Synthesis of substituted in benzene ring 4-[(2-aminophenyl)thio]-, 4-[(2-mercaptophenyl)amino]-2-methylquinolines and (4E)-4-[(2-mercaptophenyl) imino]-2-methyl-1,4-dihydroquinolines

Article abstract of DOI:10.1134/S1070428008050151

By a reaction of 2-methyl-4-chloroquinolines with o-mercaptoaniline under various conditions synteses were performed of substituted in the benzene ring 4-[(2-aminophenyl)thio]-2-methylquinolines and (4E)-4-[(2-mercaptophenyl)imino]- 2-methyl-1,4-dihydroquinolines that were respectively by isomerization or rearrangement converted into 4-[(2-mercaptophenyl)amino]-2-methylquinolines.

Full text of DOI:10.1134/S1070428008050151

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 723−727. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.A. Avetisyan, I.L. Aleksanyan, L.P. Ambartsumyan, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 5,
pp. 732−735.
Synthesis of Substituted in Benzene Ring 4-[(2-Aminophenyl)thio]-,
4-[(2-Mercaptophenyl)amino]-2-methylquinolines
and (4E)-4-[(2-Mercaptophenyl)imino]-2-methyl-1,4-
dihydroquinolines
A. A. Avetisyan, I. L. Aleksanyan, and L. P. Ambartsumyan
Yerevan State University, Yerevan, 375025 Armenia
e-mail: organkim@sun.ysu.am
Received May 3, 2007
Abstract—By a reaction of 2-methyl-4-chloroquinolines with o-mercaptoaniline under various conditions synteses
were performed of substituted in the benzene ring 4-[(2-aminophenyl)thio]-2-methylquinolines and (4E)-4-[(2-
mercaptophenyl)imino]-2-methyl-1,4-dihydroquinolines that were respectively by isomerization or rearrangement
converted into 4-[(2-mercaptophenyl)amino]-2-methylquinolines.
DOI: 10.1134/S1070428008050151
Among nitrogen and sulfur heterocycles a special
place is reserved for derivatives of 4-amino- and 4-mer-
captoquinolines possessing antitumor, analgesic, anti-
bacterial, and other actions [1, 2].
chloric acid in 5–6 h resulted in the formation of hydro-
chlorides of the corresponding substituted (4Ε)-4-[(2-
mercaptophenyl)imino]-2-methyl-1,4-dihydroquino-
lines IVa–IVg in high yields. The corresponding free
bases Va–Vg were also obtained in the form of yellow
crystals (Scheme 2).
We report here on reactions of nucleophilic substitu-
tion by o-mercaptoaniline of 2-methyl-4-chloroquinolines
Ia–Ig containing various substituents in the benzene ring
[3]. It was shown that the reaction between equivalent
quantities of the above compounds at room temperature
in acetone solution was completed in two days to produce
hydrochlorides of the corresponding substituted 4-[(2-
aminophenyl)thio]-2-methylquinolines IIa–IIg that were
easily converted into the corresponding bases IIIa–IIIg
(Scheme 1).
The bases obtained at boiling in ethanol and aprotic
polar solvents or at long storage at room temperature
transformed into colorless substances, 4-[(2-mercapto-
phenyl)amino]-2-methylquinolines VIa–VIg evidently
through isomerization (Scheme 3).
The transition from conjugated to aromatic system
was confirmed by UV spectra of ethanol solutions of
compounds Va–Vg and VIa–VIg of concentration 5 ×
10–5 mol l−1 based on the intensity difference at the absorp-
tion maximum 334 nm characteristic of compounds V
(see the figure).
The heating in ethanol of equivalent quantities of
2-methyl-4-chloroquinolines Ia–Ig and o-mercapto-
aniline in the presence of catalytic amount of hydro-
Scheme 1.
Cl
S
S
NH2
SH
NaOH
R
NH2
CH3
NH2
CH3
aceton
.
