Annulation of pyrrole ring in 4-acylpyridine-3,5-dicarbonitriles in the presence of ammonia

Article abstract of DOI:10.1007/s10593-019-02434-4

[Figure not available: see fulltext.] 4-Acyl-2-amino-6-chloropyridine-3,5-dicarbonitriles underwent heterocyclization in the presence of ammonia in aqueous dioxane medium, involving the ortho-ketonitrile fragment while preserving the halogen atom. The pyr

Full text of DOI:10.1007/s10593-019-02434-4

DOI 10.1007/s10593-019-02434-4
Chemistry of Heterocyclic Compounds 2019, 55(2), 167–171
Annulation of pyrrole ring in
4-acylpyridine-3,5-dicarbonitriles
in the presence of ammonia
Arthur A. Grigor'ev1*, Yakov S. Kayukov1, Anastasiya L. Nikiforova1,
Sergey V. Karpov1, Ekaterina S. Shchegravina2,
Olga V. Kayukova3, Victor A. Tafeenko4
1 Chuvash State University named after I. N. Ulianov,
15 Moskovskiy Ave., Cheboksary 428015, Russia; e-mail: grigorev.arth@gmail.com
2 N. I. Lobachevsky State University of Nizhny Novgorod,
23 Gagarina Ave., Nizhny Novgorod 603950, Russia; e-mail: sc-katarina@yandex.ru
3 Chuvash State Agricultural Academy,
29 Karla Marksa St., Cheboksary 428003, Russia; e-mail: olgakajukova@mail.ru
4 M. V. Lomonosov Moscow State University,
1-3 Leninskie Gory, Moscow 119991, Russia; e-mail: tafeenko-victor@yandex.ru
Submitted November 12, 2018
Accepted February 2, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(2), 167–171
4-Acyl-2-amino-6-chloropyridine-3,5-dicarbonitriles underwent heterocyclization in the presence of ammonia in aqueous dioxane
medium, involving the ortho-ketonitrile fragment while preserving the halogen atom. The pyrrole ring annulation process proceeded
regioselectively with the formation of a single positional isomer.
Keywords: pyridine-3,5-dicarbonitriles, heteroannulation, rearrangement, regioselectivity.
Pyridine-3,5-dicarbonitrile derivatives are of interest to
researchers due to the practically useful properties
discovered for some of these compounds.1 The most
valuable results have been achieved in developing selective
agonists and antagonists of human adenosine receptors for
the prevention and treatment of cardiovascular diseases.2
The effectiveness of the obtained derivatives has been
characterized by using mathematical methods such as
QSAR, as well as experimental data.3 Besides biologically
active pyridine-3,5-dicarbonitriles, also hybrid fluorescent
compounds have been described in which the pyridine ring
acts as acceptor of electron density.4 Due to the simple one-
pot synthetic procedures and dense functionalization,
pyridine-3,5-dicarbonitriles have been recognized as
valuable precursors for fused heterocyclic compounds.5
We have previously reported methods for the synthesis
of pyridine-3,5-dicarbonitriles 1 (X = Cl, Br, SEt, Sn-Pr,
Sn-Bu, Scheme 1) that contain an ortho-ketonitrile moiety.6
The currently widely used multicomponent syntheses
starting from malononitrile7 and cyanothioacetamide8 do
not provide access to such pyridines, therefore 2-acyl-
1,1,3,3-tetracyanopropenides (ATCN) were selected as the
starting materials. Halogenated derivatives 1 were obtained by
using anhydrous gaseous HCl (X = Cl) or HBr (X = Br),6a
while alkylsulfanyl-substituted pyridines (X = SEt, Sn-Pr,
Sn-Bu) were obtained in reactions of ATCN– with aliphatic
thiols in DMSO medium in the presence of NaH.6b
The introduction of ortho-ketonitrile moiety into pyridine-
3,5-dicarbonitriles increases the synthetic potential of these
building blocks due to the possibility of including the [с]
bond in heteroannulation reactions. The addition of a water
molecule to pyridine-3,5-dicarbonitrile 1 was used as an
example to demonstrate that the cyclization process
proceeded regioselectively with the formation of one of the
possible positional isomers 2 (Scheme 1).9
In order to study the heterocyclization process in more
detail, as well as for the purpose of developing a selective
procedure for the synthesis of pyrrolo[3,4-c]pyridine
0009-3122/19/55(2)-0167©2019 Springer Science+Business Media, LLC
167

Chemistry of Heterocyclic Compounds 2019, 55(2), 167–171
Scheme 1
R
R
R
O
R
O
C
HN
X
OH
CN
NH
HO
NC
HX
+ H2O
O
NC
X
CN
O
NC
CN
X = Cl, Br, SEt,
Sn-Pr, Sn-Bu
CN CN
N
2'
NH2
N
1
NH2
X
N
NH2
ATCN–
2
R = Ph, 4-MeC6H4, 4-MeOC6H4, t-Bu, 1-Naphthyl
Not observed
systems, we are currently studying the reactions of pyridine-
3,5-dicarbonitriles 1 with various types of nucleophilic
reagents. In this work, we present the results obtained by
using ammonia as the nucleophilic species attacking
pyridine-3,5-dicarbonitriles 1 that contain a chlorine atom
at position 2.
The molecules of the studied pyridine-3,5-dicarbo-
nitriles 1a–h contain several electron-withdrawing groups
that facilitate nucleophilic aromatic substitution of halogen
atom. Similar processes have been described in sufficient
detail for structurally related compounds.10 Therefore, we
proposed that the initial stage of the reaction must be
accompanied by the formation of diamine 3. However, the
analysis of reaction mixtures and the isolated products
showed that the reaction followed an alternative route
involving ortho-ketonitrile moiety, while the halogen atom
remained intact. The reaction products were 1,4-diamino-
1-aryl(alkyl)-6-chloro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-с]-
pyridine-7-carbonitriles 4a–h (Scheme 2).
Figure 1. The molecular structure of compound 4f with atoms
represented by thermal vibration ellipsoids of 50% probability.
The structures of compounds 4a–h were characterized
using IR spectroscopy, 1Н and 13С NMR spectrometry, and
mass spectrometry. According to the spectral data, the
transformation of pyridine-3,5-dicarbonitriles 1a–h into
products 4a–h proceeded regioselectively, with the
formation of a single positional isomer, the structure of
which was determined by X-ray structural analysis in the
case of compound 4f (Fig. 1).
The proposed mechanism for the transformation of
pyridine-3,5-dicarbonitriles 1a–h into compounds 4a–h
includes nucleophilic addition of ammonia molecule at the
carbonyl group of pyridine-3,5-dicarbonitrile 1a–h, with
the formation of aminal А. The intramolecular
heterocyclization of closely positioned hydroxy and cyano
groups in aminal А leads to the furo[3,4-с]pyridine
derivative В. The molecule of the latter contains an
iminolactone moiety that undergoes rearrangement under
the reaction conditions (through intermediate structures С,
D, E) into lactam 4 (Scheme 3).
Scheme 2
NH2
NH
R
NC
Cl
O
36–68%
R
O
N
4a–h
NH2
aq NH3
NC
Cl
CN
1,4-dioxane
, 6–10 min
R
O
N
NH2
1a–h
NC
CN
a R = Ph, b R = 4-BrC6H4, c R = 4-MeC6H4,
d R = 4-MeOC6H4, e R = 4-ClC6H4,
f R =2-thienyl, g R = t-Bu, h R = 4-O2NC6H4,
H2N
N
3
NH2
The attempts to perform targeted synthesis of diamine 3
did not give the expected result, which apparently could be
explained by the insufficient nucleophilicity of ammonia in
halogen substitution reaction when compounds 1 were
used. Variation of reaction conditions did not provide a
solution to this problem, resulting in the formation of
intractable mixtures that could not be separated into
individual compounds.
In the case of compounds 4c,d the substitution of
chlorine atom with amino group becomes possible.
