Synthesis of fused derivatives of 1,8-naphthyridine

Article abstract of DOI:10.1134/S1070428017080140

Reactions of aromatic aldehyde, 2-aminoprop-1-ene-1,1,3-tricarbonitrile and cyclic enhydrazinoketones led to the formation of N-substituted 5-aryl-2,4-diamino-6-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,8]- naphthyridine-3-carbonitriles.

Full text of DOI:10.1134/S1070428017080140

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 8, pp. 1243–1248. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © A.Yu. Alekseeva, I.N. Bardasov, D.L. Mikhailov, O.V. Ershov, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53,
No. 8, pp. 1227–1232.
Synthesis of Fused Derivatives of 1,8-Naphthyridine
A. Yu. Alekseeva, I. N. Bardasov,* D. L. Mikhailov, and O. V. Ershov
I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
*e-mail: bardasov.chem@mail.ru
Received March 27, 2017
Abstract—Reactions of aromatic aldehyde, 2-aminoprop-1-ene-1,1,3-tricarbonitrile and cyclic enhydrazino-
ketones led to the formation of N-substituted 5-aryl-2,4-diamino-6-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,8]-
naphthyridine-3-carbonitriles
DOI: 10.1134/S1070428017080140
Functionally substituted naphthyridines and their
benzo- and heterofused derivatives are important
components of natural compounds and exhibit a wide
range of biologic action: antimalarial [1], antibacterial
[2, 3], antiphlogistic [4–6], antioxidant [7], antipro-
liferative [8, 9], and antitumor [10–12]. Besides a wide
application in pharmacology, naphthyridine derivatives
are used as new catalysts [13–15], fluorescence
markers [16], and sensors [17, 18] due to their
pronounced catalytic and optical properties.
substituted pyridines [19–21]. Recently the application of
multicomponent reactions in the synthesis of complica-
ted heterocyclic structures with a preliminarily defined
functionality became fashionable. The building up of
the naphthyridine scaffold is easily achieved by the
cascade formation of two pyridine rings at the use of
cyano-substituted alkenes [22–26].
We recently found a new approach to the synthesis
of highly functionalized heterocyclic structures of 5H-
chromeno[2,3-b]pyridine [27, 28] and 1,8-naphthyri-
dine [29, 30] series underlain by the process of double
fusion. In extension of research in this direction we
isolated from the reaction of arylmethylidene
The main procedures of the synthesis of 1,8-naph-
thyridine derivatives are Fridländer condensation and
its modifications based on utilization of functionally
Scheme 1.
O
O
Ar
NH2
CN
CN
CN
Ar
+
CN
R
CN
CN
R
NH
R'
NH
NH2
R
R
R'
1a_1f
2a, 2b
A
O
Ar
NH2
O
Ar
NH2
CN
CN
R
CN
NH2
R
N
N
N
NH2
R
R
R'
R'
3a_3j
B
1, Ar = Ph (a), 4-Tol (b), 2-ClC6H4 (c), 3-ClC6H4 (d), 4-FC6H4 (e), 3-NO2C6H4 (f); 2, R' = N(CH3)2, R = Me (a), H (b); 3, R'
= N(CH3)2: R = Me, Ar = Ph (a), 4-FC6H4 (b), 4-Tol (c), 3-ClC6H4 (d); R = H, Ar = Ph (e), 4-FC6H4 (f); R' = NHPh, R = Me,
Ar = Ph (g), 2-ClC6H4 (h), 4-Tol (i), 3-NO2C6H4 (j).
1243

ALEKSEEVA et al.
1244
Scheme 2.
O
O
Ar
N
NH2
CN
CN
CN
O
Ar
+
+
CN
-H2O
R
R
NH
N
NH2
NH2
R
R
R'
R'
2
3
derivatives of malononitrile dimer 1 with enhydra-
zinoketones 2 N-substituted 5-aryl-2,4-diamino-6-oxo-
5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-
carbonitriles 3а–3j (Scheme 1).
group of intermediate B and the cyano group of the
dicyanomethylene fragment leads to the formation of
the 1,8-naphthyridine scaffold.
