.76. C16H17FN2O2. Calculated, %:
C 66.65; H 5.94; N 9.72.
192

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
1
(CN). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.50
(3H, s, 6-CH3); 2.69 (3H, s, 2-CH3); 3.70 (2H, br. s, NH2);
7.37–7.49 (5H, m, H Ar); 7.64 (2H, d, J = 7.2, H Ar); 7.75
(2H, d, J = 7.8, H Ar). 13C NMR spectrum (CDCl3),
δ, ppm: 21.3; 22.9; 107.0; 117.1; 127.1 (2С); 127.8; 128.1
(2С); 128.9 (2С); 129.3 (2С); 132.4; 135.5; 135.9; 140.1;
142.3; 147.4; 150.3. Found, %: C 80.18; H 5.70; N 14.02.
C20H17N3. Calculated, %: C 80.24; H 5.72; N 14.04.
139.0; 147.3; 150.2; 154.1 (2С). Found, %: C 65.23;
H 6.09; N 13.36. C17H19N3O3. Calculated, %: C 65.16;
H 6.11; N 13.41.
Synthesis of 4-aryl-5-azido-2,6-dimethylpyridines
3, 7 a–h. A solution of the respective aminopyridine 2a–h
or 6a–h (2 mmol) in AcOH (10 ml) and H2O (4 ml) was
cooled to 0°С, and chilled 48% aqueous HBF4 (7 ml) was
added dropwise. The reaction mixture was stirred for 30 min,
then a chilled solution of NaNO2 (2.3 mmol) in H2O (2 ml)
was added dropwise. The reaction mixture was kept at 0°С
for 45 min, then NaN3 (2.3 mmol) was added in portions at
the same temperature. The reaction mixture was stirred for
30 min, diluted with H2O, and neutralized with 10%
aqueous NaOH to pH 7. The precipitated crystals were
filtered off and washed with chilled H2O.
Ethyl 5-azido-2,6-dimethyl-4-phenylnicotinate (3a).
Yield 0.52 g (87%), colorless crystals, mp 53‒54°С
(n-heptane). IR spectrum, ν, cm–1: 2110 (N3), 1722 (C=O).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.89 (3H, t,
J = 7.0, CH2CH3); 2.53 (3H, s, 6-CH3); 2.57 (3H, s,
2-CH3); 3.97 (2H, q, J = 7.0, CH2CH3); 7.30–7.32 (2H, m,
H Ar); 7.41–7.43 (3H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 13.5; 21.2; 22.1; 61.3; 115.0; 128.4 (2C);
129.0 (3C); 130.3; 133.5; 141.3; 150.6; 152.3; 167.2.
Found, %: C 64.88; H 5.46; N 18.95. C16H16N4O2.
Calculated, %: C 64.85; H 5.44; N 18.91.
5-Amino-4-(2-methoxyphenyl)-2,6-dimethylnicotino-
nitrile (6e). Yield 0.47 g (92%), colorless crystals, mp 183‒
184°С (CH3CN). IR spectrum, ν, cm–1: 3437, 3309 (NH2),
1
2227 (CN). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
2.46 (3H, s, 6-CH3); 2.64 (3H, s, 2-CH3); 3.57 (2H, br. s,
NH2); 3.80 (3H, s, OCH3); 7.04–7.10 (2H, m, H Ar); 7.19
(1H, dd, J = 7.2, J = 1.4, H Ar); 7.42–7.46 (1H, m, H Ar).
13C NMR spectrum (CDCl3), δ, ppm: 21.2; 22.8; 55.7;
108.0; 111.9; 117.2; 121.4; 122.1; 130.4; 131.1; 133.4;
136.4; 147.3; 149.8; 156.5. Found, %: C 71.19; H 6.00;
N 16.52. C15H15N3O. Calculated, %: C 71.13; H 5.97;
N 16.59.
5-Amino-4-(4-chlorophenyl)-2,6-dimethylnicotinonitrile
(6f). Yield 0.43 g (83%), colorless crystals, mp 198‒199°С
(CCl4). IR spectrum, ν, cm–1: 3484, 3385 (NH2), 2227
1
(CN). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.47
(3H, s, 6-CH3); 2.65 (3H, s, 2-CH3); 3.59 (2H, br. s, NH2);
7.32 (2H, d, J = 8.2, H Ar); 7.52 (2H, d, J = 8.2, H Ar).
13C NMR spectrum (CDCl3), δ, ppm: 21.2; 22.8; 107.0;
116.8; 129.9 (2С); 130.3 (2С); 132.1; 134.5; 135.7 (2C);
147.6; 150.4. Found, %: C 65.31; H 4.71; N 16.22.
C14H12ClN3. Calculated, %: C 65.25; H 4.69; N 16.30.
5-Amino-4-(4-fluorophenyl)-2,6-dimethylnicotinonitrile
(6g). Yield 0.31 g (65%), colorless crystals, mp 162‒163°С
(CCl4). IR spectrum, ν, cm–1: 3494, 3386 (NH2), 2231
Ethyl 5-azido-2,6-dimethyl-4-(4-methylphenyl)nico-
tinate (3b). Yield 0.51 g (82%), colorless crystals, mp 48‒
49°С (MeOH). IR spectrum, ν, cm–1: 2114 (N3), 1724
1
(C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.94
(3H, t, J = 7.1, CH2CH3); 2.39 (3H, s, CH3); 2.52 (3H, s,
6-CH3); 2.56 (3H, s, 2-CH3); 4.00 (2H, q, J = 7.1,
CH2CH3); 7.19–7.24 (4H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 13.6; 21.2; 21.3; 22.1; 61.3; 128.6; 128.9
(2C); 129.1 (2C); 130.4; 130.5; 139.0; 141.4; 150.5; 152.2;
167.4. Found, %: C 65.72; H 5.87; N 18.11. C17H18N4O2.
Calculated, %: C 65.79; H 5.85; N 18.05.
1
(CN). H NMR spectrum (CDCl3), δ, ppm: 2.58 (6H, s,
2,6-CH3); 4.70 (2H, br. s, NH2); 7.41–7.49 (4H, m, H Ar).
13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 21.1; 21.9;
105.8; 115.9 (2С, d, J = 21.7); 116.7; 130.2 (d, J = 3.5);
131.0 (2С, d, J = 8.7); 132.7; 136.9; 147.0; 147.4; 162.1 (d,
J = 245.4). Found, %: C 69.63; H 4.98; N 17.37.
