One-pot synthesis of annulated 1,8-naphthyridines

Article abstract of DOI:10.1515/hc-2017-0068

Annulated 1,8-naphthyridines were synthesized by one-pot reaction of aromatic aldehyde, malononitrile dimer and enehydrazinoketone.

Full text of DOI:10.1515/hc-2017-0068

Heterocycl. Commun. 2017; aop
Ivan N. Bardasov*, Anastasiya U. Alekseeva, Nataliya N. Yaschenko, Svetlana V. Zhitar
and Anatoliy N. Lyshchikov
One-pot synthesis of annulated 1,8-naphthyridines
DOI 10.1515/hc-2017-0068
method to obtain 2,4,10-triamino-6-oxo-5-aryl-5,6,7,8,9,10-
hexahydrobenzo[b][1,8]naphthyridine-3-carbonitrile
derivatives 2a–j by the reaction of arylmethylidene deriv-
atives of malononitrile dimer 1 and enehydrazinoketones
(Scheme 1).
Received April 7, 2017; accepted June 17, 2017
Abstract: Annulated 1,8-naphthyridines were synthesized
by one-pot reaction of aromatic aldehyde, malononitrile
dimer and enehydrazinoketone.
The presence of the nucleophilic and electrophilic
Keywords: cyano compounds; heterocycles; Knoevenagel centers in the Michael adduct A permits intramolecular
condensation; Michael addition; 1,8-naphthyridines.
heterocyclizations, leading to the formation of 1,8-naph-
thyridine 2. Thus, following the Michael addition, the first
pyridine is formed by nucleophilic attack of the enehy-
drazine nitrogen atom to the proximal cyano group. The
resulting amine B is then captured by the cyano group of
the dicyanomethylene moiety to give compound 2.
Introduction
The naphthyridine moiety is part of many biologically
active compounds possessing antimalarial [1], antibac-
terial [2, 3], anti-inflammatory [4–6], antiproliferative
[7, 8], anticancer [9–11] and antioxidant activity [12]. In
addition, naphthyridine derivatives are used as catalysts
[13–15], fluorescent dyes [16] and sensors [17, 18]. Gener-
ally, 1,8-naphthyridines are synthesized by the Friedländer
reaction and its modifications using pyridine derivatives
as starting materials [19–21]. In recent years, multicompo-
nent reactions have gained significant attention and have
been used for the synthesis of polyfunctional compounds
[22–27]. In the current work, naphthyridines were synthe-
sized from an aromatic aldehyde, the malononitrile dimer
and a 3-hydrazinylcyclohex-2-en-1-one through a sequen-
tial Michael reaction followed by two sequential heterocy-
clizations involving amine additions to nitriles.
The most effective way of constructing condensed het-
erocycles from simple substrates is the use of a multicom-
ponent reaction. This strategy lowers the number of steps,
as well as the amount of chemicals, thereby reducing the
energy consumption of the process and increasing yield
of the product. In this work, a three-component system
comprising of aromatic aldehyde, malononitrile dimer
and enehydrazinoketone was used to carry out a tandem
Knoevenagel–Michael reaction that led to 1,4-dihydro-
1,8-naphthyridines 2 in 65%–90% yields.
The structures of compounds 2a–j were confirmed by
1
spectral methods. H NMR spectra taken at 27°C indicate
that compounds 2g–j exist as diastereomers because of
the slow rate of inversion of the nitrogen atom of the dihy-
dropyridine ring (Figure 1). To confirm this analysis, the 1H
NMR spectrum of 2g was acquired at 70°C. As expected, a
simpler spectrum due to averaging of signals is observed
at the higher temperature.
Results and discussion
Previously, we have described a new method for obtain-
ing 5H-chromeno[2,3-b]pyridines and 1,4-dihydro-
1,8-naphthyridines by using double heteroannulation
reactions of Michael adducts (DHARMA) strategy [28–31].