R
HCl
R
N
Ia_Ig
CH3
N
N
IIa_IIg
IIIa_IIIg
723

AVETISYAN et al.
724
Scheme 2.
Cl
NH2
SH
C2H5OH (H+)
N
N
NaOH
R
SH
SH
.
R
2HCl
R
N
CH3
Ia_Ig
N
CH3
N
H
Va_Vg
CH3
H
IVa_IVg
spectra were recorded on a spectrophotometer Specord-
50 in ethanol at room temperature from solutions of
concentration 5 × 10–5 mol l−1. The purity of compounds
obtained was checked by TLC on Silufol UV-254 plates
(development in iodine vapor).
Scheme 3.
N
HN
N
SH
CH3
SH
Substituted 4-[(2-aminophenyl-)thio]--2-methyl-
quinolines IIIa–IIIg. A mixture of 0.01 mol of an
appropriate substituted 2-methyl-4-chloroquinoline [3]
and 1.7 ml (0.01 mol) of o-mercaptoaniline in 5 ml of
anhydrous acetone was stirred at room temperature for 2
days. The obtained hydrochloride crystals were filtered
off and washed with anhydrous acetone, dried, the yield
and melting point were estimated. Water solution of 0.01
mol of the corresponding substituted 4-[(2-aminophenyl)-
thio]-2-methylquinoline hydrochloride was filtered from
any possible impurities and alkalinized with water
solution of NaOH to pH 9. The separated precipitate was
filtered off, washed with water, dried, and its yield with
respect to hydrochloride was estimated.
R
R
..
N
H
Va_Vg
CH3
VIa_VIg
Compounds VIa–VIg were also obtained by a rear-
rangement of the corresponding 4-[(2-amino-phenyl)-
thio]quinolines IIIa–IIIg. Optimum conditions of the
reaction were developed; it was shown that the
rearrangement occurred at heating the initial compounds
either in alcoholic or aqueous solution in the presence
of acid.
EXPERIMENTAL
4-[(2-Aminophenyl)thio]-2-methylquinoline (IIIa).
Yield of hydrochloride IIa 2.66 g (88%), mp 202–205°C.
Yield of compound IIIa 2.27 g (97%), mp 109–110°C,
1H NMR spectra were registered on a spectrometer
Varian Mercury-300 from solutions in DMSO-d6. UV
1
Rf 0.65 (ethanol–toluene, 1:3). H NMR spectrum, δ,
ppm: 2.70 s (3H, CH3), 5.10 s (2H, NH2), 6.40–7.90 m
(9Harom). Found, %: C 72.24; H 5.18; N 10.71; S 12.17.
C16H14N2S. Calculated, %: C 72.18; H 5.26; N 10.53;
S 12.03.
4-[(2-Aminophenyl)thio]-2,6-dimethylquinoline
(IIIb). Yield of hydrochloride IIb 2.53 g (80%), mp 174–
175°C. Yield of compound IIIb 2.20 g (98%), mp 137–
138°C, Rf 0.63 (ethanol–toluene, 1:5). 1H NMR spectrum,
δ, ppm: 2.40 s (3H, CH3), 2.60 s (3H, NCCH3), 5.15 s
(2H, NH2), 6.45–7.95 m (8Harom). Found, %: C 72.67;
H 5.84; N 10.15; S 11.66. C17H16N2S. Calculated, %:
C 72.86; H 5.71; N 10.00; S 11.43.
4-[(2-Aminophenyl)thio]-2,8-dimethylquinoline
(IIIc). Yield of hydrochloride IIc 2.37 g (75%), mp 210–
211°C. Yield of compound IIIc 2.00 g (95%), mp 87–
89°C, Rf 0.62 (ethanol–toluene, 1:5). 1H NMR spectrum,
UV spectra of compounds Vf (1) and VIf (2).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

SYNTHESIS OF SUBSTITUTED IN BENZENE RING
725
Scheme 4.
_
H
+
N
S
S
H
H+
.
.
