Synthesis and transformations of 2-(4-ethoxycarbonylphenylamino)- and 2-(2-carboxyphenylamino)-4-methylquinolines

Full text of DOI:10.1134/S1070428013120270

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 12, pp. 1851–1853. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © I.L. Aleksanyan, L.P. Hambardzumyan, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 12, pp. 1866–1868.
SHORT
COMMUNICATIONS
Synthesis and Transformations
of 2-(4-Ethoxycarbonylphenylamino)- and 2-(2-Carboxyphenyl-
amino)-4-methylquinolines
I. L. Aleksanyan and L. P. Hambardzumyan
Yerevan State University, ul. Aleka Manukyana 1, Yerevan, 0025 Armenia
e-mail: ialeksanyan@ysu.am
Received November 19, 2012
DOI: 10.1134/S1070428013120270
Many quinoline derivatives are known as efficient
fluorophores [1] and are widely used in biochemistry
and medicine for studying various biological systems.
Nowadays, much attention is given to DNA fluoro-
phores based on fused aromatic systems containing
two and more rings (preferably five- or six-membered)
and at least one heteroatom. Nevertheless, search for
new more sensitive and selective compounds remains
important [2]. Quinoline derivatives, in particular
aminoquinolines, are also promising as potential anti-
oxidants and radioprotectors [3].
In view of the above stated, in the present work we
studied reactions of 2-chloro-4-methylquinolines with
2- and 4-aminobenzoic acids and ethyl 4-aminoben-
zoate to obtain new quinoline derivatives. By heating
2-chloro-4-methylquinolines Ia–Ic with 2-aminoben-
zoic acid or ethyl 4-aminobenzoate at a ratio of 1:1.1
in ethanol in the presence of HCl for 9–15 h we syn-
thesized the corresponding 2-(2-carboxyphenylamino)-
and 2-(4-ethoxycarbonylphenylamino)-4-methylquino-
lines IIa–IIc and IIIa–IIIc, respectively, in high yields
(Scheme 1). Alkaline hydrolysis of esters IIIa–IIIc
Scheme 1.
Me
R1
2-H2NC6H4COOH
N
N
H
R2
COOH
IIa–IIc
Me
Me
N
R1
R1
COOEt
4-H2NC6H4COOEt
H2O/OH–
IVa–IVc
N
Cl
N
H
R2
Ia–Ic
R2
IIIa–IIIc
Me
R1
COOH
4-H2NC6H4COOH
N
N
H
R2
IVa–IVc
R1 = R2 = H (a), R1 = Me, R2 = H (b), R1 = H, R2 = Me (c).
1851

ALEKSANYAN, HAMBARDZUMYAN
1852
quantitatively afforded 2-(4-carboxyphenylamino)-4-
methylquinolines IVa–IVc. Compounds IVa–IVc were
also synthesized directly from chloroquinolines Ia–Ic
and 4-aminobenzoic acid.
Ethyl 4-(4-methylquinolin-2-ylamino)benzoates
IIIa–IIIc. A mixture of 0.01 mol of compound Ia–Ic
[4], 1.82 g (0.011 mol) of ethyl 4-aminobenzoate, and
1 mL of concentrated aqueous HCl in 50 mL of ethanol
was heated for 9–10 h on a water bath. The solvent
was distilled off, the residue was treated with water,
the mixture was adjusted to pH 8, and the precip-
itate was filtered off and recrystallized from ethanol–
water (1:4).
2-(2-Carboxyphenylamino)-4-methylquinolines
IIa–IIc readily underwent intramolecular cyclization
by the action of phosphoryl chloride on heating on
a water bath for 3 h. The products were fused hetero-
polycyclic compounds, 5-methyl-12H-quinolino[2,1-b]-
quinazolin-12-ones Va–Vc (Scheme 2).
Ethyl 4-(4-methylquinolin-2-ylamino)benzoate
(IIIa). Yield 2.78 g (91%), mp 181–182°C, Rf 0.57
(ethanol–toluene, 1:3). Found, %: C 74.68; H 5.74;
N 9.36. C19H18N2O2. Calculated, %: C 74.45; H 5.88;
N 9.15.
Scheme 2.
R1
R2
N
O
POCl3
Ethyl 4-(4,6-dimethylquinolin-2-ylamino)ben-
zoate (IIIb). Yield 2.85 g (89%), mp 211–212°C,
Rf 0.63 (ethanol–toluene, 1:3). Found, %: C 74.92;
H 6.02; N 9.06. C20H20N2O2. Calculated, %: C 75.00;
H 6.25; N 8.75.
IIa–IIc
Me
N
Va–Vc
R1 = R2 = H (a), R1 = Me, R2 = H (b), R1 = H, R2 = Me (c).
Ethyl 4-(4,8-dimethylquinolin-2-ylamino)ben-
2-(4-Methylquinolin-2-ylamino)benzoic acids
IIa–IIc (general procedure). A mixture of 0.01 mol of
2-chloro-4-methylquinoline Ia–Ic [4], 1.507 g
(0.011 mol) of 2-aminobenzoic acid, and 1 mL of con-
centrated aqueous HCl in 50 mL of ethanol was heated
for 14–15 h on a water bath. The solvent was distilled
off, the residue was treated with water, the precipitate
was filtered off and dissolved in dilute aqueous alkali,
the solution was filtered, the filtrate was acidified to
pH 5–6, and the precipitate was filtered off and dried.
zoate (IIIc). Yield 2.91 g (91%), mp 201–202°C,
Rf 0.62 (ethanol–toluene, 1:3). H NMR spectrum, δ,
ppm: 1.39 t (3H, CH3, J = 7.1 Hz), 2.63 d (3H, CH3,
J = 0.8 Hz), 2.72 s (3H, CH3), 4.29 q (2H, OCH2, J =
7.1 Hz), 6.93 q (1H, Harom, J = 0.8 Hz), 7.17 d.d (1H,
1
Harom, J = 8.2, 7.0 Hz), 7.41 d (1H, Harom, J = 7.0 Hz),
7.65 d (1H, Harom, J = 8.2 Hz), 7.91 m and 8.11 m
(2H, Harom), 9.43 br.s (1H, NH). Found, %: C 75.32;
H 5.96; N 8.31. C20H20N2O2. Calculated, %: C 75.00;
H 6.25; N 8.75.
4-(4-Methylquinolin-2-ylamino)benzoic acids
IVa–IVc (general procedure). a. A solution of 0.60 g
(15 mmol) of sodium hydroxide in 20 mL of water was
added to a solution of 5 mmol of ester IIIa–IIIc in
40 mL of ethanol. and the mixture was heated for 4 h
on a water bath. Ethanol was distilled off from the
mixture, 50 mL of water was added, the mixture was
filtered, the filtrate was acidified with aqueous HCl to
pH 5–6, and the precipitate was filtered off.
2-(4-Methylquinolin-2-ylamino)benzoic acid
(IIa). Yield 2.53 g (91%), mp 212–213°C (decomp.),
1
Rf 0.56 (ethanol–toluene, 1:3). H NMR spectrum, δ,
ppm: 2.77 s (3H, CH3), 7.18 s (1H, Harom), 7.38 t (1H,
Harom, J = 8.1 Hz), 7.45 t (1H, Harom, J = 7.8 Hz), 7.62 t
(1H, Harom, J = 8.2 Hz), 7.79 t (1H, Harom, J = 8.1 Hz),
7.92–8.14 m (4H, Harom), 11.1 br.s (1H, NH). Found,
%: C 73.51; H 4.91; N 10.18. C17H14N2O2. Calculated,
%: C 73.38; H 5.04; N 10.07.
b. A mixture of 0.01 mol of 2-chloro-4-methyl-
quinoline Ia–Ic [4], 1.51 g (0.011 mmol) of 4-amino-
benzoic acid, and 1 mL of concentrated aqueous HCl
in 50 mL of ethanol was heated for 10–12 h on a water
bath. The solvent was distilled off, the residue was
treated with water, the precipitate was filtered off and
dissolved in dilute alkali, the solution was filtered, the
filtrate was acidified to pH 5–6, and the precipitate was
filtered off. Samples of IVa–IVc prepared as described
in a and b showed no depression of the melting point
on mixing.
2-(4,6-Dimethylquinolin-2-ylamino)benzoic acid
(IIb). Yield 2.69 g (92%), mp 164–166°C (decomp.),
Rf 0.50 (ethanol–toluene, 1:4). Found, %: C 73.63;
H 4.97; N 10.21. C18H16N2O2. Calculated, %: C 73.97;
H 5.48; N 9.59.
2-(4,8-Dimethylquinolin-2-ylamino)benzoic acid
(IIc). Yield 2.62 g (90%), mp 205–206°C (decomp.),
Rf 0.49 (ethanol–toluene, 1:4). Found, %: C 73.71;
H 5.08; N 10.09. C18H16N2O2. Calculated, %: C 73.97;
H 5.48; N 9.59.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 12 2013

SYNTHESIS AND TRANSFORMATIONS OF 2-(4-ETHOXYCARBONYL-...
1853
4-(4-Methylquinolin-2-ylamino)benzoic acid
(IVa). Yield 1.31 g (94%) (a), 2.56 g (92%) (b),
mp 271–273°C (decomp.), Rf 0.58 (ethanol–toluene,
1:3). Found, %: C 73.51; H 4.91; N 10.18. C17H14N2O2.
Calculated, %: C 73.38; H 5.04; N 10.07.
3,5-Dimethyl-12H-quinolino[2,1-b]quinazolin-
12-one (Vb). Yield 1.30 g (95%), mp 259–260°C
(decomp.), Rf 0.53 (ethanol–toluene, 1:6). H NMR
spectrum, δ, ppm: 2.56 s (3H, CH3), 2.77 d (3H, CH3,
J = 0.8 Hz), 7.59 d.d (1H, Harom, J = 9.0, 2.4 Hz),
7.60 m (1H, Harom), 7.84 q (1H, Harom, J = 0.8 Hz),
7.85 d (1H, Harom, J = 2.4 Hz), 7.95 m (1H, Harom),
1
4-(4,6-Dimethylquinolin-2-ylamino)benzoic acid
(IVb). Yield 1.40 g (96%) (a), 2.66 g (91%) (b),
mp 272–275°C (decomp.), Rf 0.57 (ethanol–toluene,
8.07 br.d (1H, Harom, J = 8.1 Hz), 8.34 d.d (1H, Harom
,
1
J = 8.1, 1.1 Hz), 9.39 d (1H, Harom, J = 9.0 Hz). Found,
%: C 79.11; H 4.87; N 10.48. C18H14N2O. Calculated,
%: C 78.83; H 5.11; N 10.22.
1:3). H NMR spectrum, δ, ppm: 2.54 t (3H, CH3),
2.70 d (3H, CH3, J = 0.8 Hz), 7.35 q (1H, Harom, J =
0.8 Hz), 7.25 d (1H, Harom, J = 2.0 Hz), 7.59 d.d (1H,
H
H
arom, J = 8.4, 2.0 Hz), 7.59 m and 8.06 m (2H each,
arom), 7.84 d (1H, Harom, J = 8.4 Hz), 11.54 br.s (1H,
1,5-Dimethyl-12H-quinolino[2,1-b]quinazolin-
12-one (Vc). Yield 1.36 g (99%), mp 217–218°C
(decomp.), Rf 0.49 (ethanol–toluene, 1:5). Found, %:
C 78.62; H 5.36; N 10.09. C18H14N2O. Calculated, %:
C 78.83; H 5.11; N 10.22.