C14H12FN3. Calculated, %: C 69.70; H 5.01; N 17.42.
5-Amino-4-(3,4-dimethoxyphenyl)-2,6-dimethylnicotino-
nitrile (6h). Yield 0.45 g (79%), colorless crystals, mp 184‒
185°С (CH31CN). IR spectrum, ν, cm–1: 3476, 3382 (NH2),
2225 (CN). H NMR spectrum (CDCl3), δ, ppm: 2.46 (3H,
s, 6-CH3); 2.64 (3H, s, 2-CH3); 3.66 (2H, br. s, NH2); 3.88
(3H, s, OCH3); 3.92 (3H, s, OCH3); 6.87 (1H, s, H Ar);
6.93–7.01 (2H, m, H Ar). 13C NMR spectrum (CDCl3),
δ, ppm: 21.2; 22.8; 56.0; 56.1; 107.3; 112.1 (2С); 117.2;
121.5; 125.9; 135.9; 136.0; 147.2; 149.8; 150.0; 150.2.
Found; %: C 67.88; H 6.09; N 14.77. C16H17N3O2.
Calculated; %: C 67.83; H 6.05; N 14.83.
Ethyl 5-azido-4-(4-methoxyphenyl)-2,6-dimethylnico-
tinate (3c). Yield 0.59 g (90%), colorless crystals, mp 73‒
74°С (n-heptane). IR spectrum, ν, cm–1: 2113 (N3), 1715
1
(C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.99
(3H, t, J = 7.2, CH2CH3); 2.54 (3H, s, 6-CH3); 2.58 (3H, s,
2-CH3); 3.84 (3H, s, OCH3); 4.04 (2H, q, J = 7.2,
CH2CH3); 6.94–6.98 (2H, m, H Ar); 7.23–7.27 (2H, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 13.7; 21.0;
21.9; 55.3; 61.4; 113.9 (2C); 115.9; 125.5; 128.9; 130.3
(2C); 144.7; 150.2; 152.0; 160.3; 167.3. Found, %:
C 62.51; H 5.59; N 17.10. C17H18N4O3. Calculated, %:
C 62.57; H 5.56; N 17.17.
Ethyl 5-azido-4-(biphenyl-4-yl)-2,6-dimethylnicoti-
nate (3d). Yield 0.66 g (88%), colorless crystals, mp 111‒
112°С (MeOH). IR spectrum, ν, cm–1: 2129 (N3), 1736
5-Amino-2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)nico-
tinonitrile (6i). Yield 0.51 g (82%), colorless crystals,
mp 219‒220°С (PhMe). IR spectrum, ν, cm–1: 3439, 3355
1
(C=O). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
0.83 (3H, t, J = 6.9, CH2CH3); 2.49 (3H, s, 6-CH3); 2.56
(3H, s, 2-CH3); 3.99 (2H, q, J = 6.9, CH2CH3); 7.37–7.50
(5H, m, H Ar); 7.72 (2H, d, J = 7.4, H Ar); 7.82 (2H, d,
J = 7.4, H Ar). 13C NMR spectrum (DMSO-d6), δ, ppm:
13.3; 20.0; 20.7; 61.5; 126.6; 126.7 (2C); 128.0 (2C);
128.6; 129.1 (2C); 129.4 (2C); 131.0; 131.8; 139.0; 141.0;
1
(NH2), 2228 (CN). H NMR spectrum (CDCl3), δ, ppm:
2.47 (3H, s, 6-CH3); 2.66 (3H, s, 2-CH3); 3.49 (2H, br. s,
NH2); 3.87 (6H, s, OCH3); 3.91 (3H, s, OCH3); 6.57 (2H, s,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.2; 22.8;
56.4; 60.9; 106.2 (2С); 107.1; 117.1; 128.7; 135.9 (2C);
193

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
142.3; 148.8; 151.4; 165.9. Found, %: C 71.02; H 5.38;
N 15.07. C22H20N4O2. Calculated, %: C 70.95; H 5.41;
N 15.04.
N 28.07. C14H11N5. Calculated, %: C 67.46; H 4.45;
N 28.10.
5-Azido-2,6-dimethyl-4-(4-methylphenyl)nicotinonitrile
Ethyl 5-azido-4-(2-methoxyphenyl)-2,6-dimethylnico-
tinate (3e). Yield 0.59 g (90%), colorless crystals, mp 98‒
99°С (n-heptane). IR spectrum, ν, cm–1: 2114 (N3), 1724
(7b). Yield 0.45 g (85%), colorless crystals, mp 110‒111°С
(n-heptane). IR spectrum, ν, cm–1: 2228 (CN), 2108 (N3).
1H NMR spectrum (CDCl3), δ, ppm: 2.43 (3H, s, CH3);
2.59 (3H, s, 6-CH3); 2.73 (3H, s, 2-CH3); 7.25–7.38 (4H,
m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.4; 21.8;
23.5; 108.4; 115.9; 128.9 (2C); 129.2; 129.7 (2C); 130.9;
140.3; 146.0; 155.7; 157.7. Found, %: C 68.38; H 4.96;
N 26.58. C15H13N5. Calculated, %: C 68.42; H 4.98;
N 26.60.
5-Azido-4-(4-methoxyphenyl)-2,6-dimethylnicotinonit-
rile (7c). Yield 0.48 g (86%), colorless crystals, mp 108‒
109°С (n-heptane). IR spectrum, ν, cm–1: 2224 (CN), 2106
(N3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.58 (3H,
s, 6-CH3); 2.72 (3H, s, 2-CH3); 3.86 (3H, s, OCH3); 7.04
(2H, d, J = 8.4, H Ar); 7.36 (2H, d, J = 8.4, H Ar).
13C NMR spectrum (CDCl3), δ, ppm: 21.9; 23.5; 55.3;
108.4; 114.5 (2C); 116.0; 124.2; 130.5 (2C); 131.0; 145.6;
155.7; 157.7; 160.9. Found, %: C 64.45; H 4.71; N 25.12.
C15H13N5O. Calculated, %: C 64.51; H 4.69; N 25.07.
