2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides 7*. Synthesis of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-с]pyridine-7-carbonitriles

Article abstract of DOI:10.1007/s10593-017-2093-x

[Figure not available: see fulltext.] The reaction of 2-acyl(aroyl)-1,1,3,3-tetracyanopropenides with gaseous hydrogen halides was used to obtain 2-amino-3-aroyl(acyl)-6-halopyridine-3,5-dicarbonitriles, which were subsequently converted to the respective

Full text of DOI:10.1007/s10593-017-2093-x

DOI 10.1007/s10593-017-2093-x
Chemistry of Heterocyclic Compounds 2017, 53(5), 568–574
2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides
7*. Synthesis of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-
1H-pyrrolo[3,4-с]pyridine-7-carbonitriles
Yakov S. Kayukov1, Sergey V. Karpov1*, Arthur A. Grigor'ev1, Anastasiya L. Nikiforova1,
Oleg E. Nasakin1, Ekaterina S. Shchegravina2, Olga V. Kayukova3, Victor A. Tafeenko4
1 Chuvash State University named after I. N. Ulyanov,
15 Moskovsky Ave., Cheboksary 428015, Russia; e-mail: serg31.chem@mail.ru
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 428032, Russia; e-mail: olgakajukova@mail.ru
4 M. V. Lomonosov Moscow State University,
1 Build. 3 Leninskie Gory, Moscow 119991, Russia; e-mail: tafeenko-victor@yandex.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(5), 568–574
Submitted December 19, 2016
Accepted February 21, 2017
The reaction of 2-acyl(aroyl)-1,1,3,3-tetracyanopropenides with gaseous hydrogen halides was used to obtain 2-amino-3-aroyl(acyl)-
6-halopyridine-3,5-dicarbonitriles, which were subsequently converted to the respective 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles by treatment with concentrated sulfuric acid, followed by aqueous workup.
Keywords: pyridines, pyrrolo[3,4-с]pyridines, tetracyanopropenides, annulation, iminolactone–lactam rearrangement.
2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides are relatively
easily available2 and have attracted interest as promising
precursors for the synthesis of various polyfunctional
heterocyclic compounds. 2-Acyl(aroyl)-1,1,3,3-tetracyano-
propenides have been used as starting materials for the
development of preparative methods for the synthesis of
substituted furans,3–6 pyridines,6–9 as well as the fused ring
systems of furo[3,4-c]pyridine1 and thieno[2,3-b]-
pyridine.10 It has been noted that the interaction of
propenides 1 with hydrogen halides in formic acid also
resulted in the formation of 4-amino-1-aryl-6-halo-
1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-
7-carbonitriles as by-products in low yields. Pyrrolo[3,4-c]-
pyridines are of interest as scaffolds for the synthesis of
biologically active compounds. The examples of such
derivatives include ligands of serotonin 5-HT3 receptor,11
caspase-3 inhibitors,12 and anthelmintic agents.13 The
1-hydroxy-3-oxo-1-pyridylpyrrolo[3,4-c]pyridine fragment
represents a structural feature of the INH-NAD adduct,
which is formed in vivo from the prodrug isoniazid and
NAD and suppresses the development of Mycobacterium
tuberculosis.14–17 Synthetic analogs of INH-NAD adduct
that contain the pyrrolo[3,4-c]pyridine ring system in their
structure have been studied as potential tuberculostatic
drugs.14–18
In the current work, we studied the possibilities for the
synthesis of pyrrolo[3,4-c]pyridine derivatives from propeni-
des 1a–f through 6-halopyridine intermediates 2, 3 a–f,
which were obtained according to a previously published
procedure6 by treating a solution of propenide 1a–f in
isopropyl alcohol with gaseous hydrogen halide (НСl,
HBr) at 85°С for 15–20 min (Scheme 1, Table 1).
The transformation of pyridine derivatives 2, 3 a–f to
the respective pyrrolo[3,4-с]pyridines 4, 5 a–f was
* For Communication 6, see 1.
0009-3122/17/53(05)-0568©2017 Springer Science+Business Media New York
568

Chemistry of Heterocyclic Compounds 2017, 53(5), 568–574
Scheme 1
(Scheme 2). In our opinion, the fact that this reaction
proceeded under mild conditions precluded the alternative
route starting from an addition of hydroxide ion to the
nitrile group.
The second method (method II) was based on the use of
acidic catalysis. It should be noted that acidic catalysis
generally was not very effective for performing this type of
process: even when pyridine 2b was refluxed for many
hours in aqueous acetic acid medium in the presence of
H2SO4, the procedure led to the formation of only trace
amounts of compound 4b. Another method based on
stepwise treatment of pyridines 2, 3 a–e first with
concentrated H2SO4 and then with water was found to be
superior. The reaction under these conditions proceeded
quickly with an exothermic effect and gave high yields of
compounds 4, 5 а–е. The likely sequence of reactions
included the formation of cationic furopyridine inter-
mediate А (Scheme 3), as the solution of pyridines 2, 3 а–е
in concentrated H2SO4 had a bright-red color. The addition
of water resulted in hydration and iminolactone–lactam
rearrangement. This method was not suitable for the
preparation of derivatives 4f and 5f containing a thiophene
moiety that was unstable in the presence of H2SO4.