However, as it was observed, this transformation was
accompanied by the substitution of aminal amino group
with a hydroxy group, with the formation of hydroxylactam
ring in compounds 5a,b (Scheme 4). The formation of
intermediate products F and G was proposed by us on the
Scheme 3
168

Chemistry of Heterocyclic Compounds 2019, 55(2), 167–171
Scheme 4
R
R
R
R
N
NH
NH
NH
H2N
NC
H2N
NC
HO
NC
H2O
NH3
NC
O
O
O
O
69–72%
– NH4Cl
– NH3
H2N
N
NH2
Cl
N
NH2
H2N
N
NH2
H2N
N
NH2
5a (72%)
b (69%)
F
G
4c R = 4-MeC6H4
d R = 4-MeOC6H4
basis of NMR spectra of the reaction mixture.
Unfortunately, we were not able to isolate these inter-
mediates as individual compounds.
condenser (control by TLC method), followed by cooling
and evaporation at reduced pressure. The dry residue was
purified by crystallization from MeCN.
All of the synthesized pyrrolo[3,4-с]pyridine derivatives
4a–h and 5a,b had similar structures with poor solubility in
many organic solvents (EtOAc, i-PrOH, MeCN, EtOH),
therefore the formation of product mixtures created serious
problems with their separation and purification. In order to
avoid such problems, we performed TLC control of the
reaction progress (eluent EtOAc–CH2Cl2, 1:1) at each step,
and the products were isolated after complete conversion of
the starting substrate.
Thus, we have shown that the cyclization of 4-acyl-
2-amino-6-chloropyridine-3,5-dicarbonitriles in the presence
of ammonia involved the ortho-ketonitrile moiety while the
halogen atom was preserved. The cyclization reaction
proceeded regioselectively with the formation of one
positional isomer, the structure of which was determined
by X-ray structural analysis. The substitution of halogen
atom with amino group was possible after conversion of
the carbonyl group. The results obtained at this stage of our
study will be used for developing a selective method for the
synthesis of pyrrolo[3,4-с]pyridine systems bearing many
functional groups.
1,4-Diamino-6-chloro-3-oxo-1-phenyl-2,3-dihydro-1H-
pyrrolo[3,4-c]pyridine-7-carbonitrile (4a). Yield 186 mg
(62%), white crystals, mp 256–257°С (decomp.). IR spect-
rum, ν, cm–1: 3396, 3145 (NH2), 2225 (C≡N), 1689 (C=O).
1H NMR spectrum, δ, ppm: 3.10 (2H, s, NН2); 7.32–7.47
(4H, m, 3H Ar, NH2); 7.53–7.57 (2H, m, H Ar); 8.47 (1H,
br. s, NH2); 9.11 (1H, s, NH). 13C NMR spectrum, δ, ppm:
76.0; 90.3; 107.1; 113.6; 126.5; 128.3; 128.4; 138.8;
154.0; 156.2; 166.0; 166.4. Mass spectrum, m/z (Irel, %):
301 [М(37Сl)]+ (3), 299 [М(35Сl)]+ (9), 285
[М(37Сl)–NH2]+ (4), 283 [М(35Сl)–NH2]+ (13), 256
[М(37Сl)–CONH]+ (3), 254 [М(35Сl)–CONH]+ (8), 247
[М–Cl–NH3]+ (15), 224 [М(37Сl)–Ar]+ (29), 222
[М(35Сl)–Ar]+ (82), 207 [М(37Сl)–Ar–NH3]+ (3), 205
[М(35Сl)–Ar–NH3]+ (9), 116 (13), 104 (44), 90 (59), 77
(100). Found, %: C 56.09; H 3.35; N 23.23. C14H10ClN5O2.
Calculated, %: C 56.10; H 3.36; N 23.37.
1,4-Diamino-1-(4-bromophenyl)-6-chloro-3-oxo-2,3-di-
hydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(4b).