5-Azido-4-(biphenyl-4-yl)-2,6-dimethylnicotinonitrile
(7d). Yield 0.57 g (88%), colorless crystals, mp 147‒148°С
(n-heptane). IR spectrum, ν, cm–1: 2226 (CN), 2112 (N3).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.62 (3H, s,
6-CH3); 2.76 (3H, s, 2-CH3); 7.36–7.51 (5H, m, H Ar);
7.65 (2H, d, J = 7.4, H Ar); 7.76 (2H, d, J = 8.2, H Ar).
13C NMR spectrum (CDCl3), δ, ppm: 21.9; 23.6; 108.2;
115.9; 127.2 (2C); 127.6 (2C); 128.0; 128.9 (2C); 129.5
(2C); 130.9; 131.0; 140.0; 143.0; 145.6; 155.9; 157.9.
Found, %: C 73.79; H 4.63; N 21.50. C20H15N5. Calculated,
%: C 73.83; H 4.65; N 21.52.
5-Azido-4-(2-methoxyphenyl)-2,6-dimethylnicotino-
nitrile (7e). Yield 0.35 g (63%), colorless crystals, mp 101‒
102°С (n-heptane). IR spectrum, ν, cm–1: 2223 (CN), 2120
(N3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.58 (3H,
s, 6-CH3); 2.73 (3H, s, 2-CH3); 3.84 (3H, s, OCH3); 7.03–
7.11 (2H, m, H Ar); 7.20–7.25 (1H, m, H Ar); 7.50 (1H, t,
J = 7.2, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.8;
23.4; 55.7; 109.3; 111.3; 115.9; 120.9; 121.0; 130.5; 131.3;
132.0; 143.2; 155.4; 157.0; 157.2. Found, %: C 64.45;
H 4.71; N 25.14. C15H13N5O. Calculated, %: C 64.51;
H 4.69; N 25.07.
5-Azido-4-(4-chlorophenyl)-2,6-dimethylnicotinonitrile
(7f). Yield 0.47 g (82%), colorless crystals, mp 144‒145°С
(n-heptane). IR spectrum, ν, cm–1: 2228 (CN), 2113 (N3).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.55 (3H, s,
6-CH3); 2.65 (3H, s, 2-CH3); 7.54‒7.56 (2H, m, H Ar);
7.64‒7.66 (2Н, m, H Ar). 13C NMR spectrum (DMSO-d6),
δ, ppm: 21.5; 23.0; 107.4; 110.3; 115.6; 128.7 (2C); 131.0
(2C); 131.1; 134.8; 144.1; 155.5; 157.0. Found, %:
C 59.21; H 3.56; N 24.61. C14H10ClN5. Calculated, %:
C 59.27; H 3.55; N 24.68.
1
(C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.88
(3H, t, J = 6.9, CH2CH3); 2.52 (3H, s, 6-CH3); 2.53 (3H, s,
2-CH3); 3.78 (3H, s, OCH3); 3.94 (2H, q, J = 6.9,
CH2CH3); 6.92–6.98 (2H, m, H Ar); 7.09 (1H, dd, J = 7.4,
J = 1.8, H Ar); 7.36–7.40 (1H, m, H Ar). 13C NMR
spectrum (CDCl3), δ, ppm: 13.5; 21.2; 22.4; 55.6; 61.0;
110.4; 120.3; 122.6; 128.4; 130.3; 130.6; 130.7; 138.5;
150.9; 152.0; 157.1; 167.2. Found, %: C 62.52; H 5.59;
N 17.12. C17H18N4O3. Calculated, %: C 62.57; H 5.56;
N 17.17.
Ethyl 5-azido-4-(4-chlorophenyl)-2,6-dimethylnicoti-
nate (3f). Yield 0.58 g (88%), colorless crystals, mp 85‒
86°С (MeOH). IR spectrum, ν, cm–1: 2120 (N3), 1722
1
(C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.98
(3H, t, J = 7.1, CH2CH3); 2.56 (3H, s, 6-CH3); 2.61 (3H, s,
2-CH3); 4.03 (2H, q, J = 7.1, CH2CH3); 7.25–7.27 (2H, m,
H Ar); 7.42–7.44 (2H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 13.6; 20.8; 21.7; 61.7; 128.6; 128.8 (2C);
130.3 (2C); 130.7; 131.7; 135.5; 140.7; 150.6; 152.3;
166.7. Found, %: C 58.05; H 4.59; N 16.87. C16H15ClN4O2.
Calculated, %: C 58.10; H 4.57; N 16.94.
Ethyl 5-azido-4-(4-fluorophenyl)-2,6-dimethylnicoti-
nate (3g). Yield 0.43 g (69%), colorless crystals, mp 55‒
56°С (n-heptane). IR spectrum, ν, cm–1: 2111 (N3), 1728
1
(C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.97
(3H, t, J = 7.0, CH2CH3); 2.52 (3H, s, 6-CH3); 2.56 (3H, s,
2-CH3); 4.01 (2H, q, J = 7.0, CH2CH3); 7.11–7.15 (2H, m,
H Ar); 7.29–7.32 (2H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm (J, Hz): 13.7; 21.4; 22.3; 61.4; 115.6 (2C,
d, J = 22.6); 128.4; 129.6 (d, J = 3.5); 130.2; 131.0 (2C, d,
J = 8.7); 140.0; 150.9; 152.6; 163.1 (d, J = 249.7); 167.3.
Found, %: C 61.08; H 4.79; N 17.78. C16H15FN4O2.
Calculated, %: C 61.14; H 4.81; N 17.83.
Ethyl 5-azido-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-
nicotinate (3h). Yield 0.58 g (82%), colorless crystals,
mp 111‒112°С (n-heptane). IR spectrum, ν, cm–1: 2110
1
(N3), 1729 (C=O). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 0.98 (3H, t, J = 7.0, CH2CH3); 2.50 (3H, s, 6-CH3);
2.54 (3H, s, 2-CH3); 3.85 (3H, s, OCH3); 3.90 (3H, s,
OCH3); 4.02 (2H, q, J = 7.0, CH2CH3); 6.83–6.91 (3H, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 13.8; 21.4;
22.2; 55.9; 56.0; 61.3; 110.9; 112.3; 121.8; 125.9; 128.6;
130.4; 140.7; 148.9; 149.7; 150.5; 152.3; 167.6. Found, %:
C 60.70; H 5.70; N 15.79. C18H20N4O4. Calculated, %:
C 60.66; H 5.66; N 15.72.