S
NH2
CH3
NH2
CH3
+
EtOH or H2O
R
R
R
+
N
H
N
N
CH3
H
IIIa_IIIg
H
N
2H+
2HO_
_2H2O
V
IV
VI
S
EtOH
_H+
R
N
H
CH3
N 8.03; S 9.17. C16H13BrN2S. Calculated, %: C 55.65;
H 3.77; N 8.12; S 9.28.
δ, ppm: 2.42 s (3H, CH3), 2.60 s (3H, NCCH3), 5.15 s
(2H, NH2), 6.40–7.99 m (8Harom). Found, %: C 72.74;
H 5.86; N 9.87; S 11.61. C17H16N2S. Calculated, %:
C 72.86; H 5.71; N 10.00; S 11.43.
4-[(2-Aminophenyl)thio]-2-methyl-8-chloro-
quinoline (IIIg). Yield of hydrochloride IIg 2.13 g
(90%), mp 218–220°C. Yield of compound IIIg 2.48 g
(92%), mp 129–130°C, Rf 0.60 (ethanol–toluene, 1:10).
1H NMR spectrum, δ, ppm: 2.40 s (3H, NCCH3), 5.10 s
(2H, NH2), 6.40–7.50 m (8Harom). Found, %: C 63.97;
H 4.22; N 9.41; S 10.72. C16H13ClN2S. Calculated, %:
C 63.89; H 4.33; N 9.32; S 10.65.
4-[(2-Aminophenyl)thio]-2-methyl-6-methoxy-
quinoline (IIId). Yield of hydrochloride IId 2.63 g
(79%), mp 191–193°C. Yield of compound IIId 2.28 g
(97%), mp 172–173°C, Rf 0.50 (ethanol–toluene, 1:5).
1H NMR spectrum, δ, ppm: 2.60 s (3H, NCCH3), 3.90 s
(3H, OCH3), 5.20 s (2H, NH2), 6.45–7.95 m (8Harom).
Found, %: C 68.87; H 5.56; N 9.40; S 10.94.
C17H16N2OS. Calculated, %: C 68.92; H 5.41; N 9.46;
S 10.81.
Substituted (4Ε)-4-[(2-mercaptophenyl)imino]-2-
methyl-1,4-dihydroquinolines Va–Vg. a. A mixture of
0.01 mol of substituted 2-methyl-4-chloro-quinoline [3],
1.25 g (1.07 ml, 0.01 mol) of o-mercaptoaniline, 1 ml of
concn. HCl in 30 ml of ethanol was heated on a water
bath for 5–6 h. The precipitated crystals were filtered
off, dried, the yield and melting point were estimated.
4-[(2-Aminophenyl)thio]-2-methyl-8-methoxy-
quinoline (IIIe). Yield of hydrochloride IIe 2.69 g
(81%), mp 168–171°C. Yield of compound IIIe 2.30 g
(96%), mp 103–105°C, Rf 0.47 (ethanol–toluene, 1:5).
1H NMR spectrum, δ, ppm: 2.65 s (3H, NCCH3), 3.93 s
(3H, OCH3), 5.20 s (2H, NH2), 6.40–7.90 m (8Harom).
Found, %: C 68.99; H 5.37; N 9.37; S 10.68.
C17H16N2OS. Calculated, %: C 68.92; H 5.41; N 9.46;
S 10.81.
b. Amixture of 0.005 mol of an appropriate substituted
4-[(2-aminophenyl)thio]-2-methyl-quinoline IIIa–IIIg,
10 ml of ethanol, and 0.75 ml of concn. HCl was heated
on a water bath for 3–5 h. Then the reaction mixture was
subjected to workup as in procedure a. The corresponding
dihydrochlorides were isolated.
4-[(2-Aminophenyl)thio]-6-bromo-2-methyl-
quinoline (IIIf). Yield of hydrochloride IIf 2.67 g (70%),
mp 168–170°C. Yield of compound IIIf 2.37 g (98%),
mp 96–98°C, Rf 0.68 (ethanol–aqueous HCl). 1H NMR
spectrum, δ, ppm: 2.70 s (3H, NCCH3), 5.15 s (2H, NH2),
6.90–8.00 m (8Harom). Found, %: C 55.72; H 3.65;
Dihydrochlorides IVa–IVg obtained by procedures
a and b were dissolved in water, the water solution was
filtered from any possible impurities and alkalinized with
water solution of NaOH to pH ~7–7.5. The separated
precipitates were filtered off.
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AVETISYAN et al.
726
Mixed samples of compounds Va–Vg obtained by
procedures a and b do not show depression of the melting
S 10.48. C16H14ClN2S. Calculated, %: C 63.89; H 4.33;
N 9.32; S 10.65.
point.
Substituted 4-[(2-mercaptophenyl)amino]-2-
methylquinolines VIa–VIg. Compounds Va–Vg (0.005
mol) at boiling in ethanol or aprotic polar solvents for
~0.5 h were converted into white crystals of compounds
VIa–VIg.
(4Ε)-4-[(2-Mercaptophenyl)imino]-2-methyl-1,4-
dihydroquinoline (Va). Yield of dihydrochloride IVa
3.17 g (94%) (a), 1.67 g (99%) (b), mp 249–251°C. Yield
of compound Va 2.45 g (98%), mp 194–197°C. Found,
%: C 72.36; H 5.17; N 10.45; S 12.14. C16H14N2S.
Calculated, %: C 72.18; H 5.26; N 10.53; S 12.03.
4-[(2-Mercaptophenyl)amino]-2-methylquinoline
(VIa). Yield 1.21 g (91%), mp 214–216°C, Rf 0.58
(ethanol–toluene, 2:1). 1H NMR spectrum, δ, ppm: 2.60 s
(3H, CH3), 6.00–8.20 m (9Harom), 10.70 s (1H, NH).
Found, %: C 72.36; H 5.17; N 10.45; S 12.14. C16H14N2S.
Calculated, %: C 72.18; H 5.26; N 10.53; S 12.03.
(4Ε)-4-[(2-Mercaptophenyl)imino]-2,6-dimethyl-
1,4-dihydroquinoline (Vb). Yield -of dihydrochloride
IVb 3.44 g (98%) (a), 1.70 g (97%) (b), mp 237–238°C.
Yield of compound Vb 2.66 g (97%), mp 225–227°C.
Found, %: C 72.76; H 5.87; N 10.12; S 11.28. C17H16N2S.
Calculated, %: C 72.86; H 5.71; N 10.00; S 11.43.
4-[(2-Mercaptophenyl)amino]-2,6-dimethyl-
quinoline (VIb). Yield 1.33 g (95%), mp 247–248°C,
1
Rf 0.58 (ethanol–toluene, 1:1). H NMR spectrum, δ,
(4Ε)-4-[(2-Mercaptophenyl)imino]-2,8-dimethyl-
1,4-dihydroquinoline (Vc). Yield of dihydrochloride
IVc 3.47 g (99%) (a), 1.68 g (96%) (b), mp 202–203°C.
Yield of compound Vc 2.71 g (98%), mp 182–183°C.
Found, %: C 72.94; H 5.64; N 9.89; S 11.56. C17H16N2S.
Calculated, %: C 72.86; H 5.71; N 10.00; S 11.43.
ppm: 2.40 s (3H, CH3), 2.60 s (3H, NCCH3), 6.10–
8.20 m (8Harom), 10.65 s (1H, NH). Found, %: C 72.93;
H 5.65; N 9.87; S 11.58. C17H16N2S. Calculated, %:
C 72.86; H 5.71; N 10.00; S 11.43.
4-[(2-Mercaptophenyl)amino]-2,8-dimethyl-
quinoline (VIc). Yield 1.29 g (92%), mp 206–207°C,
(4Ε)-4-[(2-Mercaptophenyl)imino]-2-methyl-6-
methoxy-1,4-dihydroquinoline (Vd). Yield of
dihydrochloride IVd 3.52 g (96%) (a), 1.78 g (97%) (b),
mp 197–199°C. Yield of compound Vd 2.73 g (96%),
mp 168–170°C. Found, %: C 68.81; H 5.52; N 9.38;
S 10.68. C17H16N2OS. Calculated, %: C 68.92; H 5.41;
N 9.46; S 10.81.
1
Rf 0.49 (ethanol–toluene, 1:1). H NMR spectrum, δ,
ppm: 2.25 s (3H, CH3), 2.50 s (3H, NCCH3), 6.50–
8.50 m (8Harom), 10.15 C (1H, NH). Found, %: C 72.75;
H 5.86; N 10.17; S 11.27. C17 H16N2S. Calculated, %:
C 72.86; H 5.71; N 10.00; S 11.43.
4-[(2-Mercaptophenyl)amino]-2-methyl-6-
methoxyquinoline (VId). Yield 1.38 g (93%), mp 263–
264°C, Rf 0.55 (ethanol–toluene, 2:1). 1H NMR spectrum,
δ, ppm: 2.60 s (3H, NCCH3), 3.93 s (3H, OCH3), 6.00–
8.20 m (8Harom), 10.05 s (1H, NH). Found, %: C 68.78;
H 5.54; N 9.56; S 10.95. C17H16N2OS. Calculated, %:
C 68.92; H 5.41; N 9.46; S 10.81.
(4Ε)-4-[(2-Mercaptophenyl)imino]-2-methyl-8-
methoxy-1,4-dihydroquinoline (Ve). Yield of
dihydrochloride IVe 3.56 g (97%) (a), 1.76 g (96%) (b),
mp 182–183°C. Yield of compound Ve 2.79 g (97%),
mp 172–174°C. Found, %: C 68.79; H 5.47; N 9.54;
S 10.93. C17H16N2OS. Calculated, %: C 68.92; H 5.41;
N 9.46; S 10.81.
4-[(2-Mercaptophenyl)amino]-2-methyl-8-
methoxyquinoline (VIe). Yield 1.35 g (91%), mp 249–
251°C, Rf 0.67 (ethanol–toluene, 1:2). 1H NMR spectrum,
δ, ppm: 2.65 s (3H, NCCH3), 3.95 s (3H, OCH3), 6.20–
8.25 m (8Harom), 10.10 s (1H, NH). Found, %: C 68.80;
H 5.60; N 9.40; S 10.65. C17H16N2OS. Calculated, %:
C 68.92; H 5.41; N 9.46; S 10.81.
(4Ε)-6-Bromo-4-[(2-mercaptophenyl)imino]-2-
methyl-8-methoxy-1,4-dihydroquinoline (Vf). Yield of
dihydrochloride IVf 3.33 g (80%) (a), 2.04 g (98%) (b),
mp 256–257°C. Yield of compound Vf 2.65 g (96%),
mp 207–208°C. Found, %: C 55.71; H 3.68; N 8.23;
S 9.12. C16H13BrN2S. Calculated, %: C 55.65; H 3.77;
N 8.12; S 9.28.
6-Bromo-4-[(2-mercaptophenyl)amino]-2-
methylquinoline (VIf). Yield 1.60 g (93%), mp 224–
225°C, Rf 0.62 (ethanol–toluene, 1:3). 1H NMR spectrum,
δ, ppm: 2.70 s (3H, NCCH3), 6.20–8.30 m (8Harom),
10.20 s (1H, NH). Found, %: C 55.70; H 3.65; N 8.25;
S 9.12. C16H13BrN2S. Calculated, %: C 55.65; H 3.77;
N 8.12; S 9.28.
(4Ε)-4-[(2-Mercaptophenyl)imino]-2-methyl-8-
chloro-1,4-dihydroquinoline (Vg). Yield of
dihydrochloride IVg 3.64 g (98%) (a), 1.80 g (97%) (b),
mp 210–211°C. Yield of compound Vg 2.82 g (96%),
mp 124–126°C. