One-stage synthesis of highly functionalized n-substituted 1,8-naphthyridines

Full text of DOI:10.1134/S1070428013110286

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 11, pp. 1715−1717. © Pleiades Publishing, Ltd., 2013.
Original English Text © A.Yu. Alekseeva, D.L. Mikhailov, I.N. Bardasov, O.V. Ershov, O.E. Nasakin, 2013, published in Zhurnal Organicheskoi Khimii, 2013,
Vol. 49, No. 11, pp. 1731−1732.
SHORT
COMMUNICATIONS
One-Stage Synthesis of Highly Functionalized
N-Substituted 1,8-Naphthyridines
A. Yu. Alekseeva, D. L. Mikhailov, I. N. Bardasov, O. V. Ershov, and O. E. Nasakin
Ul’yanov Chuvash State University, Cheboksary, 428015 Russia
e-mail: bardasov.chem@mail.ru
Received May 2, 2013
DOI: 10.1134/S1070428013110286
Functionally substituted 1,8-naphthyridines are found
in many natural objects and they exhibit a wide range of
biological action [1–3]. N-substituted 1,8-naphthyridine
derivatives are worth special mention, many among them
are used in medicine as efficient antibacterial agents,
antibiotics (for instance, nalidixic acid, enoxacin. gemi-
floxacin [4–7]).
as Michael donors [8].
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 (IIIa). A solution of
0.183 g (0.001 mol) of enhydrazinoketone IIа, 0.22 g
(0.001 mol) of malononitrile dimer benzylidene deriva-
tive I, and 0.085 g (0.001 mol) of piperidine in 5 mL of
ethanol was heated at reflux for 10–15 min. On cooling
the separated precipitate was filtered off and washed with
a little 2-propanol. Yield 0.32 g (79%), mp 237–238°С
(decomp.). IR spectrum ν, cm–1: 3456, 3427, 3337 (NH2),
2190 (C≡N), 1630 (С=О). 1Н NMR spectrum (DMSO-
d6), δ, ppm: 0.78 s (3H, CH3), 1.02 s (3H, CH3), 1.96 d
(1H, CH2CO, J 16.6 Hz), 2.17 d (1H, CH2CO, 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 68.58; H 6.50; N 20.92.
C23H26N6O. Calculated, %: C 68.63; H 6.51; N 20.88.
Many synthetic procedures for the preparation of
highly functionalized 1,8-naphthyridines are multistage
and labor-consuming for they include the stage by stage
introduction of the functional groups. We have developed
in this study a one-stage synthetic method underlain by
the reaction of a benzylidene derivative of malononitrile
dimer I with enaminoketones IIа–IId. As a result we
obtained in 75–93% yields N-substituted 2,4-diamino-
6-oxo-5-phenyl-5,6,7,8,9,10-hexahydrobenzo[b][1,8]
naphthyridine-3-carbonitriles IIIа–IIId.
The structure of the synthesized 1,8-naphthyridine de-
rivatives IIIа–IIId was established based on IR, 1Н NMR,
and mass spectra.
The formation of compounds IIIа–IIId apparently
involves the building of Michael adduct А, which un-
dergoes an intramolecular cyclization into B derivative
.
Compounds IIIb–IIId were analogously obtained.
The formation of the final 1,8-naphthyridines IIIа–IIId
is completed by the cyclization involving the spatially
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 (IIIb). Yield (87%),
mp 229–230°С (decomp.). IR spectrum, ν, cm–1: 3430,
3347 (NH2), 3217 (NH), 2196 (C≡N), 1620 (С=О).
1Н NMR spectrum (DMSO-d6), 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, CH2CO, J 16.9 Hz)*, 2.11 d
(1H, CH2CO, J 16.0 Hz), 2.21 (1H, CH2, J 14.0 Hz)*,
contiguous amino and cyano groups
.
Compound IIIb according to the 1Н NMR data exists
as two isomers apparently due to the slow inversion of
the nitrogen atom. The reported method of 1,8-naph-
thyridines IIIа–IIId preparation is a modification of the
previously developed procedure of the synthesis of 5H-
chromeno[2,3-b]pyridines with the use of 1,3-diketones
1715

ALEKSEEVA et al.
1716
Scheme.
O
O
NH2
CN
CN
CN
+
R
NH
X
CN
R
CN
CN
R
NH2
NH
X
R
I
II
A
O
NH2
O
NH2
N
CN
CN
CN
NH2
R
R
NH2
N
X
N
X
R
R
IIIa_IIId
B
CN
R = Me, X = NMe2 (a), NHPh (b); R = H, X = NMe2 (c),
(d).
S
2.24 d (1H, CH2CO, J 16.0 Hz), 2.28 d (1H, CH2CO,
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 (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),
6.76–6.73 m (1Н, С6Н5)*, 6.81 t (1Н, С6Н5, J 7.3 Hz),
7.08 t (1Н, С6Н5, J 7.3 Hz)*, 7.27–7.12 m (7Н, 2С6Н5),
7.27–7.12 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, %: C 71.94;
H 5.83; N 18.68. C27H26N6O. Calculated, %: C 71.98;
H 5.82; N 18.65.
m/z (Irel, %): 374 (5) [M]+, 330 (16) [M – 44]+, 297 (25)
[M – 77]+, 254 (100) [M – 120]+. Found, %: C 67.40;
H 5.91; N 22.48. C21H22N6O. Calculated, %: C 67.36;
H 5.92; N 22.44.
2,4-Diamino-6-oxo-10-(3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-yl)-5-phenyl-
5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-
3-carbonitrile (IIId). Yield 93%, mp 308–309°С
(decomp.). IR spectrum, ν, cm–1: 3508, 3400, 3339
(NH2), 2224, 2191 (C≡N), 1602 (С=О). 1Н NMR spec-
trum (DMSO-d6), δ, ppm: 1.62–1.93 m (6Н, 3СН2),
2.20–2.41 m (4Н, 2СН2), 2.65 s (2Н, СН2), 2.77 s (2Н,
СН2), 5.20 s (1Н, СН), 6.12 s (2H, NH2), 6.36 s (2H,
NH2), 7.10 t (1Н, С6Н5, J 7.0 Hz), 7.13–7.56 m (4Н,
С6Н5). Mass spectrum, m/z (Irel, %): 492 (12) [M]+, 415
(54) [M – 77]+, 330 (6) [M – 162]+. Found, %: С 68.32;
Н 4.88; N 17.10. C28H24N6OS. Calculated, %: C 68.27;
H 4.91; N 17.06.
2,4-Diamino-10-(dimethylamino)-6-oxo-5-phenyl-
5,6,7,8,9,10-hexahydrobenzo[b][1,8]-naphthyridine-
3-carbonitrile (IIIc). Yield 75%, mp 239–240°С (de-
comp.). IR spectrum, ν, cm–1: 3474, 3360 (NH2), 2201
(C≡N), 1650 (С=О). 1Н NMR spectrum (DMSO-d6), 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), 7.16 t (3Н, С6Н5,
J 7.5 Hz), 7.22 t (1Н, С6Н5, J 7.2 Hz). Mass spectrum,
The purity of compounds obtained was checked by
TLC on Silufol UV-254 plates, development under UV ir-
radiation, in iodine vapor, and by thermal decomposition.
IR spectra were taken on an IR Fourier spectrophotometer
FSM-1202 from thin film (mull in mineral oil). 1Н NMR
spectra were registered on a spectrometer Bruker DRX-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

ONE-STAGE SYNTHESIS OF HIGHLY FUNCTIONALIZED
1717
Chem. Pharm. Bull., 1982, vol. 30, p. 2399.
500, operating frequency 500.13 MHz, internal reference
TMS. Mass spectra were measured on an instrument
Finnigan MАT INCOS-50 (EI, 70 eV).
4. Lesher, G.Y., Froelich, E.J., Gruett, M.D., Bailey, J.H.,
and Brundage, R.P., J. Med. Pharm. Chem., 1962, vol. 5,
p. 1063.
5. Miamoto, T., Egawa, H., and Matsumoto, J., Chem. Pharm.
Bull., 1987, vol. 35, p. 2280.
REFERENCES
6. Tillotson, G.S., J. Med. Microbiol., 1996, vol. 44, p. 320.
7. Kerawala, M., Ambler, J.E., Lee, P.Y.C., and Drabu, Y.J.,
Eur. J. Clin. Microbiol. Infect. Dis., 2001, vol. 20, p. 271.
8. Ershov, O.V., Melekhin, E.A., Bardasov, I.N., Kayu-
kov, Ya.S., Eremkin,A.V., and Nasakin, O.E., Russ. J. Org.
Chem., 2006, vol. 42, p. 1395.
1. Santilli, A.A., Scotese, A.C., and Yurchenco, J.A. J. Med.
Chem. 1975, 18, 1038.
2. Zhang, S.-X., Bastow, K.F., Tachibana, Y., Kuo, S.-C.,
Hamel, E., Mauger,, A., Narayanan, V.L., and Lee, K.-H.,
J. Med. Chem. 1999, vol. 42, p. 4081.
3. Hirose, T., Mishio, S., Matsumoto, J.-I., and Minami, S.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013