As part of our continued research, we have extended our
Conclusion
A one-pot synthesis scheme of new 1,8-naphthyridines
involves a double heteroannulation reaction.
Experimental
Progress of all reactions and purity of compounds were analyzed by
TLC on Silufol UV-254 plates (development by UV irradiation, expo-
sure to iodine vapor or thermal decomposition). IR spectra were
recorded on an FT-IR spectrophotometer FSM-1202 using mulls in
*Corresponding author: Ivan N. Bardasov, Ulyanov Chuvash State
University, Moskovsky pr. 15, Cheboksary 428015, Russia,
e-mail: bardasov.chem@mail.ru
Anastasiya U. Alekseeva, Nataliya N. Yaschenko, Svetlana V. Zhitar
and Anatoliy N. Lyshchikov: Ulyanov Chuvash State University,
Moskovsky pr. 15, Cheboksary 428015, Russia
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ꢀꢀꢀꢁ
2ꢀ
ꢀI.N. Bardasov et al.: Synthesis of annulated 1,8-naphthyridines
O
R
HN
CN
R
NH2
O
N
NH2
R′′
R′
B
CN
+
Ar
Ar
H
–H2O
CN CN
NC
CN
1
NH2
O
Ar
O
Ar
NH2
Ar
O
NH2
CN
CN
N
CN
R
R
C
CN
R
C
R
NH
N
N
NH2
N
N
N
N
N
NH2
R
R
R′
R′′
R′′
R′
R′′
R′
2a–j
A
B
a: Ar = Ph; R = R′ = R′′ = Me
f: Ar = 4-F-C6H4; R = H; R′ = R′′ = Me
g: Ar = Ph; R = Me; R′ = H; R′′ = Ph
b: Ar = 4-F-C6H6; R = R′ = R′′ = Me
c: Ar = 4-CH3-C6H4; R = R′ = R′′ = Me
d: Ar = 3-Cl-C6H4; R = R′ = R′′ = Me
h: Ar = 2-Cl-C6H4; R = Me; R′ = H; R′′ = Ph
i: Ar = 4-Me-C6H4; R = Me; R′ = H; R′′ = Ph
j: Ar = 3-NO2-C6H4; R = Me; R′ = H; R′′ = Ph
e: Ar = Ph; R = H; R′ = R′′ = Me
Scheme 1ꢀSynthesis of 2,4,10-triamino-6-oxo-5-aryl-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-carbonitrile derivatives 2a–j.
27°C
122
142
10
114
0
133
1
8
52
3
44
0
41
3
40
3
31
2
16
15
1
1
8.9
1
8.5
1
5.1
*
4.2
*
4.2
*
4.4
*
*
Water
DMSO-d5
TMS
ppm
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
7.1
*
16
1
20
1
23
0
41
3
61
4
66
0
72
5
142
11
122
122
1
70°C
9
Figure 1ꢀ1H NMR spectra of compound 2g at 27°C and at 70°C.
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ꢀ3
mineral oil. 1H NMR spectra were registered on a spectrometer Bruker
DRX-500 (500.13 MHz) in DMSO-d6 using TMS as the internal stand-
ard. Mass spectra (EI, 70 eV) were obtained using a Finnigan MAT
INCOS-50 instrument. The signals of a second isomer in NMR spectra
of compounds 2g–j are indicated by an asterisk.
1
(0.35 g) as a pale yellow solid; mp 251–252°C (dec); H NMR: δ 0.78
(s, 3H, CH3), 1.02 (s, 3H, CH3), 1.98 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.18 (d, 1H,
Jꢁ=ꢁ16 Hz, CH2), 2.48 (d, 1H, Jꢁ=ꢁ18 Hz, CH2), 2.92 (d, 1H, Jꢁ=ꢁ18 Hz, CH2),
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, Jꢁ=ꢁ8 Hz, C6H4),
7.37 (t, 1H, Jꢁ=ꢁ2 Hz, C6H4); IR: 3465, 3343, 3211 (NH2), 2196 (CN), 1625 cm−1
+
+
(C=O); MS: m/z (%) 436 [M] (3), 393 [M–43] (20). Anal. Calcd for
C23H25ClN6O: C, 63.22; H, 5.77; N, 19.23. Found: C, 63.09; H, 5.86; N, 19.37.