The most effective way of constructing fused
heterocycles from simple substrates is obviously the
application of multicomponent reactions. To reduce
the number of stages in the synthesis of compounds
3a–3j we used a three-component system including
enhydrazinoketone 2, aromatic aldehyde, and 2-
aminoprop-1-ene-1,1,3-tricarbonitrile (malononitrile
dimer) (Scheme 2). Knoevenagel–Michael tandem
reaction afforded 1,8-naphthyridines 3a–3j in 65–90%
yields.
The presence in the formed Michael adduct A of
nucleophilic and electrophilic sites provides
a
possibility to perform a series of intramolecular
heterocyclizations resulting in the formation of 1,8-
naphthyridine scaffold. For instance, the first pyridine
ring is formed as a result of a nucleophilic attack of the
nitrogen atom of the enhydrazine fragment on the
spatially close cyano group in the Michael adduct A.
The intramolecular reaction between the formed amino
133
122
142
NH2
NH
NH2
52
CH
2C6H*
5
CH3
CH3
2C6H5
41
40
31
CH*
CH*
3
3
CH2
CH2
16
15
CH*
NH* NH*
2
2
NH*
4.2
CH*
CH*
2
2
8.9
8.5
5.1
4.2
4.4
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
3.0
2.5
2.0
1.5
1.0
δ, ppm
Fig. 1. Fragments of 1Н NMR spectrum of 2,4-diamino-8,8-dimethyl-6-oxo-5-phenyl-10-(phenylamino)-5,6,7,8,9,10-
hexahydrobenzo[b][1,8]-naphthyridine-3-carbonitrile 3g at 27°С (DMSO-d6, 500.13 MHz).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 8 2017

SYNTHESIS OF FUSED DERIVATIVES OF 1,8-NAPHTHYRIDINE
122
1245
122
142
72
61
41
CH3
2C6H5
CH2
20
CH3
NH
16
2NH2
CH2
2.0
CH
8.0
7.5
7.0
6.5
6.0
5.5
5.0
1.5
1.0
2.5
δ, ppm
Fig. 2. Fragments of 1Н NMR spectrum of 2,4-diamino-8,8-dimethyl-6-oxo-5-phenyl-10-(phenylamino)-5,6,7,8,9,10-
hexahydrobenzo[b][1,8]-naphthyridine-3-carbonitrile 3g at 70°С (DMSO-d6, 500.13 MHz).
The structure of synthesized 1,8-naphthyridine
derivatives 3a–3j was proved by a complex of
physicochemical methods. According to 1Н NMR
spectra compounds 3a–3j exist as diastereomers
mixtures apparently due to the low inversion rate of
the nitrogen atom of the dihydropyridine ring (Fig. 1).
To prove the formation of the diastereisomers mixture
analysis was carried out on a CHN-analyzer vario
Micro cube. Melting points were determined on an
automatic apparatus OptiMelt MPA100. The reaction
progress was monitored and the homogeneity of
compounds synthesized was checked by TLC on
Sorbfil PTCKh-AF-A-UV plates (eluent EtOAc,
development under UV irradiation, with iodine vapor,
and by thermal decomposition).
1
due to the slow inversion the Н NMR spectrum of
compound 3g was registered at 70°С, where averaging
of the signals was observed (Fig. 2).
2,4-Diamino-10-(dimethylamino)-8,8-dimethyl-6-
oxo-5-phenyl-5,6,7,8,9,10-hexahydrobenzo[b][1,8]-
naphthyridine-3-carbonitrile (3а). A mixture of
0.085 g (1 mmol) of piperidine, 0.182 g (1 mmol) of
enaminoketone 2, 0.132 g (1 mmol) of 2-aminoprop-1-
ene-1,1,3-tricarbonitrile, and 0.106 g (1 mmol) of
benzaldehyde in 5 mL of ethanol was stirred at 30–40°С
for 30 min. On the completion of the reaction (TLC
monitoring) the mixture was cooled, the separated
precipitate was filtered off, washed with a little 2-
propanol. Yield 0.282 g (70%), mp 237–238°С
(decomp.). IR spectrum, ν, cm–1: 3456, 3427, 3337 (NH2),
Thus, the multicomponent reaction afforded new
polyfunctional 1,8-naphthyridine derivatives.
