Synthesis of 6,8-substituted 4-(hydroxyphenylamino)- and 4-(aminophenylamino)-2-methylquinolines

Article abstract of DOI:10.1134/S1070428007070184

A procedure has been developed for the synthesis of 4-(hydroxyphenylamino)- and 4-(aminophenylamino)-2-methylquinolines having a substituent in the 6(8)-position of the quinoline ring from the corresponding 4-chloro-2- methylquinolines and o-, m-, and p-a

Full text of DOI:10.1134/S1070428007070184

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 7, pp. 1048–1051. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © A.A. Avetisyan, I.L. Aleksanyan, L.P. Ambartsumyan, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 7,
pp. 1054–1057.
Synthesis of 6,8-Substituted 4-(Hydroxyphenylamino)-
and 4-(Aminophenylamino)-2-methylquinolines
A. A. Avetisyan, I. L. Aleksanyan, and L. P. Ambartsumyan
Erevan State University, ul. A. Manukyana 1, Erevan, 375025 Armenia
e-mail: organkim@sun.ysu.am
Received June 26, 2006
Abstract—A procedure has been developed for the synthesis of 4-(hydroxyphenylamino)- and 4-(amino-
phenylamino)-2-methylquinolines having a substituent in the 6(8)-position of the quinoline ring from the corre-
sponding 4-chloro-2-methylquinolines and o-, m-, and p-aminophenols and o-, m-, and p-phenylenediamines.
DOI: 10.1134/S1070428007070184
Functionally substituted 4-aminoquinoline deriva-
tives are used as effective medical agents; examples
are such drugs as Haloquin, Quingamin, Amino-
acrichin, Hydroxychloroquin, etc. [1]. Substituted
4-aminoquinolines inhibit protein kinase enzymes re-
sponsible for some cellular activity. High biological
activity of these compounds may lead to a number of
diseases, including cancer [2–4].
With a view to synthesize new substituted 4-amino-
quinoline derivatives, in the present work we examined
nucleophilic substitution of the chlorine atom in
6,8-substituted 4-chloro-2-methylquinolines Ia–Ie by
the action of o-, m-, and p-aminophenols and o-, m-,
and p-phenylenediamines. Optimal conditions for the
reaction were found. The corresponding substituted
4-(2-hydroxyphenylamino)-, 4-(3-hydroxyphenyl-
amino)-, and 4-(4-hydroxyphenylamino)-2-methyl-
quinolines IIa–IIn and 4-(2-aminophenylamino)-2-
methylquinolines IIIa, IIId, IIIg, IIIj, and IIIm were
obtained in high yield by heating equimolar amounts
of 4-chloro-2-methylquinolines Ia–Ie with o-, m-, and
p-aminophenols or o-phenylenediamine in ethanol
in the presence of hydrochloric acid for 6–10 h
(Scheme 1). m-Phenylenediamine dihydrochloride and
p-phenylenediamine sulfate reacted with quinolines
only at elevated temperature to give, respectively,
Scheme 1.
OH
HN
H2NC6H4OH
R
Cl
N
N
Me
IIa–IIo
R
Me
NH2
Ia–Ie
HN
H2NC6H4NH2
R
N
Me
IIIa–IIIo
I, R = H (a), 6-Me (b), 8-Me (c), 6-MeO (d), 8-MeO (e); II, III, R = H (a–c), 6-Me (d–f), 8-Me (g–i), 6-MeO (j–l), 8-MeO (m–o);
II, 2-HO (a, d, g, j, m), 3-HO (b, e, h, k, n), 4-HO (c, f, i, l, o); III, 2-H2N (a, d, g, j, m), 3-H2N (b, e, h, k, n), 4-H2N (c, f, i, l, o).
1048

SYNTHESIS OF 6,8-SUBSTITUTED 4-(HYDROXYPHENYLAMINO)- ...