5-Azido-2,6-dimethyl-4-phenylnicotinonitrile (7a).
Yield 0.44 g (89%), colorless crystals, mp 110‒111°С
(n-heptane). IR spectrum, ν, cm–1: 2222 (CN), 2114 (N3).
1H NMR spectrum (CDCl3), δ, ppm: 2.60 (3H, s, 6-CH3);
2.74 (3H, s, 2-CH3); 7.41–7.43 (2H, m, H Ar); 7.53–7.54
(3H, m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.9;
23.5; 108.3; 115.8; 129.0 (2C); 129.1 (2C); 130.2; 130.7;
132.1; 145.7; 155.8; 157.7. Found, %: C 67.40; H 4.43;
5-Azido-4-(4-fluorophenyl)-2,6-dimethylnicotinonitrile
(7g). Yield 0.40 g (75%), colorless crystals, mp 137‒138°С
(n-heptane). IR spectrum, ν, cm–1: 2226 (CN), 2109 (N3).
13C NMR spectrum (DMSO-d6), δ, ppm: 2.55 (3H, s,
6-CH3); 2.65 (3H, s, 2-CH3); 7.39–7.43 (2H, m, H Ar);
194

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
7.57–7.60 (2H, m, H Ar). 13C NMR spectrum (DMSO-d6),
(79%, method II), colorless crystals, mp 120‒121°С
(PhMe). IR spectrum, ν, cm–1: 3137 (NH), 1719 (C=O).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.47 (3H, t,
J = 7.1, CH2CH3); 2.70 (3H, s, 3-CH3); 2.73 (3H, s,
1-CH3); 3.82 (3H, s, OCH3); 4.59 (2H, q, J = 7.2,
CH2CH3); 7.13–7.17 (1H, m, H-6); 7.22–7.26 (1H, m,
H-8); 7.94‒7.97 (1H, m, H-5); 9.01 (1H, br. s, NH).
13C NMR spectrum (CDCl3), δ, ppm: 14.3; 20.1; 22.6;
55.4; 61.5; 94.2; 109.9; 114.3; 118.1; 124.7; 126.6; 133.0;
141.7; 142.7; 145.1; 160.9; 169.3. Found, %: C 68.49;
H 6.10; N 9.36. C17H18N2O3. Calculated, %: C 68.44;
H 6.08; N 9.39.
Ethyl 1,3-dimethyl-7-phenyl-9H-pyrido[3,4-b]indole-
4-carboxylate (4d). Yield 0.50 g (73%, method II),
colorless crystals, mp 222‒223°С (EtOH). IR spectrum,
ν, cm–1: 3418 (NH), 1722 (C=O). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.41 (3H, t, J = 7.1, CH2CH3);
2.72 (3H, s, 3-CH3); 2.95 (3H, s, 1-CH3); 4.61 (2H, q,
J = 7.0, CH2CH3); 7.44 (1H, t, J = 7.5, H Ar); 7.53 (2H, t,
J = 7.5, H Ar); 7.66 (1H, dd, J = 8.7, J = 1.6, H-6); 7.77–
7.79 (2H, m, H Ar); 7.88 (1H, s, H-8); 8.13 (1H, d, J = 8.7,
H-5); 12.82 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 14.1; 17.0; 18.4; 62.7; 110.2; 117.6; 119.9; 120.9;
124.6; 127.4 (2C); 127.7; 128.5; 129.4 (2C); 133.4; 139.2;
139.7; 140.8; 143.4; 144.2; 165.8. Found, %: C 76.79;
H 5.89; N 8.15. C22H20N2O2. Calculated, %: C 76.72;
H 5.85; N 8.13.
Ethyl 5-methoxy-1,3-dimethyl-9H-pyrido[3,4-b]indole-
4-carboxylate (4e). Yield 0.36 g (60%, method II),
colorless crystals, mp 103‒104°С (PhMe). IR spectrum,
ν, cm–1: 3146 (NH), 1717 (C=O). 1H NMR spectrum
(CDCl3), δ, ppm(J, Hz): 1.41 (3H, t, J = 6.8, CH2CH3);
2.65 (3H, s, 3-CH3); 2.66 (3H, s, 1-CH3); 3.94 (3H, s,
OCH3); 4.48–4.54 (2H, m, CH2CH3); 6.57 (1H, d, J = 7.8,
H-6); 6.97 (1H, d, J = 7.8, H-8); 7.36 (1H, t, J = 7.8, H-7);
9.28 (1H, br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm:
14.2; 19.9; 21.6; 55.5; 61.0; 100.7; 104.2; 110.6; 120.8;
124.0; 129.7; 132.2; 141.0; 142.4; 142.8; 156.5; 170.0.
Found, %: C 68.37; H 6.06; N 9.35. C17H18N2O3.
Calculated, %: C 68.44; H 6.08; N 9.39.
Ethyl 7-chloro-1,3-dimethyl-9H-pyrido[3,4-b]indole-
4-carboxylate (4f). Yield 0.44 g (72%, method II),
colorless crystals, mp 186‒187°С (PhMe). IR spectrum,
ν, cm–1: 3156 (NH), 1724 (C=O). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.48 (3H, t, J = 7.1, CH2CH3);
2.77 (3H, s, 3-CH3); 2.83 (3H, s, 1-CH3); 4.59 (2H, q,
J = 7.2, CH2CH3); 7.15 (1H, dd, J = 8.8, J = 1.4, H-6); 7.46
(1H, s, H-8); 7.99 (1H, d, J = 8.8, H-5); 9.49 (1H, br. s,
NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.2; 19.8;
22.0; 61.8; 111.7; 118.9; 119.0; 121.2; 124.8; 126.3; 133.2;
134.9; 141.8; 142.3; 144.8; 168.5. Found, %: C 63.53;
H 5.00; N 9.23. C16H15ClN2O2. Calculated, %: C 63.48;
H 4.99; N 9.25.
δ, ppm (J, Hz): 21.4; 22.8; 107.5; 115.5; 115.7 (2C, d,
J = 22.5); 128.5 (d, J = 3.5); 130.2; 131.5 (2C, d, J = 8.7);
144.3; 155.3; 156.8; 162.8 (d, J = 248.0). Found, %: C 62.98;
H 3.75; N 26.12. C14H10FN5. Calculated, %: C 62.92; H 3.77;
N 26.20.