EXPERIMENTAL
IR spectra were recorded on a Fourier spectropho-
tometer FSM-1202 in thin films (mulls in mineral oil).
1Н NMR spectra were registered on a spectrometer
Bruker DRX-500 in DMSO-d6, internal reference
TMS. Mass spectra were measured on an instrument
Finnigan MАT INCOS-50 (EI, 70 eV). Elemental
1
2190 (C≡N), 1630 (С=О). Н NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 8 2017

ALEKSEEVA et al.
1246
0.78 s (3H, CH3), 1.02 s (3H, CH3), 1.96 d (1H, CH2, J
16.6 Hz), 2.17 d (1H, CH2, J 16.0 Hz), 2.48 d (1H,
CH2, J 17.1 Hz), 2.92 d (1H, CH2, J 17.2 Hz), 2.98 s
[3H, N(CH3)2], 3.00 s [3H, N(CH3)2], 5.03 s (1H, CH),
6.08 s (2H, NH2), 6.25 s (2H, NH2), 7.06 t (1H, C6H5, J
7.3 Hz), 7.16 t (2H, C6H5, J 7.6 Hz), 7.23 d (2H, C6H5,
J 7.2 Hz). Mass spectrum, m/z (Irel, %): 402 (10) [M]+,
358 (25) [M – 44]+, 325 (38) [M – 77]+, 281 (100) [M –
120]+. Found, %: С 68.77; H 6.42; N 20.72.
C23H26N6O. Calculated, %: C 68.63; H 6.51; N 20.88.
M 402.50.
1.02 s (3H, CH3), 1.98 d (1H, CH2, J 16.1 Hz), 2.18 d
(1H, CH2, J 16.0 Hz), 2.48 d (1H, CH2, J 17.9 Hz), 2.92
d (1H, CH2, J 17.9 Hz), 2.98 s [3H, N(CH3)2], 3.00 s
[3H, N(CH3)2], 5.07 s (1H, CH), 6.22 s (2H, NH2),
6.30 s (2H, NH2), 7.08–7.14 m (2H, C6H4), 7.21 t
(1H, C6H4, J 7.8 Hz), 7.37 t (1H, C6H4, J 1.9 Hz).
Mass spectrum, m/z (Irel, %): 436 (3) [M]+, 393 (20)
[M – 43]+. Found, %: С 63.09; H 5.86; N 19.37.
C23H25ClN6O. Calculated, %: C 63.22; H 5.77; N
19.23. M 436.94.
2,4-Diamino-10-(dimethylamino)-6-oxo-5-phe-
nyl-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naph-
thyridine-3-carbonitrile (3e). Yield 65%, mp 239–
240°С (decomp.). IR spectrum, ν, cm–1: 3474, 3360
Compounds 3b–3j were prepared similarly.
2,4-Diamino-10-(dimethylamino)-8,8-dimethyl-6-
oxo-5-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-
benzo[b][1,8]naphthyridine-3-carbonitrile (3b).
Yield 76%, mp 254–255°С (decomp.). IR spectrum, ν,
cm–1: 3459, 3320 (NH2), 2190 (C≡N), 1680 (С=О). 1Н
NMR spectrum, δ, ppm: 0.78 s (3H, CH3), 1.02 s (3H,
CH3), 1.96 d (1H, CH2, J 15.9 Hz), 2.17 d (1H, CH2, J
15.9 Hz), 2.48 d (1H, CH2, J 16.8 Hz), 2.91 d (1H,
CH2, J 16.9 Hz), 2.98 s [3H, N(CH3)2], 3.00 s [3H, N
(CH3)2], 5.06 s (1H, CH), 6.14 s (2H, NH2), 6.27 s
(2H, NH2), 6.99 t (2H, C6H4, J 9.2 Hz), 7.25 d.d (2H,
C6H4, J 8.7, 5.7 Hz). Mass spectrum, m/z (Irel, %): 420
(18) [M]+, 377 (100) [M – 43]+, 325 (59) [M – 95]+.
Found, %: С 65.54; H 5.87; N 20.12. C23H25FN6O.
Calculated, %: C 65.70; H 5.99; N 19.99. M 420.49.
1
(NH2), 2201 (C≡N), 1650 (С=О). Н NMR spectrum,
δ, ppm: 1.60–1.69 m (2H, CH2), 1.88–1.94 m (2H,
CH2), 2.12–2.24 m (2H, CH2), 2.98 s (3H, CH3), 3.01 s
(3H, CH3), 5.07 s (1Н, СН), 6.08 s (2H, NH2), 6.24 s
(2H, NH2), 7.06 t (1Н, С6Н5, J 7.2 Hz), 7.14–7.25 m
(4Н, С6Н5). Mass spectrum, m/z (Irel, %): 374 (5) [M]+,
330 (16) [M – 44]+, 297 (25) [M – 77]+, 254 (100) [M –
120]+. Found, %: С 67.50; H 5.83; N 22.35.
C21H22N6O. Calculated, %: C 67.36; H 5.92; N 22.44.
M 374.45.
2,4-Diamino-10-(dimethylamino)-6-oxo-5-(4-
fluorophenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,8]-
naphthyridine-3-carbonitrile (3f). Yield 68%, mp
237–238°С (decomp.). IR spectrum, ν, cm–1: 3460,
3340 (NH2), 2204 (C≡N), 1656 (С=О). 1Н NMR spec-
trum, δ, ppm: 1.64–1.68 m (2H, CH2), 1.89–1.94 m
(2H, CH2), 2.14–2.22 m (2H, CH2), 2.97 s (3H, CH3),
3.01 s (3H, CH3), 5.09 s (1Н, СН), 6.13 s (2H, NH2),
6.24 s (2H, NH2), 6.98 t (2Н, С6Н4, J 8.9 Hz), 7.23 d.d
(2Н, С6Н4, J 8.7, 5.7 Hz). Mass spectrum, m/z (Irel, %):
392 (1) [M]+, 348 (4) [M – 44]+, 254 (43) [M – 138]+.
Found, %: С 64.38; H 5.28; N 21.30. C21H21FN6O.
Calculated, %: C 64.27; H 5.39; N 21.42. M 392.44.
2,4-Diamino-10-(dimethylamino)-8,8-dimethyl-6-
oxo-5-(p-tolyl)-5,6,7,8,9,10-hexahydrobenzo[b]-[1,8]
naphthyridine-3-carbonitrile (3c). Yield 67%, mp
265–266°С (decomp.). IR spectrum, ν, cm–1: 3430,
3333, 3239 (NH2), 2187 (C≡N), 1641 (С=О). 1Н NMR
spectrum, δ, ppm: 0.79 s (3H, CH3), 1.02 s (3H, CH3), 1.95
d (1H, CH2, J 15.8 Hz), 2.16 d (1H, CH2, J 15.8 Hz),
2.18 s (3Н, СН3), 2.47 d (1H, CH2, J 17.9 Hz), 2.91 d
(1H, CH2, J 17.9 Hz), 2.97 s [3H, N(CH3)2], 3.00 s
[3H, N(CH3)2], 4.97 s (1H, CH), 6.03 s (2H, NH2),
6.23 s (2H, NH2), 6.96 d (2H, C6H4, J 7.9 Hz), 7.11 d
(2H, C6H4, J 7.9 Hz). Mass spectrum, m/z (Irel, %): 416
(20) [M]+, 373 (90) [M – 43]+, 325 (50) [M – 91]+, 282
(100) [M – 134]+. Found, %: С 69.08; H 6.79; N 20.30.
C24H28N6O. Calculated, %: C 69.21; H 6.78; N 20.18.
M 416.53.
2,4-Diamino-8,8-dimethyl-6-oxo-5-phenyl-10-
(phenylamino)-5,6,7,8,9,10-hexahydrobenzo[b][1,8]-
naphthyridine-3-carbonitrile (3g). Yield 70%, mp
229–230°С (decomp.). IR spectrum, ν, cm–1: 3430,
3347 (NH2), 3217 (NH), 2196 (C≡N), 1620 (С=О). 1Н
NMR spectrum, δ, ppm: 0.76 s (3H, CH3)*, 0.79 s (3H,
CH3), 0.93 s (3H, CH3)*, 0.99 s (3H, CH3), 1.97 d (1H,
CH2, J 16.9 Hz)*, 2.11 d (1H, CH2, J 16.0 Hz), 2.21 d
(1H, CH2, J 14.0 Hz)*, 2.24 d (1H, CH2, J 16.0 Hz),
2.28 d (1H, CH2, J 18.0 Hz)*, 2.48 d (1H, CH2, J
17.9 Hz), 2.64 d (1H, CH2, J 17.9 Hz), 2.89 d (1H, CH2,
J 17.3 Hz)*, 5.16 s (1H, CH)*, 5.31 s (1H, CH), 5.80 s
2,4-Diamino-10-(dimethylamino)-8,8-dimethyl-6-
oxo-5-(3-chlorophenyl)-5,6,7,8,9,10-hexahydro-
benzo[b][1,8]naphthyridine-3-carbonitrile (3d).
Yield 80%, mp 251–252°С (decomp.). IR spectrum, ν,
cm–1: 3465, 3343, 3211 (NH2), 2196 (C≡N), 1625
1
(С=О). Н NMR spectrum, δ, ppm: 0.78 s (3H, CH3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 8 2017

SYNTHESIS OF FUSED DERIVATIVES OF 1,8-NAPHTHYRIDINE
1247
(2H, NH2)*, 6.11 s (2H, NH2), 6.16 s (2H, NH2)*, 6.29
s (2H, NH2), 6.56 d (2Н, С6Н5, J 7.9 Hz)*, 6.71 d (2Н,
С6Н5, J 7.7 Hz), 6.74 t (1Н, С6Н5, J 7.3 Hz)*, 6.81 t
(1Н, С6Н5, J 7.3 Hz), 7.08 t (1Н, С6Н5, J 7.3 Hz)*,
7.12–7.27 m (7Н, 2С6Н5), 7.12–7.27 m (4Н, 2С6Н5)*,
7.35 d (2Н, С6Н5, J 7.2 Hz)*, 8.21 s (1H, NH), 8.62 s
(1H, NH)*. Mass spectrum, m/z (Irel, %): 450 (55) [M]+,
373 (95) [M – 77]+, 358 (56) [M – 92]+, 282 (100) [M –
168]+. Found, %: С 71.88; H 5.90; N 18.78.
C27H26N6O. Calculated, %: C 71.98; H 5.82; N 18.65.
M 450.55.
6.98 d (2Н, С6Н4, J 8.1 Hz), 7.02 d (2Н, С6Н4, J
8.0 Hz)*, 7.13–7.19 m (2Н, С6Н5), 7.13–7.19 m (2Н,
С6Н5)*, 7.13–7.19 m (1Н, С6Н4), 7.23 d (1Н, С6Н4, J
8.0 Hz)*, 8.21 s (1H, NH), 8.61 s (1H, NH)*. Mass
spectrum, m/z (Irel, %): 464 (10) [M]+, 373 (43) [M –
91]+, 282 (67) [M – 182]+, 93 (100) [M – 371]+. Found,
%: С 72.56; H 5.99; N 18.23. C28H28N6O. Calculated,
%: C 72.39; H 6.08; N 18.09. M 464.57.
2,4-Diamino-8,8-dimethyl-5-(3-nitrophenyl)-6-
oxo-10-(phenylamino)-5,6,7,8,9,10-hexahydrobenzo-
[b][1,8]naphthyridine-3-carbonitrile (3j). Yield 87%,
mp 231–232°С (decomp.). IR spectrum, ν, cm–1: 3492,
3316 (NH2), 3238 (NH), 2198 (C≡N), 1660 (С=О). 1Н
NMR spectrum, δ, ppm: 0.75 s (3H, CH3)*, 0.77 s (3H,
CH3), 0.94 s (3H, CH3)*, 1.00 s (3H, CH3), 1.98 d (1H,
CH2, J 16.6 Hz)*, 2.10 d (1H, CH2, J 15.5 Hz), 2.24 d
(1H, CH2, J 16.0 Hz)*, 2.27 d (1H, CH2, J 16.0 Hz),
2.31 d (1H, CH2, J 17.8 Hz)*, 2.52 d (1H, CH2, J
17.8 Hz), 2.69 d (1H, CH2, J 18.0 Hz), 2.91 d (1H,
CH2, J 17.6 Hz)*, 5.40 s (1H, CH)*, 5.48 s (1H, CH),
5.92 s (2H, NH2)*, 6.20 s (2H, NH2), 6.39 s (2H, NH2)*,
6.47 c (2H, NH2), 6.59 d (2Н, С6Н5, J 7.7 Hz)*, 6.74–
6.80 m (1Н, С6Н5)*, 6.74–6.80 m (2Н, С6Н5), 6.84 t
(1Н, С6Н5, J 7.3 Hz), 7.15–7.20 m (2Н, С6Н5), 7.15–7.20
m (2Н, С6Н5)*, 7.52 t (1Н, С6Н4, J 7.9 Hz)*, 7.56 t
(1Н, С6Н4, J 7.9 Hz), 7.75 d.t (1Н, С6Н4, J 7.8, 0.8 Hz)*,
7.80 d.t (1Н, С6Н4, J 7.8, 0.8 Hz), 7.99 d.d.d (1Н,
С6Н4, J 8.0, 2.3, 0.8 Hz)*, 8.04 d.d.d (1Н, С6Н4, J 8.2,
2.3, 0.8 Hz), 8.17 t (1Н, С6Н4, J 2.0 Hz), 8.26 s (1H,
NH), 8.33 t (1Н, С6Н4, J 2.0 Hz)*, 8.66 s (1Н, NH)*.
Mass spectrum, m/z (Irel, %): 495 (17) [M]+, 373 (74)
[M – 122]+, 93 (100) [M – 402]+. Found, %: С 65.30;
H 5.00; N 19.87. C27H25N7O3. Calculated, %: C 65.44;
H 5.09; N 19.79. M 495.54.
2,4-Diamino-8,8-dimethyl-6-oxo-10-(phenyl-
amino)-5-(2-chlorophenyl)-5,6,7,8,9,10-hexahydro-
benzo[b][1,8]naphthyridine-3-carbonitrile (3h).
Yield 90%, mp 225–226°С (decomp.). IR spectrum, ν,
cm–1: 3430, 3347 (NH2), 3217 (NH), 2196 (C≡N),
1
1620 (С=О). Н NMR spectrum, δ, ppm: 0.82 s (3H,
CH3)*, 0.86 s (3H, CH3), 0.95 s (3H, CH3)*, 1.00 s
(3H, CH3), 1.93 d (1H, CH2, J 16.1 Hz)*, 2.01 d (1H,
CH2, J 17.2 Hz), 2.19 d (1H, CH2, J 16.1 Hz)*, 2.21 d
(1H, CH2, J 16.1 Hz), 2.31 d (1H, CH2, J 17.7 Hz)*,
2.59 d (1H, CH2, J 16.9 Hz), 2.74 d (1H, CH2, J 18.1 Hz),
2.93 d (1H, CH2, J 17.0 Hz)*, 5.25 s (1H, CH), 5.29 s
(1H, CH)*, 5.82 s (2H, NH2), 5.82 s (2H, NH2)*, 5.92
s (2H, NH2)*, 6.17 s (2H, NH2), 6.62 d (2Н, С6Н5, J
7.7 Hz)*, 6.76 t (1Н, С6Н5, J 7.3 Hz)*, 6.89 t (1Н,
С6Н5, J 7.3 Hz), 6.95 d (2Н, С6Н5, J 7.7 Hz), 7.13–
7.36 m (2Н, С6Н5)*, 7.13–7.36 m (2Н, С6Н5), 7.13–
7.36 m (3Н, С6Н4), 7.13–7.36 m (3Н, С6Н4)*, 7.47 d.d
(1Н, С6Н4, J 7.8, 1.6 Hz)*, 7.54 d (1Н, С6Н4, J
7.3 Hz), 8.19 s (1H, NH), 8.59 s (1H, NH)*. Mass
spectrum, m/z (Irel, %): 484 (5) [M]+. Found, %: С
66.74; H 5.09; N 17.47. C27H25ClN6O. Calculated, %:
C 66.87; H 5.20; N 17.33. M 484.99.
2,4-Diamino-8,8-dimethyl-6-oxo-5-(p-tolyl)-10-
(phenylamino)-5,6,7,8,9,10-hexahydrobenzo[b][1,8]-
naphthyridine-3-carbonitrile (3i). Yield 70%, mp
234–235°С (decomp.). IR spectrum, ν, cm–1: 3494,
3302 (NH2), 3234 (NH), 2200 (C≡N), 1660 (С=О). 1Н
NMR spectrum, δ, ppm: 0.77 s (3H, CH3)*, 0.80 s (3H,
CH3), 0.93 s (3H, CH3)*, 0.99 s (3H, CH3), 1.96 d (1H,
CH2, J 15.6 Hz)*, 2.09 d (1H, CH2, J 15.4 Hz), 2.20 s
(3H, CH3)*, 2.23 s (3H, CH3), 2.24 d (1H, CH2, J
15.9 Hz), 2.28 d (1H, CH2, J 18.2 Hz)*, 2.48 d (1H,
CH2, J 18.0 Hz), 2.52 d (1H, CH2, J 17.8 Hz)*, 2.64 d
(1H, CH2, J 18.0 Hz), 2.88 d (1H, CH2, J 17.8 Hz)*,
5.10 s (1H, CH)*, 5.24 s (1H, CH), 5.79 s (2H, NH2)*,
6.10 s (2H, NH2), 6.11 s (2H, NH2)*, 6.22 s (2H, NH2),
6.56 d (2Н, С6Н5, J 7.8 Hz)*, 6.74–6.76 m (2Н, С6Н5),
6.74–6.76 m (1Н, С6Н5)*, 6.82 t (1Н, С6Н5, J 7.3 Hz),
ACKNOWLEDGMENTS
The study was carried out under the financial
support of the Russian Foundation for Basic Research
(grant no. 16-33-00909 mol_а).
REFERENCES
1. Zhu, S., Zhang, Q., Gudise, C., Meng, L., Wei, L.,
Smith, E., and Kong, Y., Bioorg. Med. Chem. Lett.,
2007, vol. 17, p. 6101.
2. Peraman, R., Varma, R.V., and Reddy, Y.P., Bioorg.
Med. Chem. Lett., 2015, vol. 25, p. 4314.
3. Huang, X.G., Zhang, A.Q., Chen, D.L., Jia, Z.H., and
Li, X.S., Bioorg. Med. Chem. Lett., 2010, vol. 20,
p. 2859.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 8 2017

ALEKSEEVA et al.
1248
4. Srivastava, S.K., Jaggi, M., Singh, A.T., Madan, A.,
Rani, N., Vishnoi, M., Agarwal, S.K., Mukherjee, R.,
and Burman, A.C., Bioorg. Med. Chem. Lett., 2007,
vol. 17, p. 6660.
5. Roma, G., Di Braccio, M., Grossi, G., Piras, D.,
Ballabeni, V., Tognolini, M., Bertoni, S., and Barocelli, E.,
Eur. J. Med. Chem., 2010, vol. 45, p. 352.
16. Tao, J., Song, P., Sato, Y., Nishizawa, S., Teramae, N.,
Tonga, A., and Xiang, Y., Chem. Commun., 2015,
vol. 51, p. 929.
17. Li, H.J., Fu, W.F., Li, L., Gan, X., Mu, W.H.,
Chen, W.Q., Duan, X.M., and Song, H.B., Org. Lett.,
2010, vol. 12, p. 2924.
18. Ghosh, K., Sen, T., and Fröhlich, R., Tetrahedron Lett.,
6. Di Braccio, M., Grossi, G., Roma, G.D., Piras, D.,
Mattioli, F., and Gosmar, M., Eur. J. Med. Chem., 2008,
vol. 43, p. 584.
2007, vol. 48, p. 2935.
19. Nammalwar, B., Murie, M., Fortenberry, C., and
Bunce, R.A., Tetrahedron Lett., 2014, vol. 55, p. 3181.
7. Nam, T.G., Rector, C.L., Kim, H.Y., Sonnen, A.F.P.,
Meyer, R., Nau, W.M., Atkinson, J., Rintoul, J.,
Pratt, D.A., and Porter, N.A., J. Am. Chem. Soc., 2007,
vol. 129, p. 10211.
8. Rudys, S., Ríos-Luci, C., Pérez-Roth, E., Cikotiene, I.,
and Padrón, J.M., Bioorg. Med. Chem. Lett., 2010,
vol. 20, p. 1504.
9. Manera, C., Saccomanni, G., Malfitano, A.M., Bertini, S.,
Castelli, F., Laezza, C., Ligresti, A., Lucchesi, V.,
Tuccinardi, T., Rizzolio, F., Bifulco, M., Di Marzo, V.,
Giordano, A., Macchia, M., and Martinelli, A., Eur.
J. Med. Chem., 2012, vol. 52, p. 284.
10. Madaan, A., Kumar, V., Verma, R., Singh, A.T.,
Jain, S.K., and Jaggi, M., Int. Immunopharm., 2013,
vol. 15, p. 606.
20. Li, B., Nguyen, S., Huang, J., Wang, G., Wei, H.,
Pereshivko, O.P., and Peshkov, V.A., Tetrahedron Lett.,
2016, vol. 57, p. 1958.
21. Litvinov, V.P., Russ. Chem. Rev., 2004, vol. 73, p. 637.
doi 10.1070/RC2004v073n07ABEH000856
22. Anderson, D.R., Hegde, S., Reinhard, E., Gomez, L.,
Vernier, W.F., Lee, L., Liu, S., Sambandam, A.,
Snider, P.A., and Masih, L., Bioorg. Med. Chem. Lett.,
2005, vol. 15, p. 1587.
23. Ibrahim, M.A. and El-Gohary, N.M., J. Heterocycl.
Chem., 2016, vol. 53, p. 859.
24. Naidu, P.S., Kolita, S., Majumder, S., and Bhuyan, P.J.,
Synthesis, 2015, vol. 47, p. 701.
25. Sun, F., Zhu, F., Shao, X., and Li, Z., Synlett., 2015,
vol. 26, p. 2306.
11. Manera, C., Malfitano, A.M., Parkkari, T., Lucchesi, V.,
Carpi, S., Fogli, S., Bertini, S., Laezza, C., Ligresti, A.,
Saccomanni, G., Savinainen, J.R., Ciaglia, E.,
Pisanti, S., Gazzerro, P., Di Marzo, V., Nieri, P.,
Macchia, M., and Bifulco, M., Eur. J. Med. Chem.,
2015, vol. 97, p. 10.
26. Shaabani, A., Hooshmand, S.E., and Tabatabaei, A.T.,
Tetrahedron Lett., 2015, vol. 57, p. 351.
27. Bardasov, I.N., Alekseeva, A.Yu., Malyshkina, N.L.,
Ershov, O.V., and Grishanov, D.A., Russ. J. Org. Chem.,
2016, vol. 52, p. 830. doi 10.1134/S1070428016060117
12. Kumar, V., Jaggi, M., Singh, A.T., Madaan, A., Sanna, V.,
Singh, P., Sharma, P.K., Irchhaiya, R., and Burman,
A.C., Eur. J. Med. Chem., 2009, vol. 44, p. 3356.
28. Bardasov, I.N., Alekseeva, A.U., Mihailov, D.L.,
Ershov, O.V., and Grishanov, D.A., Tetrahedron Lett.,
2015, vol. 56, p. 1830.
13. Kaveevivitchai, N., Chitta, R., Zong, R.F.,
El Ojaimi, M., and Thummel, R.P., J. Am. Chem. Soc.,
2012, vol. 134, p. 10721.
29. Alekseeva, A.Yu., Mikhailov, D.L., Bardasov, I.N.,
Timrukova, D.V., and Ershov, O.V., Russ. J. Org.
Chem., 2016, vol. 52, p. 1463. doi 10.1134/
S1070428016100158
14. Daw, P., Ghatak, T., Doucet, H., and Bera, J.K.,
Organometallics, 2013, vol. 32, p. 4306.
30. Alekseeva, A.Yu., Mikhailov, D.L., Bardasov, I.N.,
Ershov, O.V., Nasakin, O.E., and Lyshchikov, A.N.,
Russ. J. Org. Chem., 2014, vol. 50, p. 244. doi 10.1134/
S1070428014020171
15. Daw, P., Petakamsetty, R., Sarbajna, A., Laha, S.,
Ramapanicker, R., and Bera, J.K., J. Am. Chem. Soc.,
2014, vol. 136, p. 13987.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 8 2017