In order to confirm the proposed sequence of
mechanistic steps and to exclude a possible mechanism
involving Ritter cyclization, the reaction of pyridine 2b
with methanol was performed under analogous conditions.
It was expected that the process in this case should stop
with the formation of iminofuran В (Scheme 4) or
pyrrolopyridine С (in the case of Ritter reaction), but
according to the data of NMR spectra the main product was
4-amino-6-chloro-1-methoxy-3-oxo-1-phenyl-2,3-dihydro-
Table 1. Substituents and yields of compounds 2, 3 а–f
Yield, %
R
X = Cl
2a (86)
2b (85)
2c (79)
2d (70)
2e (67)
2f (76)
X = Br
t-Bu
3a (71)
3b (70)
3c (76)
3d (68)
3e (65)
3f (63)
Ph
4-MeC6H4
4-MeOC6H4
4-BrC6H4
2-Thienyl
achieved by two methods. The first one (method I) was
based on the reaction of pyridines 2, 3 a–f with water in the
presence of a basic catalyst. A drawback of this method
was the occurrence of a side reaction involving the
substitution of halide with a hydroxy group with the
formation of pyrrolo[3,4-с]pyridones 6a–f as impurities
(Scheme 2, Table 2), which required laborious purification of
the target products and lowered their yields. The
substitution of bromide was especially facile, and for that
reason the yields of pyrrolo[3,4-с]pyridines 5 a–f obtained
by this method were below 15% (not presented in Table). It
was established experimentally that the optimum condi-
tions for the synthesis of pyrrolo[3,4-с]pyridines 4, 5 a–f
involved treatment with aqueous alcohol solution of NaOH
and performing the reaction at room temperature, while
complete conversion to pyrrolo[3,4-с]pyridones 6a–f was
better achieved by heating at reflux in aqueous DMSO solu-
tion of NaOH. Pyridones 6 are known compounds, which
were previously obtained by a reaction of 3-acyl(aroyl)-
cyclopropane-1,1,2,2-tetracarbonitriles with sodium hydroxi-
de.19 By using this alternative method of synthesis, we were
able to obtain 4-amino-1-(tert-butyl)-1-hydroxy-3,6-dioxo-
2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(6а), which was not accessible via the direct method.
Table 2. Substituents and yields of compounds 4, 5
Yield, %
X = Cl
Method I
X = Br
R
Method II
Method II
t-Bu
4a (33)
4b (45)
4c (37)
4d (41)
4e (25)
4f (55)
4a (88)
4b (91)
4c (79)
4d (90)
4e (77)
–
5a (82)
5b (85)
5c (75)
5d (87)
5e (72)
–
Ph
4-MeC6H4
4-MeOC6H4
4-BrC6H4
2-Thienyl
The presumed mechanism of this reaction involved an
addition of hydroxide ion to the carbonyl group, furan ring
closure and subsequent iminolactone–lactam rearrangement
Scheme 2
R
R
R
R
Method I
O
O
NH
NH
HO
NC
HO
NC
HO
NC
HO
NC
H2O
NaOH
N
2 3 a f
,
–
NH
NH2
O
+
O
i-PrOH
H2O, rt
– HO–
X
N
NH2
X
N
X
N
NH2
O
N
H
6a–f
NH2
4a f
– (25–55%)
5a f
– (<15%)
NaOH
2a
6a
DMSO, H2O, , 2 min
71%

Chemistry of Heterocyclic Compounds 2017, 53(5), 568–574
Scheme 3
2 3 a e
Method II
,
–
rt
H2SO4
10–30 min
R
R
R
R
R
O
H
N
O
O
NH
O
HO
NC
HO
NC
NH
OH
NH2
H2O
–H+
NC
NC
Cl
NC
Cl
NH
NH
NH2
O
Cl
N
NH2
N
NH2
Cl
N
N
Cl
N
NH2
A
4, 5 a–e
Scheme 4
1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (7) (Scheme 4).
The formation of compound 7 was also confirmed by its
hydrolysis leading to the formation of pyrrolo[3,4-c]-
pyridine 4b upon heating in dilute H2SO4.
the possible isomers. The structure of compounds 4b and
5а was proved by X-ray crystallographic analysis (Figs. 2, 3).
Thus, we demonstrated the general applicability of this
process where the heterocyclization involved a cyano
group adjacent with the amino group, leading to the
formation of isomers 4', 5' a–e.
The crystal lattice formation for both compounds was
largely controlled by hydrogen bonding interactions. The
crystal of compound 4b contained molecules linked by
centrosymmetric N(2)–H(2)···O(2) hydrogen bonds (2.997 Å)
from one side and N(1)–H(31)···N(3) hydrogen bonds
(3.039 Å) from the other side. This resulted in the forma-
tion of a chain along the crystallographic axis b. The adjacent
Pyrrolo[3,4-c]pyridines 4, 5 a–e were isolated as white
crystalline solids that were readily soluble in polar organic
solvents. Some of them formed stable solvates with
2-propanol.