5-Azido-4-(3,4-dimethoxyphenyl)-2,6-dimethylnicotino-
nitrile (7h). Yield 0.54 g (87%), colorless crystals, mp 118‒
119°С (n-heptane). IR spectrum, ν, cm–1: 2224 (CN), 2118
(N3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.58 (3H,
s, 6-CH3); 2.73 (3H, s, 2-CH3); 3.90 (3H, s, OCH3); 3.94
(3H, s, OCH3); 6.91 (1H, s, H Ar); 7.00 (2H, d, J = 1.2,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 21.9; 23.5;
56.0; 56.2; 108.4; 111.5; 112.3; 116.0; 122.2; 124.4; 131.0;
145.6; 149.4; 150.7; 155.7; 157.7. Found, %:
C 62.17; H 4.91; N 22.59. C16H15N5O2. Calculated, %:
C 62.13; H 4.89; N 22.64.
Synthesis of β-carbolines 4 and 8 a–h' (General
procedure). Method I. A mixture of nitropyridine 1a–c
(2 mmol) and P(OEt)3 (10 mmol) was heated in a sealed
vial (in a nitrogen atmosphere) at 165°C for 72 h. After the
completion of the reaction, the mixture was evaporated
under reduced pressure. EtOAc was added to the residue,
the crystals were filtered off and purified by
recrystallization from PhMe.
Method II. A solution of 4-aryl-5-azidopyridine 3a–h or
7a–h (2 mmol) in m-xylene (54 ml) was heated under
reflux for 6 h. After the completion of the reaction,
m-xylene was evaporated under reduced pressure. The
resulting residue was purified by column chromatography
(eluent CHCl3–EtOAc–EtOH, 6:3:1) on silica gel.
Ethyl 1,3-dimethyl-9H-pyrido[3,4-b]indole-4-carboxy-
late (4а). Yield 0.11 g (21%, method I), 0.38 g (70%,
method II), colorless crystals, mp 145‒146°С (PhMe).
1
IR spectrum, ν, cm–1: 3136 (NH), 1710 (C=O). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.48 (3H, t, J = 7.1,
CH2CH3); 2.75 (3H, s, 3-CH3); 2.76 (3H, s, 1-CH3); 4.60
(2H, q, J = 7.2, CH2CH3); 7.21 (1H, t, J = 7.2, H-6); 7.43‒
7.50 (2H, m, H-8,7); 8.08 (1H, d, J = 8.0, H-5); 9.03 (1H,
br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.2; 20.1;
22.2; 61.6; 111.6; 119.1; 120.2; 120.5; 123.6; 126.3; 128.7;
132.9; 141.1; 142.4; 144.5; 169.1. Found, %: C 71.67;
H 5.97; N 10.40. C16H16N2O2. Calculated, %: C 71.62;
H 6.01; N 10.44.
Ethyl 1,3,7-trimethyl-9H-pyrido[3,4-b]indole-4-carb-
oxylate (4b). Yield 0.14 g (25%, method I), 0.50 g (88%,
method II), colorless crystals, mp 167‒168°С (petroleum
ether). IR spectrum, ν, cm–1: 3349 (NH), 1729 (C=O).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.47 (3H, t,
J = 7.1, CH2CH3); 2.46 (3H, s, 7-CH3); 2.73 (3H, s,
3-CH3); 2.74 (3H, s, 1-CH3); 4.59 (2H, q, J = 7.2,
CH2CH3); 7.01 (1H, d, J = 8.2, H-6); 7.19 (1H, s, H-8);
7.93 (1H, d, J = 8.2, H-5); 9.18 (1H, br. s, NH). 13C NMR
spectrum (CDCl3), δ, ppm: 14.2; 20.0; 22.1; 22.2; 61.6;
111.5; 118.1; 118.7; 122.0; 123.2; 126.4; 133.0; 139.3; 141.7;
142.1; 144.4; 169.2. Found, %: C 72.39; H 6.47; N 9.94.
C17H18N2O2. Calculated, %: C 72.32; H 6.43; N 9.92.
Ethyl 7-methoxy-1,3-dimethyl-9H-pyrido[3,4-b]indole-
4-carboxylate (4c). Yield 0.18 g (30%, method I), 0.47 g
Ethyl 7-fluoro-1,3-dimethyl-9H-pyrido[3,4-b]indole-
4-carboxylate (4g). Yield 0.51 g (89%, method II),
colorless crystals, mp 146‒147°С (PhMe). IR spectrum,
ν, cm–1: 3145 (NH), 1714 (C=O). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.48 (3H, t, J = 7.1, CH2CH3);
2.71 (3H, s, 3-CH3); 2.73 (3H, s, 1-CH3); 4.59 (2H, q,
195

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
J = 7.2, CH2CH3); 6.93 (1H, td, J = 9.1, J = 2.2, H-6); 7.04
(1H, dd, J = 9.2, J = 2.3, H-8); 8.05 (1H, dd, J = 8.8, J = 5.5,
H-5); 9.01 (1H, br. s, NH). 13C NMR spectrum (CDCl3),
δ, ppm (J, Hz): 14.3; 20.2; 22.6; 61.6; 97.8 (d, J = 26.9);
109.0 (d, J = 24.3); 118.0 (d, J = 144.8); 125.3 (d,
J = 10.4); 126.1; 133.4 (d, J = 1.7); 141.7; 141.8; 142.4;
145.5; 163.4 (d, J = 246.2); 169.1. Found, %: C 67.18;
H 5.31; N 9.73. C16H15FN2O2. Calculated, %: C 67.12;
H 5.28; N 9.78.