1049
4-(3-aminophenylamino)- and 4-(4-aminophenyl-
amino)-2-methylquinolines IIIb, IIIc, IIIe, IIIf, IIIh–
IIIl, IIIn, and IIIo in high yields. The structure of the
(decomp.), Rf 0.58 (acidic alcohol). 1H NMR spectrum,
δ, ppm: 2.70 s (3H, CH3), 6.15 s (1H, Harom), 7.20–
8.20 m (8H, Harom), 9.90 s (1H, OH), 10.30 s (1H, NH).
Found, %: C 59.51; H 4.87; N 8.81. C16H16Cl2N2O.
Calculated, %: C 59.44; H 4.95; N 8.67.
1
isolated compounds was confirmed by the H NMR
data. Preliminary tests showed that some derivatives,
in particular 4-(hydroxyphenylamino)-2-methylquino-
lines, are promising as radioprotective agents;
4-(aminophenylamino)-2-methylquinolines exhibited
a medium-strength antibacterial activity.
3-(2-Methylquinolin-4-ylamino)phenol dihydro-
chloride (IIb). Yield 3.10 g (96%), mp 300°C
(decomp.), Rf 0.56 (acidic alcohol). 1H NMR spectrum,
δ, ppm: 2.60 s (3H, CH3), 6.60 s (1H, Harom), 7.20–
8.10 m (8H, Harom), 9.70 s (1H, OH). 10.80 s (1H, NH).
Found, %: C 59.32; H 5.10; N 8.53. C16H16Cl2N2O.
Calculated, %: C 59.44; H 4.95; N 8.67.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
4-(2-Methylquinolin-4-ylamino)phenol dihydro-
chloride (IIc). Yield 2.65 g (82%), mp 360°C
(decomp.), Rf 0.62 (acidic alcohol). Found, %: C 59.53;
H 4.89; N 8.56. C16H16Cl2N2O. Calculated, %: C 59.44;
H 4.95; N 8.67.
Mercury-300 spectrometer using DMSO-d6 as solvent.
The purity of the products was checked by TLC on
Silufol UV-254 plates; spots were visualized by treat-
ment with iodine vapor.
Substituted 4-chloro-2-methylquinolines Ia–Ie
were synthesized according to the procedures de-
scribed in [5, 6] by reaction of phosphoryl chloride
with the corresponding 2-methylquinolin-4-ols.
2-(2,6-Dimethylquinolin-4-ylamino)phenol dihy-
drochloride (IId). Yield 2.73 g (81%), mp 190–192°C
(decomp.), Rf 0.56 (acidic alcohol). Found, %: C 60.48;
H 5.50; N 8.47. C17H18Cl2N2O. Calculated, %: C 60.53;
H 5.34; N 8.31.
4-Chloro-2-methylquinoline (Ia). mp 43°C [5].
4-Chloro-2,6-dimethylquinoline (Ib). Yield 18.20 g
(95%), mp 61–63°C (from aq. EtOH, 1:1). Found, %:
C 68.85; H 5.37; Cl 18.41; N 7.40. C11H10ClN. Calcu-
lated, %: C 68.93; H 5.22; Cl 18.54; N 7.31.
3-(2,6-Dimethylquinolin-4-ylamino)phenol dihy-
drochloride (IIe). Yield 2.97 g (88%), mp 263–270°C
(decomp.), Rf 0.49 (acidic alcohol). 1H NMR spectrum,
δ, ppm: 2.20 s (3H, CH3), 2.70 s (3H, CH3), 6.45 s
(1H, Harom), 6.90–7.80 m (7H, Harom), 9.70 s (1H, OH),
10.80 s (1H, NH). Found, %: C 60.46; H 5.44; N 8.26.
C17H18Cl2N2O. Calculated, %: C 60.53; H 5.34; N 8.31.
4-Chloro-2,8-dimethylquinoline (Ic). Yield 17.81 g
(93%), mp 66–68°C (from aq. EtOH, 1:1). Found, %:
C 69.05; H 5.12; Cl 18.62; N 7.27. C11H10ClN. Calcu-
lated, %: C 68.93; H 5.22; Cl 18.54; N 7.31.