The proposed structure of the synthesized compounds
1
was supported by Н and 13С NMR spectroscopy, mass
spectrometry, and was in agreement with IR spectral data
1
and the results of elemental analysis. Н NMR spectra of
pyrrolo[3,4-c]pyridines 4, 5 a–e contained two broadened
singlets at 7.32–8.57 ppm, which were assigned to the
amino group linked to pyridine ring. The hydroxy group
1
proton was represented in Н NMR spectra by a singlet in
the range of 6.78–8.57 ppm. The aryl substituents were
observed by their characteristic signals.
The structure of pyridines 2, 3 a–e featured two nitrile
groups at ortho position relative to the carbonyl group,
and for this reason the formation of two positional isomers
4', 5' a–e and 4'', 5'' a–e could be expected (Fig. 1).
According to TLC data and NMR spectra, the reaction
occurred regioselectively with the formation of only one of
Figure 1. The possible isomers of compounds 4, 5 with different
configuration of amino group and halogen atom relative to the
other groups.
570

Chemistry of Heterocyclic Compounds 2017, 53(5), 568–574
Figure 2. Molecular structure of compound 4b solvated with
Figure 3. Molecular structure of compound 5а according to X-ray
structural analysis, with atoms represented by thermal vibration
ellipsoids of 50% probability. Symmetry codes: (i) –x, 1–y,
1–z; (ii) –x, –0.5+y, 0.5–z.
2-propanol with atoms represented by thermal vibration ellipsoids of
50% probability. Symmetry codes: (i) –x, –y, –z; (ii) –x, 1–y, –z; (iii)
–1+x, y, –1+z; (iv) –0.5+x, 0.5–y, –0.5+z.
chains were linked by O(3)–H(32)···О(1), O(3)–H(32)···О(2),
and N(3)–H(2)···O(3) hydrogen bonds with solvated
2-propanol molecule (2.716 Å, 2.682 Å, and 3.272 Å,
respectively). The molecules in crystals of compound 5а
formed centrosymmetric dimers linked by N(2)–H(2)···O(1)
hydrogen bonds (2.844 Å). Besides that, O(2)–H(3)···N(1)
hydrogen bond (2.860 Å) existed between the hydroxy
group and the pyridine nitrogen atom.
Thus, based on the use of 2-acyl(aroyl)-1,1,3,3-tetra-
cyanopropenides, we have developed two-step methods for
the synthesis of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles under
the conditions of either acidic or basic catalysis. The
compounds obtained by the method that involved treatment
with concd. Н2SO4 and then water were formed in high
yields and did not contain impurities, but that method was
limited to substrates lacking any acid-labile substituents.
The method using basic catalysis gave lower yields, but
was useful for obtaining compounds containing acid-labile
substituents, for example, it was used for the synthesis of a
thiophene derivative.
Synthesis of 2-amino-3-aroyl(acyl)-6-halopyridine-3,5-di-
carbonitriles 2, 3 a–f (General method). A suspension of
propenide 1a–f (5 mmol) in 2-PrOH (50 ml) was heated to
reflux and, while continuing the heating and stirring,
gaseous HCl or HBr was bubbled through the mixture until
the reaction was complete (15–20 min). The mixture was
then poured into water (200 ml), the precipitate that formed
was filtered off and purified by recrystallization from a 1:4
mixture of MeCN–H2O.
2-Amino-4-(4-bromobenzoyl)-6-chloropyridine-3,5-
dicarbonitrile (2e). White crystals, mp >275°С (decomp.).
IR spectrum, ν, cm–1: 3201 (NH2), 2220 (C≡N), 1682
1
(C=O). H NMR spectrum, δ, ppm: 7.83–7.89 (2H, m,
H Ar); 7.93–7.99 (2H, m, H Ar); 8.46 (1H, br. s) and 8.97
(1H, br. s, NH2). 13C NMR spectrum, δ, ppm: 190.0; 160.6;
157.9; 156.0; 133.3; 132.4; 132.3; 131.5; 114.1; 113.4;
93.0; 87.0. Mass spectrum, m/z (Irel, %): 364/362/360 [М]+
(2.8/11.7/9.0), 185/183 [C6H4BrCO]+ (98/100), 157/155
[C6H4Br]+ (12/12). Found, %: C 46.36; H 1.70; N 15.45.
C14H6BrClN4O. Calculated, %: C 46.51; H 1.67; N 15.49.
2-Amino-6-chloro-4-[(thiophen-2-yl)carbonyl]pyridine-
3,5-dicarbonitrile (2f). White crystals, mp 255–257°С
(decomp.). IR spectrum, ν, cm–1: 3211 (NH2), 2217 (C≡N),
Experimental
1
1662 (C=O). H NMR spectrum, δ, ppm (J, Hz): 7.38 (1H,
IR spectra were recorded for Nujol mulls of compounds
3
3
3
1
on an FSM-1202 FT-IR spectrometer. Н and 13C NMR
dd, J = 4.2, J = 4.8, H Ar); 8.05 (1H, d, J = 3.8, H Ar);
8.40 (1H, d, 3J = 4.8, H Ar); 8.45 (1H, br. s) and 8.97 (1H,
br. s, NH2). 13C NMR spectrum, δ, ppm: 182.3; 160.2;
157.2; 148.3; 141.0; 140.6; 138.0; 130.4; 115.3; 113.6;
96.2; 87.1. Mass spectrum, m/z (Irel, %): 290/288 [М]+
(14/5), 116 (12), 111 [C4H3SCO]+ (100), 83 [C4H3S]+ (11).
Found, %: C 49.98; H 1.79; N 19.51. C12H5ClN4OS.
Calculated, %: C 49.92; H 1.75; N 19.41.
spectra were acquired on an Agilent DDR2 400 instrument
(400 and 101 MHz, respectively) in DMSO-d6, using TMS
as internal standard. Mass spectra were recorded on a
Shimadzu GCMS-QP2010S DI instrument (EI ionization,
70 eV). Elemental analysis was performed on a vario MICRO
cube CHN-analyzer. Melting points were determined on an
Electrothermal IA 9000 series II instrument. The
individuality of the synthesized compounds was confirmed
by TLC method on Sorbfil PTSH-AF-A-UF plates, eluent
EtOAc, visualization under UV light (254 nm) or by
heating. 2-Acyl(aroyl)-1,1,3,3-tetracyanopropenides 1a–f2
and 2-amino-3-aroyl(acyl)-6-halopyridine-3,5-dicarbonitriles
2a–c,6 3b,c,6 2d,7 and 3d7 were obtained according to
published procedures.
2-Amino-6-bromo-4-pivaloylpyridine-3,5-dicarbonitrile
(3a). White crystals, mp 250–252°С (decomp.). IR
spectrum, ν, cm–1: 3224 (NH2), 2208 (C≡N), 1665 (C=O).
1H NMR spectrum, δ, ppm: 1.29 (9H, s, С(CH3)3); 8.43 (1H,
br. s) and 8.95 (1H, br. s, NH2). 13C NMR spectrum, δ, ppm:
208.1; 160.1; 160.0; 148.4; 116.3; 114.5; 94.6; 85.3; 45.7;
27.2. Mass spectrum, m/z (Irel, %): 308/306 [М]+ (3/3), 116
571

Chemistry of Heterocyclic Compounds 2017, 53(5), 568–574
(11), 57 [C4H9]+ (100). Found, %: C 46.75; H 3.64;
N 18.17. C12H11BrN4O. Calculated, %: C 46.93; H 3.61;
N 18.24.
(OH), 3480, 3292 (NH2), 2213 (C≡N), 1684 (C=O). H
NMR spectrum, δ, ppm: 7.31–7.40 (4H, m, H Ph, ОН);
7.40–7.49 (3H, m, H Ph, NHA); 8.55 (1H, br. s, NHB); 9.44
(1Н, s, NH). 13C NMR spectrum, δ, ppm: 167.2; 165.3;
156.5; 155.1; 138.3; 129.0; 128.6; 126.6; 113.7; 106.9;
90.3; 87.1. Mass spectrum, m/z (Irel, %): 302/300 [М]+
(1/2), 284/282 [М–H2O]+ (3/8), 103 [PhCN]+ (16), 77 [Ph]+
(32), 51 (100). Found, %: C 56.09; H 2.99; N 18.69.
C14H9ClN4O2. Calculated, %: C 55.92; H 3.02; N 18.63.
Compound 4b was also obtained by hydrolysis of
4-amino-6-chloro-1-methoxy-3-oxo-1-phenyl-2,3-dihydro-
1Н-pyrrolo[3,4-c]pyridine-7-carbonitrile (7). A suspension of
pyrrolopyridine 7 (100 mg, 0.3 mmol) in 10% H2SO4
solution (2 ml) was refluxed with stirring for 2 min, then
cooled, the precipitate was filtered off, washed with water,
dried, and purified by recrystallization. Yield 42 mg (44%).
4-Amino-6-chloro-1-hydroxy-1-(4-methylphenyl)-3-oxo-
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4c).
White crystals, mp >250°С (decomp.). IR spectrum, ν, cm–1:
3633 (OH), 3481, 3277 (NH2), 2216 (C≡N), 1689 (C=O)
1H NMR spectrum, δ, ppm: 2.28 (3H, s, СН3); 7.15–7.17
(2H, m, H Ar); 7.32–7.33 (2H, m, H Ar); 7.35 (1H, br. s)
and 7.51 (1H, br. s, NH2); 7.41 (1H, s, ОН); 9.38 (1Н, s,
NH). 13C NMR spectrum, δ, ppm: 167.1; 165.5; 156.5;
155.1; 138.3; 135.5; 129.2; 126.6; 117.8; 106.8; 90.4; 87.1;
21.1. Mass spectrum, m/z (Irel, %): 316/314 [М]+ (0.3/1),
298/296 [М–H2O]+ (4/12), 91 [C6H4CH3]+ (100). Found, %:
C 57.41; H 3.50; N 17.85. C15H11ClN4O2. Calculated, %:
C 57.24; H 3.52; N 17.80.
1
2-Amino-6-bromo-4-(4-bromobenzoyl)pyridine-3,5-di-
carbonitrile (3e). White crystals, mp >275°С (decomp.).
IR spectrum, ν, cm–1: 3209 (NH2), 2221 (C≡N), 1665
1
(C=O). H NMR spectrum, δ, ppm: 7.85–7.91 (2H, m,
H Ar); 7.94–8.01 (2H, m, H Ar); 8.47 (1H, br. s) and 9.00
(1H, br. s, NH2). 13C NMR spectrum, δ, ppm: 190.0; 160.2;
157.4; 148.4; 133.3; 132.4; 132.3; 131.4; 115.3; 113.5;
96.1; 87.0. Mass spectrum, m/z (Irel, %): 408/406/404 [М]+
(4/9/5), 185/183 [C6H4BrCO]+ (98/100), 157/155 [C6H4Br]+
(17/17). Found, %:
C 41.32; H 1.51; N 13.77.
C14H6Br2N4O. Calculated, %: C 41.41; H 1.49; N 13.80.
2-Amino-6-bromo-4-[(thiophen-2-yl)carbonyl]pyridine-
3,5-dicarbonitrile (3f). White crystals, mp 270–272°С
(decomp.). IR spectrum, ν, cm–1: 3213 (NH2), 2217 (C≡N),
1
1667 (C=O). H NMR spectrum, δ, ppm (J, Hz): 7.38 (1H,
dd, 3J = 4.0, 3J = 4.8, H Ar); 8.07 (1H, dd, 3J = 3.8, 4J = 0.8,
H Ar); 8.41 (1H, dd, 3J = 4.8, 4J = 0.8, H Ar); 8.45 (1H, br. s)
and 8.97 (1H, br. s, NH2). 13C NMR spectrum, δ, ppm: 182.3;
160.2; 157.2; 148.3; 141.0; 140.6; 140.0; 130.4; 115.3;
113.5; 96.2; 87.1. Mass spectrum, m/z (Irel., %): 334/332 [М]+
(10/10), 116 (9), 111 [C4H3SCO]+ (100), 83 [C4H3S]+ (13).
Found, %: C 43.35; H 1.55; N 16.92. C12H5BrN4OS.
Calculated, %: C 43.26; H 1.51; N 16.82.
Synthesis of 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-
dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles 4, 5 а–f
(General method). Method I. A suspension of pyridine 2,
3 a–f (1.0 mmol) and NaOH (0.1 g, 2.5 mmol) was stirred
in 1:1 mixture of 2-PrOH–H2O (3 ml) until full dissolution,
then maintained until the reaction was complete (control by
TLC; pyridines 2, 3 a–f showed yellow-green fluorescence
under UV light, pyrrolo[3,4-c]pyridines 4, 5 a–f showed
blue fluorescence). The reaction mixture was then diluted
with H2O (5 ml), neutralized with 5% Н2SO4 solution, the
precipitate that formed was filtered off and purified by
recrystallization from 1:2 mixture of MeCN–H2O.
Method II. A mixture of pyridine 2, 3 а–e (1 mmol) in
concd. H2SO4 (1 ml) was stirred at room temperature until
full dissolution (10–30 min), then diluted with H2O (20 ml),
and the white precipitate that formed was filtered off,
washed with water until the washes became neutral, air-
dried, and purified by recrystallization.
4-Amino-6-chloro-1-hydroxy-1-(4-methoxyphenyl)-3-oxo-
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4d).
White crystals, mp 266–268°С (decomp.). IR spectrum,
ν, cm–1: 3657 (OH), 3481, 3293 (NH2), 2216 (C≡N), 1688
1
(C=O). H NMR spectrum, δ, ppm: 3.76 (3H, s, OCH3);
6.86–6.92 (2H, m, H Ar); 7.35–7.41 (4H, m, H Ar, ОН,
NHA); 8.42 (1H, br. s, NHB); 9.41 (1Н, s, NH). 13C NMR
spectrum, δ, ppm: 167.0; 165.9; 159.8; 159.5; 155.1; 130.3;
128.0 (CH); 114.2 (CH); 114.0; 106.8; 90.0; 87.0; 55.6.
Mass spectrum, m/z (Irel, %): 332/330 [М]+ (1/2), 317/315
[М–CH3]+ (2/7), 314/312 [М–H2O]+ (5/15), 107
[CH3OC6H4]+ (66), 57 (100). Found, %: C 54.52; H 3.44;
N 16.79. C15H11ClN4O3. Calculated, %: C 54.48; H 3.35;
N 16.94.
4-Amino-1-(4-bromophenyl)-6-chloro-1-hydroxy-3-oxo-
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4e).
White crystals, mp >210°С (decomp.). IR spectrum, ν, cm–1:
3652 (OH), 3485, 3286 (NH2), 2218 (C≡N), 1682 (C=O).