Yield 201 mg (53%), white crystals, mp 252–254°С
(decomp.). IR spectrum, ν, cm–1: 3390, 3148 (NH2), 2220
(C≡N), 1688 (C=O). 1H NMR spectrum, δ, ppm: 3.14 (2H,
s, NН2); 7.42 (1H, br. s, NH2); 7.48–7.52 (2H, m, H Ar);
7.55–7.60 (2H, m, H Ar); 8.49 (1H, br. s, NH2); 9.13 (1H,
s, NH). 13C NMR spectrum, δ, ppm: 75.6; 90.2; 107.1;
113.6; 121.8; 129.0; 131.2; 138.3; 154.6; 156.2; 165.4;
166.4. Mass spectrum, m/z (Irel, %): 377 [М]+ (2), 361
[М–NH2]+ (5), 224 [М(37Сl)–Ar]+ (18), 222 [М(35Сl)–Ar]+
(35), 207 [М(37Сl)–Ar–NH3]+ (12), 205 [М(35Сl)–Ar–NH3]+
(17), 90 (35), 71 (67), 57 (100). Found, %: C 44.32;
H 2.39; N 18.46. С14H9BrClN5O. Calculated, %: C 44.41;
H 2.40; N 18.50.
Experimental
IR spectra were recorded on an FSM-1202 FT-IR
spectrometer for samples prepared as thin films
(suspension in Nujol). 1Н and 13С NMR spectra were
acquired on an Agilent DDR2 400 spectrometer (400 and
101 MHz, respectively) in DMSO-d6, using residual
solvent signals as internal standard (2.50 ppm for 1Н nuclei
and 39.5 ppm for 13С nuclei). Mass spectra were recorded
on a Finnigan МАТ INCOS-50 instrument (EI ionization,
70 eV). Elemental analysis was performed on
a
PerkinElmer 2400 CHN-analyzer. Melting points were
determined on an OptiMelt MPA100 apparatus. The reaction
progress and purity of the synthesized compounds were
determined by TLC method on Sorbfil PTSKh-AF-A-UF
plates (eluent EtOAc–CH2Cl2, 1:1), visualization under UV
light (254/365 nm), in iodine vapor, or by thermal
decomposition.
The starting pyridine-3,5-dicarbonitriles 1a–h were
obtained according to a published procedure from the respec-
tive potassium 2-acyl-1,1,3,3-tetracyanopropenides.6a,9b
Synthesis of 1,4-diamino-6-chloro-3-oxo-2,3-dihydro-
1Н-pyrrolo[3,4-с]pyridine-7-carbonitriles 4a–h (General
method). Aqueous 25% ammonia solution (3 ml) was added
to a solution of pyridine-3,5-dicarbonitrile 1a–h (1 mmol)
in 1,4-dioxane (5 ml). The obtained solution was stirred
and refluxed for 6–10 min in a flask equipped with a reflux
1,4-Diamino-6-chloro-3-oxo-1-(p-tolyl)-2,3-dihydro-1H-
pyrrolo[3,4-c]pyridine-7-carbonitrile (4с). Yield 176 mg
(56%), white crystals, mp 253–254°С (decomp.). IR spect-
rum, ν, cm–1: 3379, 3148 (NH2), 2225 (C≡N), 1692 (C=O).
1H NMR spectrum, δ, ppm: 2.29 (3Н, s, СН3); 3.05 (2H, s,
NН2); 7.15–7.19 (2H, m, H Ar); 7.39 (1H, br. s, NH2); 7.41–
7.45 (2H, m, H Ar); 8.45 (1H, br. s, NH2); 9.07 (1H, s, NH).
13C NMR spectrum, δ, ppm: 25.5; 75.9; 90.3; 107.0; 113.7;
126.9; 128.8; 135.8; 137.7; 154.5; 156.2; 166.2; 166.4. Mass
spectrum, m/z (Irel, %): 315 [М(37Сl)]+ (9), 313 [М(35Сl)]+
(22), 299 [М(37Сl)–NH2]+ (11), 297 [М(35Сl)–NH2]+ (29),
261 [М–Cl–NH3]+ (15), 224 [М(37Сl)–Ar]+ (33), 222
[М(35Сl)–Ar]+ (100), 207 [М(37Сl)–Ar–NH3]+ (14), 205
[М(35Сl)–Ar–NH3]+ (32), 118 (40), 91 (67). Found, %:
C 57.26; H 3.88; N 22.26. C15H12ClN5O. Calculated, %:
C 57.42; H 3.86; N 22.32.