Ethyl 6,7-dimethoxy-1,3-dimethyl-9H-pyrido[3,4-b]-
indole-4-carboxylate (4h). Yield 0.41 g (63%, method II),
colorless crystals, mp 128‒129°С (PhMe). IR spectrum,
ν, cm–1: 3158 (NH), 1725 (C=O). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.48 (3H, t, J = 7.1, CH2CH3);
2.71 (3H, s, 3-CH3); 2.73 (3H, s, 1-CH3); 3.89 (3H, s,
7-OCH3); 3.93 (3H, s, 6-OCH3); 4.56 (2H, q, J = 6.9,
CH2CH3); 6.85 (1H, s, H-8); 7.56 (1H, s, H-5); 8.63 (1H,
br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.3; 20.1;
22.7; 56.0; 56.4; 61.4; 94.0; 105.5; 112.8; 117.9; 126.7;
133.0; 136.7; 141.9; 144.9; 145.0; 152.0; 169.3. Found, %:
C 65.91; H 6.16; N 8.50. C18H20N2O4. Calculated, %:
C 65.84; H 6.14; N 8.53.
crystals, mp 263‒264°С (PhMe). IR spectrum, ν, cm–1:
3302 (NH), 2226 (CN). H NMR spectrum (DMSO-d6),
1
δ, ppm (J, Hz): 2.67 (3H, s, 3-CH3); 2.73 (3H, s, 1-CH3);
3.88 (3H, s, OCH3); 6.90 (1H, d, J = 8.4, H-6); 6.99 (1H, s,
H-8); 8.09 (1H, d, J = 8.4, H-5); 11.80 (1H, br. s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.5; 22.3; 55.4;
94.6; 110.5; 112.5; 117.7; 122.1; 122.8; 127.3; 132.1;
143.1; 144.8; 149.9; 161.1. Found, %: C 71.63; H 5.24;
N 16.76. C15H13N3O. Calculated, %: C 71.70; H 5.21;
N 16.72.
1,3-Dimethyl-7-phenyl-9H-pyrido[3,4-b]indole-4-carbo-
nitrile (8d). Yield 0.51 g (86%, method II), colorless
crystals, mp 292‒293°С (PhMe). IR spectrum, ν, cm–1:
1
3281 (NH), 2232 (CN). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.71 (3H, s, 3-CH3); 2.79 (3H, s, 1-CH3);
7.42 (1H, t, J = 7.3, H Ar); 7.52 (2H, t, J = 7.5, H Ar); 7.60
(1H, dd, J = 8.4, J = 1.5, H-6); 7.74–7.78 (3H, m, H Ar,
H-8); 8.31 (1H, d, J = 8.4, H-5); 12.13 (1H, br. s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.8; 22.4; 95.4;
110.1; 117.6; 118.0; 119.6; 121.6; 126.5; 127.2 (2C);
127.8; 129.0 (2C); 132.6; 140.3; 141.5; 141.8; 146.0;
150.1. Found, %: C 80.70; H 5.06; N 14.07. C20H15N3.
Calculated, %: C 80.78; H 5.08; N 14.13.
Ethyl 7,8-dimethoxy-1,3-dimethyl-9H-pyrido[3,4-b]-
indole-4-carboxylate (4h'). Yield 0.20 g (31%, method II),
colorless crystals, mp 174‒175°С (PhMe). IR spectrum,
ν, cm–1: 3144 (NH), 1725 (C=O). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.44 (3H, t, J = 7.1, CH2CH3);
2.70 (3H, s, 3-CH3); 2.74 (3H, s, 1-CH3); 3.94 (3H, s,
8-OCH3); 3.97 (3H, s, 7-OCH3); 4.55 (2H, q, J = 7.2,
CH2CH3); 6.87 (1H, d, J = 9.0, H-6); 7.77 (1H, d, J = 9.0,
H-5); 9.16 (1H, br. s, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 14.2; 20.0; 22.4; 56.5; 60.8; 61.4; 107.0; 116.3;
118.3; 119.3; 126.9; 133.3; 133.4; 136.2; 142.3; 145.0;
151.7; 169.0. Found, %: C 65.90; H 6.16; N 8.50.
C18H20N2O4. Calculated, %: C 65.84; H 6.14; N 8.53.
1,3-Dimethyl-9H-pyrido[3,4-b]indole-4-carbonitrile
(8a). Yield 0.34 g (77%, method II), colorless crystals,
mp 241‒242°С (PhMe). IR spectrum, ν, cm–1: 3285 (NH),
2227 (CN). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
2.68 (3H, s, 3-CH3); 2.75 (3H, s, 1-CH3); 7.28–7.33 (1H,
m, H-7); 7.59–7.62 (2H, m, H-6,8); 8.25 (1H, d, J = 8.0,
H-5); 11.98 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 20.8; 22.4; 95.7; 112.7; 117.7; 118.8; 120.3; 121.3;
126.7; 129.5; 132.1; 141.2; 146.2; 150.2. Found, %:
C 76.05; H 4.97; N 18.91. C14H11N3. Calculated, %:
C 76.00; H 5.01; N 18.99.
5-Methoxy-1,3-dimethyl-9H-pyrido[3,4-b]indole-
4-carbonitrile (8e). Yield 0.30 g (60%, method II),
colorless crystals, mp 275‒276°С (EtOH). IR spectrum,
ν, cm–1: 3282 (NH), 2223 (CN). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.72 (3Н, s, 3-CH3); 2.74 (3H,
s, 1-CH3); 3.94 (3H, s, OCH3); 6.70 (1Н, d, J = 8.0, H-6);
7.13 (1Н, d, J = 8.0, H-8); 7.50 (1Н, t, J = 8.0, H-7); 11.90
(1Н, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
20.6; 23.3; 54.2; 97.4; 100.4; 104.5; 109.2; 118.3; 125.6;
130.7; 131.7; 142.5; 145.1; 151.4; 156.3. Found, %:
C 71.64; H 5.23; N 16.76. C15H13N3O. Calculated, %:
C 71.70; H 5.21; N 16.72.
7-Chloro-1,3-dimethyl-9H-pyrido[3,4-b]indole-4-carbo-
nitrile (8f). Yield 0.36 g (70%, method II), colorless
crystals, mp 268‒269°С (PhMe). IR spectrum, ν, cm–1:
1
3280 (NH), 2225 (CN). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.68 (3H, s, 3-CH3); 2.74 (3H, s, 1-CH3);
7.28 (1H, d, J = 6.5, H-6); 7.56 (1H, s, H-8); 8.14 (1H, d,
J = 7.6, H-5); 12.00 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 20.6; 22.2; 95.3; 111.9; 117.1; 117.4;
120.4; 122.4; 126.0; 132.2; 133.6; 141.4; 146.2; 150.3.
Found, %: C 65.83; H 3.97; N 16.48. C14H10ClN3.
Calculated, %: C 65.76; H 3.94; N 16.43.