General procedure for the synthesis of a series of 2,4-di-
amino-6-oxo-5-aryl-5,6,7,8,9,10-hexahydrobenzo[b][1,8]
naphthyridine-3-carbonitriles 2
2,4-Diamino-10-(dimethylamino)-6-oxo-5-phenyl-5,6,7,8,9,10-
hexahydrobenzo[b][1,8]naphthyridine-3-carbonitrile (2e)ꢀThis
compound was obtained in 65% yield (0.24 g) as a pale yellow solid;
A solution of enehydrazinoketone (10 mmol) and piperidine in EtOH
(10 mL) was added to a mixture of aromatic aldehyde (10 mmol) and
malononitrile dimer (10 mmol) in EtOH (10 mL). The mixture was
stirred at 40–50°C for 30 min and the resulting precipitate was fil-
tered and washed with i-PrOH. Crude products were crystallized from
a mixture of dioxane and acetonitrile.
1
mp 239–240°C (dec); H NMR: δ 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, 1H, CH), 6.08 (s, 2H, NH2), 6.24 (s, 2H, NH2), 7.06 (t, 1H,
Jꢁ=ꢁ7 Hz, C6H5), 7.14–7.25 (m, 4H, C6H5); IR: 3474, 3360 (NH2), 2201 (CN),
1650 cm−1 (C=O); MS: m/z (%) 374 [M] (5), 330 [M–44] (16), 297 [M–
+
+
+
+
77] (25), 254 [M–120] (100). Anal. Calcd for C21H22N6O: C, 67.36; H,
5.92; N, 22.44. Found: C, 67.50; H, 5.83; N, 22.35.
2,4-Diamino-10-(dimethylamino)-8,8-dimethyl-6-oxo-5-phenyl-
5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-carboni-
trile (2a)ꢀThis compound was obtained in 70% yield (0.28 g) as a
2,4-Diamino-10-(dimethylamino)-5-(4-fluorophenyl)-6-oxo-
5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-carboni-
trile (2f)ꢀThis compound was obtained in 68% yield (0.27 g) as a
1
pale yellow solid; mp 237–238°C (dec); H NMR: δ 0.78 (s, 3H, CH3),
1.02 (s, 3H, CH3), 1.96 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.17 (d, 1H, Jꢁ=ꢁ16 Hz, CH2),
2.48 (d, 1H, Jꢁ=ꢁ17 Hz, CH2), 2.92 (d, 1H, Jꢁ=ꢁ17 Hz, CH2), 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, Jꢁ=ꢁ7 Hz, C6H5), 7.16 (t, 2H, Jꢁ=ꢁ7 Hz, C6H5), 7.23
(d, 2H, Jꢁ=ꢁ7 Hz, C6H5); IR: 3456, 3427, 3337 (NH2), 2190 (CN), 1630 cm−1
1
pale yellow solid; mp 237–238°C (dec); H NMR: δ 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, 1H, CH), 6.13 (s, 2H, NH2), 6.24 (s, 2H, NH2),
6.98 (t, 2H, Jꢁ=ꢁ9 Hz, C6H4), 7.23 (m, 4H, C6H4); IR: 3460, 3340 (NH2),
2204 (CN), 1656 cm−1 (C=O); MS: m/z (%) 392 [M] (1), 348 [M–44]