4-(2,6-Dimethylquinolin-4-ylamino)phenol dihy-
drochloride (IIf). Yield 2.83 g (84%), mp 300°C
(decomp.), Rf 0.57 (acidic alcohol). 1H NMR spectrum,
δ, ppm: 2.40 s (3H, CH3), 2.75 s (3H, CH3), 6.50 s
(1H, Harom), 7.00–8.10 m (7H, Harom), 9.70 s (1H, OH),
10.80 s (1H, NH). Found, %: C 60.57; H 5.41; N 8.24.
C17H18Cl2N2O. Calculated, %: C 60.53; H 5.34; N 8.31.
4-Chloro-6-methoxy-2-methylquinoline (Id).
mp 98–99°C; published data [6]: mp 100°C.
4-Chloro-8-methoxy-2-methylquinoline (Ie).
Yield 19.71 g (95%), mp 70–72°C (from aq. EtOH,
1:1). Found, %: C 63.54; H 4.98; Cl 17.25; N 6.87.
C11H10ClNO. Calculated, %: C 63.61; H 4.82;
Cl 17.11; N 6.75.
2-(2,8-Dimethylquinolin-4-ylamino)phenol dihy-
drochloride (IIg). Yield 3.07 g (91%), mp 134–138°C
(decomp.), Rf 0.56 (acidic alcohol). 1H NMR spectrum,
δ, ppm: 2.75 s (6H, CH3), 6.20 s (1H, Harom), 6.95–
8.20 m (7H, Harom), 9.90 s (1H, OH), 10.30 s (1H, NH).
Found, %: C 60.61; H 5.24; N 8.39. C17H18Cl2N2O.
Calculated, %: C 60.53; H 5.34; N 8.31.
Substituted 4-(hydroxyphenylamino)-2-methyl-
quinoline dihydrochlorides IIa–IIn (general proce-
dure). A mixture of 0.01 mol of substituted 4-chloro-2-
methylquinoline Ia–Ie, 1.08 g (0.01 mol) of o-, m-, or
p-aminophenol (p-aminophenol was used as hydro-
chloride), and 1 ml of concentrated hydrochloric acid
in 50 ml of alcohol was heated for 8–10 h on a water
bath. The alcohol was distilled off, the residue was
treated with water, the mixture was made alkaline, the
resulting solution was filtered, the filtrate was acidified
to pH 2–3, and the precipitate was filtered off.
3-(2,8-Dimethylquinolin-4-ylamino)phenol dihy-
drochloride (IIh). Yield 3.13 g (93%), mp 186–189°C
(decomp.), Rf 0.54 (acidic alcohol). Found, %: C 60.63;
H 5.28; N 8.40. C17H18Cl2N2O. Calculated, %: C 60.53;
H 5.34; N 8.31.
2-(2-Methylquinolin-4-ylamino)phenol dihydro-
chloride (IIa). Yield 2.71 g (84%), mp 250°C
4-(2,8-Dimethylquinolin-4-ylamino)phenol dihy-
drochloride (IIi). Yield 3.13 g (93%), mp 197–200°C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

AVETISYAN et al.
1050
(decomp.), Rf 0.59 (acidic alcohol). 1H NMR spectrum,
δ, ppm: 2.80 s (6H, CH3), 6.40 s (1H, Harom), 6.95–
8.60 m (7H, Harom), 9.70 s (1H, OH), 11.85 s (1H, NH).
Found, %: C 60.69; H 5.29; N 8.42. C17H18Cl2N2O.
Calculated, %: C 60.53; H 5.34; N 8.31.
o-phenylenediamine, and 1 ml of concentrated hydro-
chloric acid in 50 ml of alcohol was heated for 6–8 h
on a water bath. The alcohol was distilled off, the
residue was treated with water and acidified to pH 3,
the solution was filtered, the filtrate was made alkaline
(pH 9), and the precipitate was filtered off.
2-(6-Methoxy-2-methylquinolin-4-ylamino)-
phenol dihydrochloride (IIj). Yield 3.14 g (89%),
mp 192–195°C (decomp.), Rf 0.40 (alcohol). Found,
%: C 57.84; H 5.03; N 7.85. C17H18Cl2N2O2. Calculat-
ed, %: C 57.79; H 5.10; N 7.93.