169

Chemistry of Heterocyclic Compounds 2019, 55(2), 167–171
1,4-Diamino-6-chloro-1-(4-methoxyphenyl)-3-oxo-
1,4-Diamino-6-chloro-1-(4-nitrophenyl)-3-oxo-2,3-di-
hydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4h).
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4d).
Yield 218 mg (66%), white crystals, mp 210–212°С
(decomp.). IR spectrum, ν, cm–1: 3385, 3157 (NH2), 2223
(C≡N), 1681 (C=O). 1H NMR spectrum, δ, ppm: 3.04 (2H,
s, NН2); 3.75 (3H, s, OCH3); 7.39 (1H, br. s, NH2); 7.44–
7.50 (2H, m, H Ar); 7.89–7.94 (2H, m, H Ar); 8.44 (1H,
br. s, NH2); 9.05 (1H, s, NH). 13C NMR spectrum, δ, ppm:
55.2; 75.8; 90.3; 106.9; 113.6; 113.7; 127.9; 130.7; 154.5;
156.2; 159.3; 166.3; 166.4. Mass spectrum, m/z (Irel, %): 331
[М(37Cl)]+ (1), 329 [М(35Cl)]+ (6), 314 [М(37Cl)–NH2]+ (7),
312 [М(35Cl)–NH2]+ (12), 224 [М(37Cl)–Ar]+ (6), 222
[М(35Cl)–Ar]+ (18), 207 [М(37Cl)–Ar–NH3]+ (10), 205
[М(35Cl)–Ar–NH3]+ (17), 153 (11), 151 (23), 90 (100).
Found, %: C 54.49; H 3.69; N 21.18. C15H12ClN5O2.
Calculated, %: C 54.64; H 3.67; N 21.24.
Yield 234 mg (68%), white crystals, mp 239–240°С
(decomp.). IR spectrum, ν, cm–1: 3377, 3153 (NH2), 2228
(C≡N), 1691 (C=O). 1H NMR spectrum, δ, ppm: 3.30 (2H,
s, NН2); 7.48 (1H, br. s, NH2); 7.81–7.85 (2H, m, H Ar);
8.21–8.26 (2H, m, H Ar); 8.54 (1H, br. s, NH2); 9.24 (1H,
s, NH). 13C NMR spectrum, δ, ppm: 75.6; 90.2; 107.3;
113.5; 123.4; 128.4; 146.1; 147.5; 154.7; 156.3; 164.8;
166.5. Mass spectrum, m/z (Irel, %): 346 [М(37Cl)]+ (2), 344
[М(35Cl)]+ (6), 329 [М(37Cl)–NH2]+ (15), 327 [М(35Cl)–NH2]+
(25), 301 (3), 299 (8); 224 [М(37Cl)–Ar]+ (26), 222
[М(35Cl)–Ar]+ (67), 207 [М(37Cl)–Ar–NH3]+ (12), 205
[М(35Cl)–Ar–NH3]+ (23), 153 (23), 151 (74), 90 (100).
Found, %: C 48.77; H 2.62; N 24.21. C14H9ClN6O3.
Calculated, %: C 48.78; H 2.63; N 24.38.
1,4-Diamino-6-chloro-1-(4-chlorophenyl)-3-oxo-2,3-di-
Synthesis of 4,6-diamino-1-aryl-1-hydroxy-3-oxo-
2,3-dihydro-1Н-pyrrolo[3,4-с]pyridine-7-carbonitriles
5a,b (General method). Aqueous 25% ammonia solution
(2 ml) was added to a solution of pyrrolo[3,4-с]pyridine
4c,d (0.5 mmol) in 1,4-dioxane (2 ml). The obtained
solution was stirred and refluxed for 2–3 days (control by
TLC), after which the reaction mixture was cooled and
evaporated at reduced pressure. The dry residue was
purified by crystallization from MeCN.
4,6-Diamino-1-hydroxy-3-oxo-1-(p-tolyl)-2,3-dihydro-
1Н-pyrrolo[3,4-с]pyridine-7-carbonitrile (5a). Yield
106 mg (72%), white crystals, mp 269–270°С (decomp.).
IR spectrum, ν, cm–1: 3349, 3177 (NH2, NH, OH), 2210
(C≡N), 1692 (C=O). 1H NMR spectrum, δ, ppm: 2.29 (3Н,
s, СН3); 6.67 (1H, br. s, NH2); 6.86 (2H, s, NН2); 7.03 (1H,
br. s, NH2); 7.13–7.17 (2H, m, H Ar); 7.30–7.34 (3H, m,
H Ar, ОН); 8.72 (1H, s, NH). 13C NMR spectrum, δ, ppm:
72.4; 86.5; 98.0; 115.3; 126.0; 128.5; 136.7; 137.3; 156.7;
162.9; 165.3; 168.1. Mass spectrum, m/z (Irel, %): 295 [М]+
(45), 278 [М–ОH]+ (25), 277 [М–Н2О]+ (26), 204 [М–Ar]+
(33); 186 [М–Ar–Н2О]+ (41), 160 (30), 132 (56); 119
[ArСО]+ (83); 91 [Ar]+ (100). Found, %: C 61.02; H 4.45;
N 23.92. C15H13N5O2. Calculated, %: C 61.01; H 4.44;
N 23.72.
hydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(4e).
Yield 197 mg (59%), white crystals, mp 287–288°С
(decomp.). IR spectrum, ν, cm–1: 3398, 3153 (NH2), 2226
(C≡N), 1681 (C=O). 1H NMR spectrum, δ, ppm: 3.15 (2H,
s, NН2); 7.40–7.46 (3H, m, 2H Ar, NH2); 7.55–7.59 (2H,
m, H Ar); 8.49 (1H, br. s, NH2); 9.13 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 75.6; 90.2; 107.1; 113.6; 128.3; 128.7;
133.2; 137.9; 154.7; 156.3; 165.5; 166.4. Mass spectrum,
m/z (Irel, %): 333 [М]+ (9), 316 [М–NH2]+ (16), 281 (24),
224 [М(37Cl)–Ar]+ (29), 222 [М(35Cl)–Ar]+ (100), 207
[М(37Cl)–Ar–NH3]+ (13), 205 [М(35Cl)–Ar–NH3]+ (33), 153
(18), 151 (45). Found, %: C 50.19; H 2.74; N 20.90.
C14H9Cl2N5O. Calculated, %: C 50.32; H 2.71; N 20.96.
1,4-Diamino-6-chloro-3-oxo-1-(thiophen-2-yl)-2,3-di-
hydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(4f).
Yield 162 mg (53%), white crystals, mp 215–216°С
(decomp.). IR spectrum, ν, cm–1: 3387, 3146 (NH2), 2228
1
(C≡N), 1681 (C=O). H NMR spectrum, δ, ppm (J, Hz):
3
3
3.25 (2H, s, NН2); 7.03 (1H, dd, J = 4.7, J = 3.5, H Ar);
3
7.27 (1H, d, J = 3.5, H Ar); 7.41 (1H, br. s, NH2); 7.51
(1H, d, J = 4.7, H Ar); 8.48 (1H, br. s, NH2); 9.31 (1H, s,
3
NH). 13C NMR spectrum, δ, ppm: 74.4; 90.2; 106.3; 113.6;
126.7; 126.8; 127.3; 144.2; 154.8; 156.2; 165.2; 165.9.
Mass spectrum, m/z (Irel, %): 307 [М(37Cl)]+ (5), 305
[М(35Cl)]+ (11), 291 [М(37Cl)–NH2]+ (8), 289 [М(35Cl)–NH2]+
(23), 272 (21); 224 [М(37Cl)–Ar]+ (5), 222 [М(35Cl)–Ar]+
(12), 207 [М(37Cl)–Ar–NH3]+ (6), 205 [М(35Cl)–Ar–NH3]+
(16), 111 (100). Found, %: C 47.00; H 2.66; N 22.84.
C12H8ClN5OS. Calculated, %: C 47.14; H 2.64; N 22.91.
1,4-Diamino-1-tert-butyl-6-chloro-3-oxo-2,3-dihydro-
1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4g). Yield 101 mg
(36%), white crystals, mp 264–265°С (decomp.). IR spect-
rum, ν, cm–1: 3396, 3142 (NH2), 2224 (C≡N), 1680 (C=O).
1H NMR spectrum, δ, ppm: 0.98 (9H, s, C(CН3)3); 2.63
(2H, s, NН2); 7.35 (1H, s, NH2); 8.32 (1H, br. s, NH2); 8.79
(1H, s, NH). 13C NMR spectrum, δ, ppm: 28.1; 40.4; 81.3;
92.2; 109.1; 115.9; 155.2; 156.0; 164.9; 166.5. Mass
spectrum, m/z (Irel, %): 249 [М(37Cl)–CONH]+ (2), 247
[М(35Cl)–CONH]+ (3), 224 [М(37Cl)–Ar]+ (36), 222
[М(35Cl)–Ar]+ (100), 207[М(37Cl)–Ar–NH3]+ (11), 205
[М(35Cl)–Ar–NH3]+ (31), 57 (93). Found, %: C 51.36; H 5.06;
N 24.96. C12H14ClN5O. Calculated, %: C 51.53; H 5.04; N 25.04.
4,6-Diamino-1-hydroxy-1-(4-methoxyphenyl)-3-oxo-
2,3-dihydro-1Н-pyrrolo[3,4-с]pyridine-7-carbonitrile (5b).
Yield 108 mg (69%), white crystals, mp 251–253°С
(decomp.). IR spectrum, ν, cm–1: 3424, 3340, 3146 (NH2,
1
NH, OH), 2209 (C≡N), 1682 (C=O). H NMR spectrum,
δ, ppm: 3.75 (3Н, s, OСН3); 6.68 (1H, br. s, NH2); 6.88
(2H, s, NН2); 6.89–6.91 (2H, m, H Ar); 6.99 (1H, s, OH);
7.35–7.37 (3H, m, H Ar, NH2); 8.70 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 55.1; 72.3; 86.3; 97.9; 113.3; 115.3;
127.4; 131.5; 156.7; 159.0; 162.9; 165.4; 168.1. Mass
spectrum, m/z (Irel, %): 311 [М]+ (22), 294 [М–ОH]+ (14),
293 [М–Н2О]+ (18), 204 [М–Ar]+ (12); 186 [М–Ar–Н2О]+
(11), 135 [ArСО]+ (100); 107 [Ar]+ (57). Found, %:
C 57.88; H 4.23; N 22.73. C15H13N5O3. Calculated, %:
C 57.87; H 4.21; N 22.50.
X-ray structural study of compound 4f was performed
on using an X-ray diffractometer Pilatus 100K STOE
(MoKα radiation). Data collection, detection, and
refinement of unit parameters, diffraction data processing
170

Chemistry of Heterocyclic Compounds 2019, 55(2), 167–171
was carried out using the STOE X-Area program set.11
Crystals suitable for X-ray structural analysis were
obtained by slow evaporation of a solution of compound 4f
in 1,4-dioxane. The structure was solved using the
SHELXS-97 software.12 The complete X-ray structural
dataset was deposited at the Cambridge Crystallographic
Data Center (deposit CCDC 1877753). The visual
representation of structure was prepared using the DIAMOND
program.13
4. (a) Soumya, T. V.; Muhammed Ajmal, C.; Bahulayan, D.
Bioorg. Med. Chem. Lett. 2017, 27, 450. (b) Bardasov, I. N.;
Alekseeva, A. U.; Chunikhin, S. S.; Tafeenko, V. A.;
Ershov, O. V. Tetrahedron Lett. 2017, 58, 3919.
5. Ibrahim, D. A.; Ismail, N. S. M. Eur. J. Med. Chem. 2011, 46,
5825.
6. (a) Karpov, S. V.; Kayukov, Ya. S.; Bardasov, I. N.;
Kayukova, O. V.; Lipin, K. V.; Nasakin, O. E. Russ. J. Org.
Chem. 2011, 47, 1492. [Zh. Org. Khim. 2011, 47, 1492.]
(b) Grigor'ev, A. A.; Karpov, S. V.; Kayukov, Ya. S.;
Belikov, M. Yu.; Nasakin, O. E. Tetrahedron Lett. 2015, 56,
6279. (c) Grigor'ev, A. A.; Karpov, S. V.; Kayukov, Ya. S.;
Nasakin, O. E.; Gracheva, Iu. A.; Tafeenko, V. A. Chem.
Heterocycl. Compd. 2017, 53, 230. [Khim. Geterotsikl.
Soedin. 2017, 53, 230.] (d) Karpov, S. V.; Grigor'ev, A. A.;
Kayukov, Ya. S.; Karpova, I. V.; Nasakin, O. E.; Tafeenko, V. A.
J. Org. Chem. 2016, 81, 6402.
This study received financial support from the Russian
Foundation for Basic Research (project No. 18-33-01204
mol_a).
X-ray structural analysis was performed with support
from M. V. Lomonosov Moscow State University
development program.
7. Grigor'ev, A. A.; Shtyrlin, N. V.; Gabbasova, R. R.; Zeldi, M. I.;
Grishaev, D. Yu.; Gnezdilov, O. I.; Balakin, K. V.;
Nasakin, O. E.; Shtyrlin, Yu. G. Synth. Commun. 2018, 48, 2288.
8. Attia, A. M. E.; Ismail, A. E.-H. A. A. Tetrahedron 2003, 59, 1749.
9. (a) Grigor'ev, A. A.; Karpov, S. V.; Kayukov, Ya. S.;
Gracheva, Iu. A.; Tafeenko, V. A. Synlett 2017, 1592.
(b) Kayukov, Ya. S.; Karpov, S. V.; Grigor'ev, A. A.;
Nikiforova, A. L.; Nasakin, O. E.; Shchegravina, E. S.;
Kayukova, O. V.; Tafeenko, V. A. Chem. Heterocycl. Compd.
2017, 53, 568. [Khim. Geterotsikl. Soedin. 2017, 53, 568.]
10. Maksimova, V. N.; Ershov, O. V.; Lipin, K. V.; Eremkin, A. V.;
Nasakin, O. E. Russ. J. Org. Chem. 2012, 48, 426. [Zh. Org.
Khim. 2012, 48, 429.]
References
1. (a) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.;
Kornienko A. Org. Lett. 2006, 8, 899. (b) Evdokimov, N. M.;
Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Yu.;
Magedov, I. V.; Kornienko A. J. Org. Chem. 2007, 72,
3443.
2. (a) Louvel, J.; Guo, D.; Soethoudt, M.; Mocking, T. A. M.;
Lenselink, E. B.; Mulder-Krieger, T.; Heitman, L. H.;
IJzerman, A. P.; Eur. J. Med. Chem. 2015, 101, 681.
(b) Meibom, D.; Albrecht-Kupper, B.; Diedrichs, N.; Hubsch, W.;
Kast, R.; Kramer, T.; Krenz, U.; Lerchen, H.-G.; Mittendorf, J.;
Nell, P. G.; Susmeier, F.; Vakalopoulos, A.; Zimmermann, K.
ChemMedChem 2017, 12, 728.
11. Stoe & Cie, X-AREA, version 1.30. Stoe & Cie GmbH:
Darmstadt, Germany, 2005.
12. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, A64, 112.
3. (a) Mais, F.-J.; Heilman, W.; Olenik, B.; Keil, B.; Becker, G.;
Meibom, D.; Kuhlmann, T. US Patent 20180155336A1.
(b) Rodríguez, D.; Gao, Z.-G.; Moss, S. M.; Jacobson, K. A.;
Carlsson, J. J. Chem. Inf. Model. 2015, 55, 550.
13. Brandenburg, K. DIAMOND, Release 2.1d; Crystal Impact
GbR: Bonn, 2000.
171