+
+
+
+
+
(C=O); MS: m/z (%) 402 [M] (10), 358 [M–44] (25), 325 [M–77] (38),
+
(4), 254 [M–138] (43). Anal. Calcd for C21H21FN6O: C, 64.27; H, 5.39; N,
21.42. Found: C, 64.38; H, 5.28; N, 21.30.
+
281 [M–120] (100). Anal. Calcd for C23H26N6O: C, 68.63; H, 6.51; N,
20.88. Found: C, 68.77; H, 6.42; N, 20.72.
2,4-Diamino-8,8-dimethyl-6-oxo-5-phenyl-10-(phenylamino)-
5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-carboni-
trile (2g)ꢀThis compound was obtained in 70% yield (0.32 g) as a
2,4-Diamino-10-(dimethylamino)-5-(4-fluorophenyl)-8,8-dime-
thyl-6-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-
3-carbonitrile (2b)ꢀThis compound was obtained in 76% yield
1
white solid; mp 229–230°C (dec); H NMR: δ 0.76 (s, 3H, CH3)*, 0.79
1
(0.32 g) as a white solid; mp 254–255°C (dec); H NMR: δ 0.78 (s, 3H,
(s, 3H, CH3), 0.93 (s, 3H, CH3)*, 0.99 (s, 3H, CH3), 1.97 (d, 1H, Jꢁ=ꢁ17 Hz,
CH2)*, 2.11 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.21 (d, 1H, Jꢁ=ꢁ14 Hz, CH2)*, 2.24 (d,
1H, Jꢁ=ꢁ16 Hz, CH2), 2.28 (d, 1H, Jꢁ=ꢁ18.0 Hz, CH2)*, 2.48 (d, 1H, Jꢁ=ꢁ18 Hz,
CH2), 2.64 (d, 1H, Jꢁ=ꢁ18 Hz, CH2), 2.89 (d, 1H, Jꢁ=ꢁ17 Hz, CH2)*, 5.16 (s,
1H, CH)*, 5.31 (s, 1H, CH), 5.80 (s, 2H, NH2)*, 6.11 (s, 2H, NH2), 6.16
(s, 2H, NH2)*, 6.29 (s, 2H, NH2), 6.56 (d, 2H, Jꢁ=ꢁ8 Hz, C6H5)*, 6.71 (d,
2H, Jꢁ=ꢁ8 Hz, C6H5), 6.74 (t, 1H, Jꢁ=ꢁ7 Hz, C6H5)*, 6.81 (t, 1H, Jꢁ=ꢁ7 Hz,
C6H5), 7.08 (t, 1H, Jꢁ=ꢁ7 Hz, C6H5)*, 7.12–7.27 (m, 7H, 2C6H5), 7.12–7.27 (m,
4H, 2C6H5)*, 7.35 (d, 2H, Jꢁ=ꢁ7 Hz, C6H5)*, 8.21 (s, 1H, NH), 8.62 (s, 1H,
NH)*; IR: 3430, 3347 (NH2), 3217 (NH), 2196 (CN), 1620 cm−1 (C=O); MS:
CH3), 1.02 (s, 3H, CH3), 1.96 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.17 (d, 1H, Jꢁ=ꢁ16 Hz,
CH2), 2.48 (d, 1H, Jꢁ=ꢁ17 Hz, CH2), 2.92 (d, 1H, Jꢁ=ꢁ17 Hz, CH2), 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, Jꢁ=ꢁ9 Hz, C6H4), 7.25 (dd, 2H, Jꢁ=ꢁ9 Hz, Jꢁ=ꢁ6 Hz,
C6H4); IR: 3459, 3320 (NH2), 2190 (CN), 1680 cm−1 (C=O); MS: m/z (%)
420 [M] (18), 377 [M–43] (100), 325 [M–95] (59). Anal. Calcd for
C23H25FN6O: C, 65.70; H, 5.99; N, 19.99. Found: C, 65.54; H, 5.87; N, 20.12.