1H NMR spectrum, δ, ppm: 7.41–7.48 (3H, m, H Ar, ОН);
7.52 (1H, br. s) and 8.57 (1H, br. s, NH2); 7.57–7.59 (2H,
m, H Ar); 9.47 (1Н, s, NH). 13C NMR spectrum, δ, ppm:
167.0; 164.8; 156.5; 155.2; 137.8; 131.6; 129.0; 122.4;
113.7; 106.9; 90.1; 86.7. Mass spectrum, m/z (Irel, %):
364/362/360 [М–H2O]+ (2/8/6), 185/183 [C6H4BrCO]+
(26/27), 157/155 [C6H4Br]+ (30/31), 43 (100). Found, %:
C 44.40; H 2.10; N 14.79. C14H8BrClN4O2. Calculated, %:
C 44.30; H 2.12; N 14.76.
4-Amino-1-(tert-butyl)-6-chloro-1-hydroxy-3-oxo-2,3-
dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4a).
White crystals, mp 260–265°С (decomp.). IR spectrum,
ν, cm–1: 3365 (OH), 3272, 3211 (NH2), 2225 (C≡N), 1710
1
(C=O). H NMR spectrum, δ, ppm: 0.98 (9H, s, С(CH3)3);
6.79 (1H, br. s, OH); 7.37 (1H, br. s) and 8.41 (1H, br. s,
NH2); 8.96 (1H, s, NH). 13C NMR spectrum, δ, ppm: 166.9;
164.3; 156.4; 155.7; 116.2; 108.9; 93.2; 92.3; 40.8; 26.1. Mass
spectrum, m/z (Irel, %): 264/262 [М–H2O]+ (0.3/1), 238 (3),
179 (8), 57 [C4H9]+ (100). Found, %: C 51.53; H 4.64;
N 20.03. C12H13ClN4O2. Calculated, %: C 51.35; H 4.67;
N 19.96.
4-Amino-6-chloro-1-hydroxy-3-oxo-1-phenyl-2,3-di-
hydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4b). White
crystals, mp >210°С (decomp.). IR spectrum, ν, cm–1: 3654
4-Amino-6-chloro-1-hydroxy-3-oxo-1-(thiophen-2-yl)-
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (4f).
White crystals, mp >190°С (decomp.). IR spectrum, ν, cm–1:
572

Chemistry of Heterocyclic Compounds 2017, 53(5), 568–574
3627 (OH), 3479, 3281 (NH2), 2219 (C≡N), 1688 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 6.99–7.05 (1H, m, H Ar);
4-Amino-6-bromo-1-(4-bromophenyl)-1-hydroxy-3-oxo-
2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (5e).
White crystals, mp >210°С (decomp.). IR spectrum, ν, cm–1:
3650 (OH), 3491, 3274 (NH2), 2220 (C≡N), 1683 (C=O).
1H NMR spectrum, δ, ppm: 7.38–7.41 (4H, m, H Ar, ОН,
NHA); 7.55–7.57 (2H, m, H Ar); 8.56 (1H, br. s, NHB);
9.43 (1Н, s, NH). 13C NMR spectrum, δ, ppm: 167.2;
164.4; 156.5; 147.3; 137.8; 131.6; 129.0; 122.4; 114.9;
107.0; 93.5; 86.7. Mass spectrum, m/z (Irel, %):
408/406/404 [М–H2O]+ (5/10/5), 185/183 [C6H4BrCO]+
(16/16), 157/155 [C6H4Br]+ (24/25), 43 (100). Found, %:
C 39.80; H 1.98; N 13.12. C14H8Br2N4O2. Calculated, %:
C 39.65; H 1.90; N 13.21.
3
3
7.12 (1H, dd, J = 4.8, J = 1.0, H Ar); 7.48 (1H, br. s) and
8.52 (1H, br. s, NH2); 7.54 (1H, dd, 3J = 5.0, 3J = 1.0, H Ar);
7.63 (1H, s, ОН); 9.64 (1Н, s, NH). 13C NMR spectrum,
δ, ppm: 167.0; 164.1; 156.5; 147.4; 144.0; 127.1; 126.3; 125.1;
112.8; 105.1; 93.6; 86.6. Found, %: C 47.08; H 2.33; N 18.22.
C12H7ClN4O2S. Calculated, %: C 46.99; H 2.30; N 18.27.
4-Amino-6-bromo-1-(tert-butyl)-1-hydroxy-3-oxo-2,3-
dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (5a).
White crystals, mp >270°С (decomp.). IR spectrum, ν, cm–1:
3366 (OH), 3275, 3211 (NH2), 2225 (C≡N), 1710 (C=O).
1H NMR spectrum, δ, ppm: 0.98 (9H, s, С(CH3)3); 6.78
(1H, br. s, OH); 7.37 (1H, br. s) and 8.42 (1H, br. s, NH2);
8.94 (1H, s, NH). 13C NMR spectrum, δ, ppm: 167.1;
163.9; 156.3; 148.1; 117.4; 109.0; 95.6; 93.2; 40.8; 26.2.
Mass spectrum, m/z (Irel., %): 308/306 [M–H2O]+ (1/1), 278
(3), 222 (8), 116 (20), 57 [C4H9]+ (100). Found, %:
C 44.41; H 4.13; N 17.21. C12H13BrN4O2. Calculated, %:
C 44.33; H 4.03; N 17.23.
4-Amino-1-(tert-butyl)-1-hydroxy-3,6-dioxo-2,3,5,6-
tetrahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (6а).
Pyridine 2а (260 mg, 1 mmol) was added to a solution of
NaOH (100 mg, 2.5 mmol) in a 1:1 mixture of DMSO–Н2О
(2 ml). The mixture was refluxed for 2 min, then cooled,
treated with Н2О (5 ml), neutralized with 5% Н2SO4
solution, the precipitate that formed was filtered off and
purified by recrystallization from a 1:5 MeCN–EtOH mixture.
Yield 186 mg (71%), white crystals, mp 238–240°С
(decomp.). IR spectrum, ν, cm–1: 3602 (OH), 3270, 3212
(NH2), 2222 (C≡N), 1705, 1691 (C=O). 1H NMR spectrum,
δ, ppm: 0.99 (9H, s, С(CH3)3); 6.52 (1H, s, OH); 7.35 (2H,
br. s, NH2); 8.50 (1H, s, NH); 11.40 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 168.6; 165.2; 162.1; 151.3; 115.8; 92.3;
89.1; 79.2; 40.7; 26.2. Found, %: C 55.04; H 5.40; N 21.31.
C12H14N4O3. Calculated, %: C 54.96; H 5.38; N 21.36.
4-Amino-6-chloro-1-methoxy-3-oxo-1-phenyl-2,3-di-
hydro-1Н-pyrrolo[3,4-c]pyridine-7-carbonitrile (7). A
mixture of pyridine 2c (280 mg, 1 mmol) and concd.
H2SO4 (1 ml) was stirred until full dissolution. Then MeOH
(10 ml) was added, the white precipitate that formed was
filtered off, washed with water until the washes became
neutral, air-dried, and purified by recrystallization from a
1:4 mixture of MeCN–H2O. Yield 198 mg (63%), white
crystals, mp >210°С (decomp.). IR spectrum, ν, cm–1: 3461,
4-Amino-6-bromo-1-hydroxy-3-oxo-1-phenyl-2,3-di-
hydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile (5b). White
crystals, mp >270°С (decomp.). IR spectrum, ν, cm–1: 3649
(OH), 3482, 3275 (NH2), 2217 (C≡N), 1678 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 7.32–7.40 (5H, m,
H Ph, ОН, NHA); 7.42–7.49 (2H, m, H Ph); 8.53 (1H, br. s,
NHB); 9.40 (1Н, s, NH). 13C NMR spectrum, δ, ppm:
167.2; 165.0; 156.5; 147.3; 138.3; 129.0; 128.6; 126.6;
114.9; 107.0; 93.7; 87.1. Mass spectrum, m/z (Irel, %): 346/344
[М]+ (1/1), 328/326 [М–H2O]+ (11/11), 103 [PhCN]+ (25),
77 [Ph]+ (30), 51 (100). Found, %: C 48.81; H 2.72; N 16.09.
C14H9BrN4O2. Calculated, %: C 48.72; H 2.63; N 16.23.
4-Amino-6-bromo-1-hydroxy-1-(4-methylphenyl)-
3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(5c). White crystals, mp >270°С (decomp.). IR spectrum,
ν, cm–1: 3642 (OH), 3479, 3293 (NH2), 2217 (C≡N), 1678
(C=O). 1H NMR spectrum, δ, ppm: 2.30 (3H, s, CH3); 7.17–
7.20 (2H, m, H Ar); 7.31–7.38 (3H, m, H Ar, OH); 7.40
(1H, br. s) and 8.54 (1H, br. s, NH2); 9.38 (1Н, s, NH).
13C NMR spectrum, δ, ppm: 167.2; 165.1; 156.5; 147.3;
138.3; 135.3; 129.2; 126.2; 114.9; 106.9; 93.7; 87.1; 21.1.
Mass spectrum, m/z (Irel, %): 360/358 [М]+ (1/1), 342/340
[М–H2O]+ (9/9), 91 [C6H4CH3]+ (100). Found, %: C 50.24;
H 3.17; N 15.47. C15H11BrN4O2. Calculated, %: C 50.16;
H 3.09; N 15.60.
4-Amino-6-bromo-1-hydroxy-1-(4-methoxyphenyl)-
3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile
(5d). White crystals, mp 270–272°С (decomp.). IR
spectrum, ν, cm–1: 3651 (OH), 3478, 3294 (NH2), 2216
(C≡N), 1694 (C=O). 1H NMR spectrum, δ, ppm: 3.75 (3H, s,
CH3); 6.88–6.93 (2H, m, H Ar); 7.32–7.44 (4H, m, H Ar,
OH, NHA); 8.49 (1H, br. s, NHB); 9.36 (1Н, s, NH). 13C
NMR spectrum, δ, ppm: 167.0; 165.6; 159.8; 156.5; 155.1;
130.1; 128.0 (CH); 113.9 (CH); 113.8; 106.8; 90.2; 87.0;
55.6. Mass spectrum, m/z (Irel, %): 376/374 [М]+ (1/1),
361/359 [М–CH3]+ (5/5), 358/356 [М–H2O]+ (16/16), 107
[CH3OC6H4]+ (56), 43 (100). Found, %: C 48.12; H 3.04;
N 14.81. C15H11BrN4O3. Calculated, %: C 48.02; H 2.96;
N 14.93.
1
3255 (NH2), 2224 (C≡N), 1682 (C=O). H NMR spectrum,
δ, ppm: 3.20 (3H, s, OCH3); 7.34–7.44 (3H, m, H Ph); 7.46–
7.49 (2H, m, H Ph); 7.53 (1H, br. s) and 8.68 (1H, br. s,
NH2); 9.40 (1Н, s, NH). 13C NMR spectrum, δ, ppm: 167.5;
161.8; 156.5; 155.7; 137.2; 129.4; 128.8; 126.7; 113.6;
108.0; 91.5; 90.2; 50.9. Found, %: C 57.14; H 3.57;
N 17.71. C15H11ClN4O2. Calculated, %: C 57.24; H 3.52;
N 17.80.
X-ray structural study of compounds 4b, 5a. Crystals
suitable for X-ray structural analysis were obtained by slow
evaporation of solvent at room temperature: compound 4b –
from a 1:1 mixture of MeСN–2-PrOH, compound 5a –
from MeСN. Crystallographic studies were performed on a
STOE diffractometer with Pilatus100K detector, focussing
mirror collimation, CuKα-radiation (λ 1.54186 Å). Unit
cell parameters and tables of structure factors were
obtained by using the STOE X-Area (STOE&Cie GmbH)
software.20 The compound structures were solved by direct
method and refined by using the SHELX software.21 The
positions and thermal parameters of non-hydrogen atoms
were refined in full-matrix anisotropic approximation. The
573

Chemistry of Heterocyclic Compounds 2017, 53(5), 568–574
8. Grigor'ev, A. А.; Karpov, S. V.; Kayukov, Ya. S.;
hydrogen atom positions were calculated or determined
from difference Fourier syntheses and refined according to
the "rider" model or freely in isotropic approximation.
Visualization was performed with the DIAMOND
program.22 The complete X-ray structural dataset was
deposited at the Cambridge Crystallographic Data Center
(deposits CCDC 1523242 (compound 4b) and ССDC
1523243 (compound 5a)).
Belikov, M. Yu.; Nasakin, O. E. Tetrahedron Lett. 2015, 56, 6279.
9. Kayukov, Ya. S.; Karpov, S. V.; Rizatdinov, M. M.;
Bardasov, I. N.; Ershov, O. V.; Nasakin, O. E.; Tafeenko, V. A.
Russ. J. Org. Chem. 2013, 49, 707. [Zh. Org. Khim. 2013, 49,
724.]
10. Grigor'ev, A. A.; Karpov, S. V.; Kayukov, Y. S.; Nasakin, O. E.;
Gracheva, I. A.; Tafeenko, V. A. Chem. Heterocycl. Compd.
2017, 53, 230. [Khim. Geterotsikl. Soedin. 2017, 53, 230.]
11. Cappelli, A.; Anzini, M.; Vomero, S.; Mennuni, L.; Makovec, F.;
Doucet, E.; Hamon, M.; Menziani, M. C.; De Benedetti, P. G.;
Giorgi, G.; Ghelardini, C.; Collina, S. Bioorg. Med. Chem.
2002, 10, 779.
12. Kravchenko, D. V.; Kuzovkova, Y. A.; Kysil, V. M.;
Tkachenko, S. E.; Maliarchouk, S.; Okun, I. M.; Balakin, K. V.;
Ivachtchenko, A. V. J. Med. Chem. 2005, 48, 3680.
13. Kosulina, T. P.; Kaigorodova, E. A.; Kul'nevich, V. G.;
Sapunov, A. Ya.; Govorova, S. A. Pharm. Chem. J. 1997, 31,
191. [Khim.-Farm. Zh. 1997, 31(4), 30.]
14. Delaine, T.; Bernardes-Génisson, V.; Meunier, B.; Bernadou, J.
J. Org. Chem. 2007, 72, 675.
15. Delaine, T.; Bernardes-Génisson, V.; Stigliani, J.-L.;
Gornitzka, H.; Meunier, B.; Bernadou, J. Eur. J. Org. Chem.
2007, 1624.
16. Delaine, T.; Bernardes-Génisson, V.; Quémard, A.; Constant, P.;
Meunier, B.; Bernadou, J. Eur. J. Med. Chem. 2010, 45, 4554.
17. Broussy, S.; Bernardes-Génisson, V.; Quémard, A.; Meunier, B.;
Bernadou, J. J. Org. Chem. 2005, 70, 10502.
This work was performed with support from the
Scholarship of the President of the Russian Federation for
young scientists and doctoral students SP-3725.2015.4.
X-ray structural analysis was performed with support
from the program for development of the M. V. Lomonosov
Moscow State University.
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