N-(2-Aminophenyl)-2-methylquinolin-4-amine
(IIIa). Yield 2.09 g (84%), mp 117–120°C, Rf 0.51
1
(acidic alcohol). H NMR spectrum, δ, ppm: 2.65 s
(3H, CH3), 5.10 s (2H, NH2), 6.20 s (1H, Harom), 7.20–
8.10 m (8H, Harom), 10.20 s (1H, NH). Found, %:
C 77.20; H 5.98; N 16.94. C16H15N3. Calculated, %:
C 77.11; H 6.02; N 16.87.
3-(6-Methoxy-2-methylquinolin-4-ylamino)-
phenol dihydrochloride (IIk). Yield 2.86 g (81%),
mp 196–198°C (decomp.), Rf 0.42 (alcohol–hexane,
1
2:1). H NMR spectrum, δ, ppm: 2.60 s (3H, CH3),
N-(2-Aminophenyl)-2,6-dimethylquinolin-4-
amine (IIId). Yield 2.10 g (80%), mp 120–121°C,
4.00 s (3H, OCH3), 6.20 s (1H, Harom), 6.90–8.20 m
(7H, Harom), 9.90 s (1H, OH), 10.30 s (1H, NH).
Found, %: C 57.67; H 5.20; N 8.01. C17H18Cl2N2O2.
Calculated, %: C 57.79; H 5.10; N 7.93.
1
Rf 0.68 (acidic alcohol). H NMR spectrum, δ, ppm:
2.30 s (3H, CH3), 2.70 s (3H, CH3), 5.20 s (2H, NH2),
6.40 s (Harom), 7.00–8.10 m (7H, Harom), 8.90 s (1H,
NH). Found, %: C 77.67; H 6.38; N 16.03. C17H17N3.
Calculated, %: C 77.57; H 6.46; N 15.97.
4-(6-Methoxy-2-methylquinolin-4-ylamino)-
phenol dihydrochloride (IIl). Yield 2.93 g (83%),
mp 335–337°C (decomp.), Rf 0.59 (acidic alcohol).
1H NMR spectrum, δ, ppm: 2.60 s (3H, CH3), 4.00 s
(3H, OCH3), 6.40 s (1H, Harom), 6.95–8.20 m (7H,
Harom), 9.50 s (1H, OH), 10.40 s (1H, NH). Found, %:
C 57.81; H 4.98; N 7.87. C17H18Cl2N2O2. Calculated,
%: C 57.79; H 5.10; N 7.93.
N-(2-Aminophenyl)-2,8-dimethylquinolin-4-
amine (IIIg). Yield 2.21 g (84%), mp 74–76°C,
Rf 0.56 (acidic alcohol). Found, %: C 77.49; H 6.55;
N 15.88. C17H17N3. Calculated, %: C 77.57; H 6.46;
N 15.97.
N-(2-Aminophenyl)-6-methoxy-2-methylquino-
lin-4-amine (IIIj). Yield 2.29 g (82%), mp 122–
125°C, Rf 0.62 (acidic alcohol). Found, %: C 73.03;
H 6.15; N 15.13. C17H17N3O. Calculated, %: C 73.12;
H 6.09; N 15.05.
2-(8-Methoxy-2-methylquinolin-4-ylamino)-
phenol dihydrochloride (IIm). Yield 2.97 g (84%),
1
mp 164–165°C (decomp.), Rf 0.60 (alcohol). H NMR
spectrum, δ, ppm: 2.65 s (3H, CH3), 4.00 s (3H,
OCH3), 6.60–8.00 m (7H, Harom), 9.20 s (1H, OH),
10.00 s (1H, NH). Found, %: C 57.68; H 5.21; N 7.98.
C17H18Cl2N2O2. Calculated, %: C 57.79; H 5.10;
N 7.93.
N-(2-Aminophenyl)-8-methoxy-2-methylquino-
lin-4-amine (IIIm). Yield 2.48 g (89%), mp 152–
154°C, Rf 0.48 (acidic alcohol). Found, %: C 73.20;
H 6.03; N 15.13. C17H17N3O. Calculated, %: C 73.12;
H 6.09; N 15.05.
3-(8-Methoxy-2-methylquinolin-4-ylamino)-
phenol dihydrochloride (IIn). Yield 3.25 g (92%),
mp 173–174°C (decomp.), Rf 0.60 (alcohol–hexane,
2:1). Found, %: C 57. 72; H 5. 17; N 7. 88.
C17H18Cl2N2O2. Calculated, %: C 57.79; H 5.10;
N 7.93.
Substituted N-(3-aminophenyl)-2-methylquino-
lin-4-amines IIIb, IIIe, IIIh, IIIk, and IIIn (general
procedure). A mixture of 0.01 mol of substituted
4-chloro-2-methylquinoline Ia–Ie and 1.81 g
(0.01 mol) of m-phenylenediamine dihydrochloride in
50 ml of alcohol was heated for 8–10 h on a water
bath. The alcohol was distilled off, the residue was
treated with water and acidified to pH 3, the solution
was filtered, the filtrate was made alkaline (pH 9), and
the precipitate was filtered off.
4-(8-Methoxy-2-methylquinolin-4-ylamino)-
phenol dihydrochloride (IIo). Yield 3.04 g (86%),
mp 193–200°C (decomp.), Rf 0.58 (acidic alcohol).
Found, %: C 57.84; H 5.03; N 7.85. C17H18Cl2N2O2.
Calculated, %: C 57.79; H 5.10; N 7.93.
Substituted N-(2-aminophenyl)-2-methylquino-
lin-4-amines IIIa, IIId, IIIg, IIIj, and IIIm (general
procedure). A mixture of 0.01 mol of substituted
4-chloro-2-methylquinoline Ia–Ie, 1.2 g (0.01 mol) of
N-(3-Aminophenyl)-2-methylquinolin-4-amine
(IIIb). Yield 2.12 g (85%), mp 151–152°C, Rf 0.51
(acidic alcohol). Found, %: C 77.05; H 6.10; N 16.78.
C16H15N3. Calculated, %: C 77.11; H 6.02; N 16.87.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

SYNTHESIS OF 6,8-SUBSTITUTED 4-(HYDROXYPHENYLAMINO)- ...
1051
N-(3-Aminophenyl)-2,6-dimethylquinolin-4-
amine (IIIe). Yield 2.55 g (97%), mp 176–178°C,
Rf 0.53 (acidic alcohol). Found, %: C 77.65; H 6.40;
N 15.89. C17H17N3. Calculated, %: C 77.57; H 6.46;
N 15.97.
N-(4-Aminophenyl)-2,6-dimethylquinolin-4-
amine (IIIf). Yield 2.58 g (98%), mp 262–263°C,
Rf 0.46 (acidic alcohol). H NMR spectrum, δ, ppm:
2.40 s (3H, CH3), 2.75 s (3H, CH3), 5.15 s (2H, NH2),
6.45 s (1H, Harom), 7.10–8.15 m (7H, Harom), 9.00 s
(1H, NH). Found, %: C 77.48; H 6.52; N 15.90.
C17H17N3. Calculated, %: C 77.57; H 6.46; N 15.97.
1
N-(3-Aminophenyl)-2,8-dimethylquinolin-4-
amine (IIIh). Yield 2.31 g (88%), mp 195–198°C,
1
Rf 0.46 (acidic alcohol). H NMR spectrum, δ, ppm:
N-(4-Aminophenyl)-2,8-dimethylquinolin-4-
amine (IIIi). Yield 2.16 g (82%), mp 226–227°C,
2.75 s (6H, CH3), 5.20 s (2H, NH2), 6.10 s (1H, Harom),
6.90–7.80 m (7H, Harom), 8.30 s (1H, NH). Found, %:
C 77.51; H 6.53; N 16.07. C17H17N3. Calculated, %:
C 77.57; H 6.46; N 15.97.
1
Rf 0.56 (acidic alcohol). H NMR spectrum, δ, ppm:
2.80 s (6H, CH3), 5.00 s (2H, NH2), 6.20 s (1H, Harom),
7.00–8.00 m (7H, Harom), 8.40 s (1H, NH). Found, %:
C 77.64; H 6.37; N 16.04. C17H17N3. Calculated, %:
C 77.57; H 6.46; N 15.97.
N-(3-Aminophenyl)-6-methoxy-2-methylquino-
lin-4-amine (IIIj). Yield 2.37 g (85%), mp 223–
1
225°C, Rf 0.69 (acidic alcohol). H NMR spectrum, δ,
N-(4-Aminophenyl)-6-methoxy-2-methylquino-
lin-4-amine (IIIk). Yield 2.71 g (97%), mp 150–
153°C, Rf 0.60 (acidic alcohol). Found, %: C 73.21;
H 6.02; N 15.16. C17H17N3O. Calculated, %: C 73.12;
H 6.09; N 15.05.
ppm: 2.60 s (3H, CH3), 3.90 s (3H, OCH3), 5.30 s (2H,
NH2), 6.90 s (1H, Harom), 7.20–8.00 m (7H, Harom),
8.40 s (1H, NH). Found, %: C 73.01; H 6.17; N 14.97.
C17H17N3O. Calculated, %: C 73.12; H 6.09; N 15.05.
N-(3-Aminophenyl)-8-methoxy-2-methylquino-
lin-4-amine (IIIm). Yield 2.62 g (94%), mp 194–
N-(4-Aminophenyl)-8-methoxy-2-methylquino-
lin-4-amine (IIIo). Yield 2.62 g (94%), mp 212–
213°C, Rf 0.40 (acidic alcohol). Found, %: C 73.19;
H 6.01 N 15.14. C17H17N3O. Calculated, %: C 73.12;
H 6.09; N 15.05.
1
196°C, Rf 0.67 (acidic alcohol). H NMR spectrum, δ,
ppm: 2.75 s (3H, CH3), 4.00 s (3H, OCH3), 5.40 s (2H,
NH2), 6.95 s (1H, Harom), 7.20–8.00 m (7H, Harom),
8.50 s (1H, NH). Found, %: C 73.04; H 6.17; N 14.89.
C17H17N3O. Calculated, %: C 73.12; H 6.09; N 15.05.
REFERENCES
Substituted N-(4-aminophenyl)-2-methylquino-
lin-4-amines IIIc, IIIf, IIIi, IIIl, and IIIo (general
procedure). A mixture of 0.01 mol of substituted
4-chloro-2-methylquinoline Ia–Ie and 2.06 g
(0.01 mol) of p-phenylenediamine sulfate in 50 ml of
alcohol was heated for 8–10 h on a water bath. The
alcohol was distilled off, the residue was treated with
water and acidified to pH 3, the solution was filtered,
the filtrate was made alkaline (pH 9), and the precip-
itate was filtered off.
1. Mashkovskii, M.D., Lekarstvennye sredstva (Medicines),
Moscow: Novaya Volna, 2002, vol. 2, p. 336.
2. Wang, Y.D., Boschelli, D.H., Johnson, S., and Hono-
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4. Frame, M.C., Biochim. Biophys. Acta, 2002, vol. 114,
p. 1602.
5. Beilsteins Handbuch der organischen Chemie, H, vol. 20,
N-(4-Aminophenyl)-2-methylquinolin-4-amine
(IIIc). Yield 2.27 g (91%), mp 298-299°C, Rf 0.48
(acidic alcohol). Found, %: C 77.19; H 5.95; N 16.95.
C16H15N3. Calculated, %: C 77.11; H 6.02; N 16.87.
p. 392.
6. Rubtsov, M.V. and Baichikov, A.T., Sinteticheskie khimi-
ko-farmatsevticheskie preparaty (Synthetic Chemical and
Pharmaceutical Preparations). 1971, p. 222.
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