1,3,7-Trimethyl-9H-pyrido[3,4-b]indole-4-carbonitrile
(8b). Yield 0.38 g (80%, method II), colorless crystals,
mp 250‒251°С (PhMe). IR spectrum, ν, cm–1: 3298 (NH),
2228 (CN). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
2.49 (3H, s, 7-CH3); 2.66 (3H, s, 3-CH3); 2.73 (3H, s,
1-CH3); 6.90 (1H, d, J = 8.4, H-6); 6.99 (1H, s, H-8); 8.09
(1H, d, J = 8.4, H-5); 11.75 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 20.7; 21.9; 22.3; 95.1;
112.0; 116.5; 117.6; 120.8; 121.8; 126.8; 132.0; 139.4;
141.7; 145.5; 149.8. Found, %: C 76.62; H 5.61; N 17.81.
C15H13N3. Calculated, %: C 76.57; H 5.57; N 17.86.
7-Fluoro-1,3-dimethyl-9H-pyrido[3,4-b]indole-4-carbo-
nitrile (8g). Yield 0.36 g (75%, method II), colorless
crystals, mp 285‒286°С (MeOH). IR spectrum, ν, cm–1:
1
3297 (NH), 2221 (CN). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.72 (3H, s, 3-CH3); 2.77 (3H, s, 1-CH3);
7.08‒7.12 (1H, m, H-6); 7.33 (1Н, s, H-8); 8.32 (1Н, dd,
J = 8.3, J = 5.6, H-5); 11.86 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 20.3; 20.0; 95.1;
98.2 (d, J = 26.0); 108.6 (d, J = 25.1); 115.5; 117.0; 122.7
(d, J = 11.3); 126.4; 132.5; 141.8 (d, J = 13.9); 145.5;
150.2; 162.8 (d, J = 244.5). Found, %: C 70.35; H 4.24;
N 17.51. C14H10FN3. Calculated, %: C 70.28; H 4.21;
N 17.56.
7-Methoxy-1,3-dimethyl-9H-pyrido[3,4-b]indole-4-carbo-
nitrile (8c). Yield 0.37 g (73%, method II), colorless
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Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
6,7-Dimethoxy-1,3-dimethyl-9H-pyrido[3,4-b]indole-
2,6-Dimethyl-3-nitro-4-phenylpyridine (10a). Yield
0.59 g (52%), colorless crystals, mp 40‒41°С (n-heptane).
IR spectrum, ν, cm–1: 1522, 1362 (NO2). 1H NMR
spectrum (CDCl3), δ, ppm: 2.58 (3H, s, 2-CH3); 2.60 (3H,
s, 6-CH3); 7.07 (1Н, s, H-5); 7.32‒7.35 (2Н, m, H Ar); 7.41‒
7.44 (3Н, m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm:
20.6; 24.4; 122.3; 127.5 (2С); 129.0 (2С); 129.5; 134.5;
142.4; 145.1; 149.7; 159.8. Found, %: C 68.47; H 5.33;
N 12.30. C13H12N2O2. Calculated, %: C 68.41; H 5.30;
N 12.27.
4-(4-Methoxyphenyl)-2,6-dimethyl-3-nitropyridine
(10b). Yield 1.04 g (81%), colorless crystals, mp 76‒77°С
(n-heptane). IR spectrum, ν, cm–1: 1527, 1365 (NO2).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.56 (3H, s,
2-CH3); 2.59 (3H, s, 6-CH3); 3.82 (3Н, s, OCH3); 6.94 (2Н,
d, J = 8.0, H Ar); 7.05 (1Н, s, H-5); 7.28 (2Н, d, J = 8.0,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 20.6; 24.4;
55.3; 114.6 (2С); 122.2; 126.6 (2С); 128.9; 142.0; 145.2;
149.6; 159.6; 160.7. Found, %: C 65.13; H 5.50; N 10.88.
C14H14N2O3. Calculated, %: C 65.11; H 5.46; N 10.85.
Synthesis of pyrido[3,4-с]cinnolines 14a,b (General
method). A solution of aminopyridine 2i or 6i (2 mmol) in
AcOH (10 ml) and H2O (4 ml) was cooled to 0°С, and
chilled 48% aqueous HBF4 (7 ml) was added dropwise.
The reaction mixture was stirred for 30 min, then a chilled
solution of NaNO2 (2.3 mmol) in H2O (2 ml) was added
dropwise, and the resulting mixture was stirred for 30 min.
It was diluted with H2O and neutralized with 10% aqueous
NaOH to pH 7. The precipitated crystals were filtered off
and washed with chilled H2O.
4-carbonitrile (8h). Yield 0.12 g (21%, method II),
colorless crystals, mp 275‒276°С (i-PrOH). IR spectrum,
ν, cm–1: 3308 (NH), 2219 (CN). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.68 (3H, s, 3-CH3); 2.72 (3H,
s, 1-CH3); 3.84 (3H, s, 7-OCH3); 3.92 (3H, s, 6-OCH3);
7.03 (1H, s, H-8); 7.64 (1H, s, H-5); 11.53 (1H, br. s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.2; 22.1; 55.6;
55.9; 94.1; 94.7; 102.5; 110.6; 117.6; 126.9; 131.7; 137.1;
144.5; 144.7; 149.4; 152.4. Found, %: C 68.38; H 5.34;
N 14.88. C16H15N3O2. Calculated, %: C 68.31; H 5.37;
N 14.94.
7,8-Dimethoxy-1,3-dimethyl-9H-pyrido[3,4-b]indole-
4-carbonitrile (8h'). Yield 0.40 g (71%, method II),
colorless crystals, mp 230‒231°С (i-PrOH). IR spectrum,
ν, cm–1: 3294 (NH), 2224 (CN). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.70 (3H, s, 3-CH3); 2.81 (3H,
s, 1-CH3); 3.94 (3H, s, 8-OCH3); 3.95 (3H, s, 7-OCH3);
7.15 (1H, d, J = 8.8, H-6); 8.00 (1H, d, J = 8.8, H-5); 11.70
(1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
20.8; 22.2; 56.6; 60.5; 94.9; 108.3; 114.8; 116.7; 117.5;
127.8; 132.7; 133.9; 136.3; 145.6; 150.0; 152.4. Found, %:
C 68.38; H 5.35; N 14.89. C16H15N3O2. Calculated, %:
C 68.31; H 5.37; N 14.94.
Synthesis of 4-aryl-2,6-dimethyl-5-nitronicotinic acids
9a,b (General method). A solution of NaOH (20 mmol) in
H2O (2 ml) was added with stirring to a solution of
pyridine 1а,b (4 mmol) in EtOH (10 ml). The reaction
mixture was heated under reflux for 2 h and cooled. H2O
was added, and the resulting mixture was acidified with
aqueous HCl to pH 3. The formed precipitate was filtered
off and recrystallized from EtOH.
2,6-Dimethyl-5-nitro-4-phenylnicotinic acid (9a).
Yield 0.89 g (82%), colorless crystals, mp 217‒218°С
(EtOH). IR spectrum, ν, cm–1: 1729 (C=O), 1542, 1373
(NO2). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.51 (3H, s,
2-CH3); 2.57 (3H, s, 6-CH3); 7.24‒7.26 (2Н, m, H Ar);
7.45‒7.46 (3Н, m, H Ar). 13C NMR spectrum (DMSO-d6),
δ, ppm: 20.2; 22.6; 127.8 (2С); 128.6 (2С); 129.1; 129.5;
131.9; 139.0; 144.9; 148.7; 155.5; 167.2. Found, %:
C 61.80; H 4.46; N 10.27. C14H12N2O4. Calculated, %:
C 61.76; H 4.44; N 10.29.
4-(4-Methoxyphenyl)-2,6-dimethyl-5-nitronicotinic acid
(9b). Yield 1.04 g (86%), colorless crystals, mp 254‒255°С
(EtOH). IR spectrum, ν, cm–1: 1725 (C=O), 1537, 1365
(NO2). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.49 (3H, s,
2-CH3); 2.55 (3H, s, 6-CH3); 3.78 (3Н, s, OCH3); 7.00‒
7.03 (2Н, m, H Ar); 7.17‒7.20 (2Н, m, H Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.1; 22.6; 55.2;
114.2 (2С); 123.8; 129.3 (2С); 129.5; 138.7; 145.2; 148.5;
155.3; 160.1; 167.4. Found, %: C 59.54; H 4.65; N 9.25.
C15H14N2O5. Calculated, %: C 59.60; H 4.67; N 9.27.
Synthesis of 2,6-dimethyl-3-nitro-4-phenylpyridines
10а,b (General method). 5-Nitronicotinic acid derivative
9а,b (5 mmol) was heated at 260°С until evolution of CO2
bubbles stopped. The mixture was cooled to room
temperature and purified by column chromatography on
silica gel, eluent PhMe. The product was recrystallized
from n-heptane.
Ethyl 7,8,9-trimethoxy-2,4-dimethylpyrido[3,4-с]cin-
noline-1-carboxylate (14a). Yield 0.62 g (84%), light-
yellow crystals, mp 83‒84°С (i-PrOH). IR spectrum, ν, cm–1:
1
1719 (C=O), 1537 (N=N). H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 1.43 (3H, t, J = 7.1, CH2CH3); 2.74 (3H, s,
2-CH3); 3.36 (3H, s, 4-CH3); 4.01 (3H, s, 8-OCH3); 4.11
(3H, s, 9-OCH3); 4.33 (3H, s, 7-OCH3); 4.56 (2H, q, J = 7.1,
CH2CH3); 7.39 (1H, s, Н-10). 13C NMR spectrum (CDCl3),
δ, ppm: 14.1; 21.4; 22.8; 56.2; 61.6; 62.3; 63.7; 98.6;
115.7; 120.2; 122.2; 136.9; 139.3; 144.9; 150.4; 153.3;
157.1; 164.0; 170.2. Found, %: C 61.39; H 5.74; N 11.34.
C19H21N3O5. Calculated, %: C 61.45; H 5.70; N 11.31.
7,8,9-Trimethoxy-2,4-dimethylpyrido[3,4-с]cinnoline-
1-carbonitrile (14b). Yield 0.42 g (64%), light-yellow
crystals, mp 184‒185°С (i-PrOH). IR spectrum, ν, cm–1:
2214 (CN), 1533 (N=N). 1H NMR spectrum (CDCl3),
δ, ppm: 2.99 (3H, s, 2-CH3); 3.36 (3H, s, 4-CH3); 4.12 (3H,
s, 8-OCH3); 4.15 (3H, s, 9-OCH3); 4.33 (3H, s, 7-OCH3);
8.73 (1H, s, Н-10). 13C NMR spectrum (CDCl3), δ, ppm:
22.1; 24.8; 56.8; 61.6; 63.7; 98.1; 98.2; 115.3; 118.8;
124.9; 136.2; 139.3; 145.6; 150.1; 157.8; 163.6; 167.5.
Found, %: C 63.01; H 5.00; N 17.31. C17H16N4O3.
Calculated, %: C 62.95; H 4.97; N 17.27.
Study of hypoglycemic activity of compounds 4c,g
and 8e,h. Compounds 4c,g and 8e,h were administered
orally at a dose of 10 mg/kg to CD-1 mice (5 animals per
group) 30 min before oral glucose loading (2.5 g/kg). The
animals were obtained from the vivarium of the Federal
Research Center, Institute of Cytology and Genetics of the
197

Chemistry of Heterocyclic Compounds 2021, 57(2), 187–198
(c) Dhiman, D.; Mishra, U. K.; Ramasastry, S. S. V. Angew.
Siberian Branch of the Russian Academy of Sciences,
where they were kept under standard vivarium conditions
with free access to water and feed. All research work with
laboratory animals was carried out in accordance with the
generally accepted ethical standards for the treatment of
animals which meet the "European Convention for the
Protection of Vertebrate Animals used for Experimental or
Other Scientific Purposes".20
Blood glucose level was measured at the tail incision
using a OneTouch Select glucometer (LifeScan Inc., USA)
before administration of the test compounds (0 min), as
well as 30, 60, 90, and 120 min after glucose admini-
stration. Vildagliptin, a dipeptidyl peptidase-4 inhibitor,
was used as a positive control. Statistical analysis was
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7. Shuvalov, V. Yu.; Elisheva, V. А.; Belousova, A. S.;
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Supplementary information file containing absorption
and fluorescence spectra of compounds 4, 8 а–h',
physicochemical characteristics of the starting compounds,
as well as the NMR spectra of the synthesized compounds
is available at the journal website at http://link.springer.com/
journal/10593.
The study was carried out with the financial support of
the Russian Foundation for Basic Research within the
framework of scientific project No. 19-33-90229.
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