NH). Found, %: C 74.19; H 5.03; N 9.21. C18H16N2O2.
Calculated, %: C 73.97; H 5.48; N 9.59.
4-(4,8-Dimethylquinolin-2-ylamino)benzoic acid
(IVc). Yield 1.43 g (98%) (a), 2.72 g (93%) (b),
mp 278–280°C (decomp.), Rf 0.55 (ethanol–toluene,
1:3). Found, %: C 73.71; H 5.08; N 10.09. C18H16N2O2.
Calculated, %: C 73.97; H 5.48; N 9.59.
1
The H NMR spectra were recorded from solutions
in DMSO-d6 on a Varian Mercury-300 spectrometer.
The purity of the isolated compounds was checked by
TLC on Silufol UV-254 plates; spots were visualized
by treatment with iodine vapor.
5-Methyl-12H-quinolino[2,1-b]quinazolin-12-
ones Va–Vc (general procedure). A mixture of 5 mmol
of compound IIa–IIc and 10 mL of phosphoryl
chloride was heated for 3 h under reflux. Excess POCl3
was distilled off under reduced pressure, the residue
was poured onto 25 g of crushed ice and neutralized,
and the precipitate was filtered off and recrystallized
from ethanol–water (1:3).
REFERENCES
1. Solntsev, K.M., Sullivan, E.N., Tolbert, L.M., Ashke-
nazi, S., Leiderman, P., and Huppert, D., J. Am. Chem.
Soc., 2004, 126, p. 12701; Strohmeier, G.A.,
Fabian, W.M.F., and Uray, G., Helv. Chim. Acta, 2004,
vol. 87, p. 215; Badgujar, N.S., Pazicky, M., Traar, P.,
Terek, A., Uray, G., and Stadlbauer, W., Eur. J. Org.
Chem., 2006, no. 12, p. 2715; Avetisyan, A.A., Aleksa-
nyan, I.L., and Ambartsumyan, L.P., Russ. J. Org. Chem.,
2007, vol. 43, p. 1052.
5-Methyl-12H-quinolino[2,1-b]quinazolin-12-one
(Va). Yield 1.25 g (96%), mp 217–218°C, Rf 0.51
(ethanol–toluene, 1:5). H NMR spectrum, δ, ppm:
1
2.59 d (3H, CH3, J = 1.2 Hz), 7.10 q (1H, Harom, J =
1.2 Hz), 7.46 d.d.d (1H, Harom, J = 8.0, 7.0, 1.2 Hz),
7.52 d.d.d (1H, Harom, J = 7.7, 7.3, 1.2 Hz), 7.61 d.d.d
(1H, Harom, J = 8.3, 7.2, 1.8 Hz), 7.64 d (1H, Harom, J =
8.0, 1.2 Hz), 7.78 d.d.d (1H, Harom, J = 8.2, 7.0,
1.6 Hz), 7.83 d.d (1H, Harom, J = 7.7, 1.8 Hz), 8.33 d
(1H, Harom, J = 8.1, 1.6 Hz), 9.55 d.d (1H, Harom, J =
8.7, 1.2 Hz). Found, %: C 78.71; H 4.21; N 10.34.
C17H12N2O. Calculated, %: C 78.46; H 4.62; N 10.77.
2. Sibirtsev, V.S., Tolmachev, A.Yu., Suslov, V.V., Garaba-
dzhiu, A.V., and Traven’, V.F., Russ. J. Org. Chem., 2003,
vol. 39, p. 881.
3. Malakyan, M.G., Badzhinyan, S.A., Vardevanyan, L.A.,
Grigoryan, D.S., Egiazaryan, D.E., Avetisyan, A.A.,
Aleksanyan, I.L., Ambartsumyan, L.P., and Sarg-
syan, K.S., Khim.-Farm. Zh., 2009, no. 1, p. 8.
4. Beilsteins Handbuch der organischen Chemie, vol. H20,
p. 392.
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