+
+
+
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-car-
bonitrile (2c)ꢀThis compound was obtained in 67% yield (0.28 g) as
a pale yellow solid; mp 265–266°C (dec); 1H NMR: δ 0.79 (s, 3H, CH3),
1.02 (s, 3H, CH3), 1.95 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.16 (d, 1H, Jꢁ=ꢁ16 Hz, CH2),
2.18 (s, 3H, CH3), 2.47 (d, 1H, Jꢁ=ꢁ18 Hz, CH2), 2.91 (d, 1H, Jꢁ=ꢁ18 Hz, CH2),
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, Jꢁ=ꢁ8 Hz, C6H4), 7.11 (d, 2H, Jꢁ=ꢁ8 Hz,
C6H4); IR: 3430, 3333, 3239 (NH2), 2187 (CN), 1641 cm−1 (C=O); MS: m/z
+
+
+
+
m/z (%) 450 [M] (55), 373 [M–77] (95), 358 [M–92] (56), 282 [M–168]
(100). Anal. Calcd for C27H26N6O: C, 71.98; H, 5.82; N, 18.65. Found: C,
71.88; H, 5.90; N, 18.78.
2,4-Diamino-5-(2-chlorophenyl)-8,8-dimethyl-6-oxo-10-
(phenylamino)-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyr-
idine-3-carbonitrile (2h)ꢀThis compound was obtained in 90%
yield (0.44 g) as a white solid; mp 225–226°C (dec); 1H NMR: δ 0.82 (s,
3H, CH3)*, 0.86 (s, 3H, CH3), 0.95 (s, 3H, CH3)*, 1.00 (s, 3H, CH3), 1.93
(d, 1H, Jꢁ=ꢁ16 Hz, CH2)*, 2.01 (d, 1H, Jꢁ=ꢁ17 Hz, CH2), 2.19 (d, 1H, Jꢁ=ꢁ16 Hz,
CH2)*, 2.21 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.31 (d, 1H, Jꢁ=ꢁ18 Hz, CH2)*, 2.59 (d,
1H, Jꢁ=ꢁ17 Hz, CH2), 2.74 (d, 1H, Jꢁ=ꢁ18 Hz, CH2), 2.93 (d, 1H, Jꢁ=ꢁ17 Hz,
CH2)*, 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, 2H, Jꢁ=ꢁ8 Hz,
C6H5)*, 6.76 (t, 1H, Jꢁ=ꢁ7 Hz, C6H5)*, 6.89 (t, 1H, Jꢁ=ꢁ7 Hz, C6H5), 6.95 (d,
+
+
+
+
(%) 416 [M] (20), 373 [M–43] (90), 325 [M–91] (50), 282 [M–134]
(100). Anal. Calcd for C24H28N6O: C, 69.21; H, 6.78; N, 20.18. Found: C,
69.08; H, 6.79; N, 20.30.
2,4-Diamino-5-(3-chlorophenyl)-10-(dimethylamino)-8,8-dime-
thyl-6-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-
3-carbonitrile (2d)ꢀThis compound was obtained in 80% yield
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2H, Jꢁ=ꢁ8 Hz, C6H5), 7.13–7.36 (m, 2H, C6H5)*, 7.13–7.36 (m, 2H, C6H5),
7.13–7.36 (m, 3H, C6H4), 7.13–7.36 (m, 3H, C6H4)*, 7.47 (dd, 1H, Jꢁ=ꢁ8 Hz,
Jꢁ=ꢁ1.6 Hz, C6H4)*, 7.54 (d, 1H, Jꢁ=ꢁ7 Hz, C6H4), 8.19 (s, 1H, NH), 8.59 (s,
1H, NH)*; IR: 3383, 3312 (NH2), 3205 (NH), 2190 (CN), 1630 (C=O); MS:
+
m/z (%) 484 [M] (5). Anal. Calcd for C27H25ClN6O: C, 66.87; H, 5.20; N,
17.33. Found: C, 66.74; H, 5.09; N, 17.47.
2,4-Diamino-8,8-dimethyl-6-oxo-10-(phenylamino)-5-(p-tolyl)-
5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-carboni-
trile (2i)ꢀThis compound was obtained in 70% yield (0.33 g) as a
1
pale yellow solid; mp 234–235°C (dec); H NMR: δ 0.77 (s, 3H, CH3)*,
0.80 (s, 3H, CH3), 0.93 (s, 3H, CH3)*, 0.99 (s, 3H, CH3), 1.96 (d, 1H,
Jꢁ=ꢁ16 Hz, CH2)*, 2.09 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.20 (s, 3H, CH3)*, 2.23
(s, 3H, CH3), 2.24 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.28 (d, 1H, Jꢁ=ꢁ18 Hz, CH2)*,
2.48 (d, 1H, Jꢁ=ꢁ18 Hz, CH2), 2.52 (d, 1H, Jꢁ=ꢁ18 Hz, CH2)*, 2.64 (d, 1H,
Jꢁ=ꢁ18 Hz, CH2), 2.88 (d, 1H, Jꢁ=ꢁ18 Hz, CH2)*, 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, 2H, Jꢁ=ꢁ8 Hz, C6H5)*, 6.74–6.76 (m, 2H, C6H5), 6.74–
6.76 (m, 1H, C6H5)*, 6.82 (t, 1H, Jꢁ=ꢁ7 Hz, C6H5), 6.98 (d, 2H, Jꢁ=ꢁ8 Hz,
C6H4), 7.02 (d, 2H, Jꢁ=ꢁ8 Hz, C6H4)*, 7.13–7.19 (m, 2H, C6H5), 7.13–7.19 (m,
2H, C6H5)*, 7.13–7.19 (m, 1H, C6H4), 7.23 (d, 1H, Jꢁ=ꢁ8 Hz, C6H4)*, 8.21
(s, 1H, NH), 8.61 (s, 1H, NH)*; IR: 3494, 3302 (NH2), 3234 (NH), 2200
+
+
(CN), 1660 cm−1 (C=O); MS: m/z (%) 464 [M] (10), 373 [M–91] (43), 282
+
+
[M–182] (67), 93 [M–371] (100). Anal. Calcd for C28H28N6O: C, 72.39; H,
6.08; N, 18.09. Found: C, 72.56; H, 5.99; N, 18.23.
[7] Rudys, S.; Ríos-Luci, C.; Pérez-Roth, E.; Cikotiene, I.; Padrón,
J. M. Antiproliferative activity of novel benzo[b][1,6]naphthyri-
dines in human solid tumor cell lines. Bioorg. Med. Chem. Lett.
2010, 20, 1504–1506.
2,4-Diamino-8,8-dimethyl-5-(3-nitrophenyl)-6-oxo-10-
(phenylamino)-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthy-
ridine-3-carbonitrile (2j)ꢀThis compound was obtained in 87%
1
yield (0.43 g) as a pale yellow solid; mp 231–232°C (dec); H NMR: δ
[8] 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.; Martinelli, A. Rational design, synthesis and
anti-proliferative properties of new CB2 selective cannabinoid
receptor ligands: An investigation of the 1,8-naphthyridin-
2(1H)-one scaffold. Eur. J. Med. Chem. 2012, 52, 284–294.
[9] Madaan, A.; Kumar, V.; Verma, R.; Singh, A. T.; Jain, S. K.;
Jaggi, M. Anti-inflammatory activity of a naphthyridine
derivative (7-chloro-6-fluoro-N-(2-hydroxy-3-oxo-1-phenyl-3-
(phenylamino)propyl)-4-oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-
1,8-naphthyridine-3-carboxamide) possessing in vitro
anticancer potential. Int. Immunopharmacol. 2013, 15,
606–613.
[10] Manera, C.; Malfitano, A. M.; Parkkari, T.; Lucchesi, V.; Carpi,
S.; Fogli, S.; Bertini, S.; Laezza, C.; Ligresti, A.; Saccomanni,
G.; et al. New quinolone- and 1,8-naphthyridine-3-carboxam-
ides as selective CB2 receptor agonists with anticancer and
immuno–modulatory activity. Eur. J. Med. Chem. 2015, 97,
10–18.
[11] Kumar, V.; Jaggi, M.; Singh, A. T.; Madaan, A.; Sanna,
V.; Singh, P.; Sharma, P. K.; Irchhaiya, R.; Burman, A. C.
1,8-Naphthyridine-3-carboxamide derivatives with anticancer
and anti-inflammatory activity. Eur. J. Med. Chem. 2009, 44,
3356–3362.
[12] 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.; Porter, N. A.
Tetrahydro-1,8-naphthyridinol analogues of α-tocopherol as
antioxidants in lipid membranes and low-density lipoproteins.
J. Am. Chem. Soc. 2007, 129, 10211–10219.
0.75 (s, 3H, CH3)*, 0.77 (s, 3H, CH3), 0.94 (s, 3H, CH3)*, 1.00 (s, 3H,
CH3), 1.98 (d, 1H, Jꢁ=ꢁ16.6 Hz, CH2)*, 2.10 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.24 (d,
1H, Jꢁ=ꢁ16 Hz, CH2)*, 2.27 (d, 1H, Jꢁ=ꢁ16 Hz, CH2), 2.31 (d, 1H, Jꢁ=ꢁ18 Hz,
CH2)*, 2.52 (d, 1H, Jꢁ=ꢁ18 Hz, CH2), 2.69 (d, 1H, Jꢁ=ꢁ18 Hz, CH2), 2.91 (d,
1H, Jꢁ=ꢁ18 Hz, CH2)*, 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 (s, 2H, NH2), 6.59 (d,
2H, Jꢁ=ꢁ8 Hz, C6H5)*, 6.74–6.80 (m, 1H, C6H5)*, 6.74–6.80 (m, 2H, C6H5),
6.84 (t, 1H, Jꢁ=ꢁ7 Hz, C6H5), 7.15–7.20 (m, 2H, C6H5), 7.15–7.20 (m, 2H,
C6H5)*, 7.52 (t, 1H, Jꢁ=ꢁ8 Hz, C6H4)*, 7.56 (t, 1H, Jꢁ=ꢁ8 Hz, C6H4), 7.75 (dt,
1H, Jꢁ=ꢁ8 Hz, Jꢁ=ꢁ1 Hz, C6H4)*, 7.80 (dt, 1H, Jꢁ=ꢁ8 Hz, Jꢁ=ꢁ1 Hz, C6H4), 7.99
(ddd, 1H, Jꢁ=ꢁ8 Hz, Jꢁ=ꢁ2 Hz, Jꢁ=ꢁ1 Hz, C6H4)*, 8.04 (ddd, 1H, Jꢁ=ꢁ8 Hz,
Jꢁ=ꢁ2 Hz, Jꢁ=ꢁ1 Hz, C6H4), 8.17 (t, 1H, Jꢁ=ꢁ2 Hz, C6H4), 8.26 (s, 1H, NH),
8.33 (t, 1H, Jꢁ=ꢁ2 Hz, C6H4)*, 8.66 (s, 1H, NH)*; IR: 3492, 3316 (NH2),
+
3238 (NH), 2198 (CN), 1660 cm−1 (C=O); MS: m/z (%) 495 [M] (17), 373
+
+
[M–122] (74), 93 [M–402] (100). Anal. Calcd for C27H25N7O3: C, 65.44;
H, 5.09; N, 19.79. Found: C, 65.30; H, 5.00; N, 19.87.
Acknowledgment: This work was supported by a stipend
of the President of the Russian Federation for young scien-
tists and graduate students (SP-2141.2016.4).
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I.N. Bardasov et al.: Synthesis of annulated 1,8-naphthyridinesꢀ
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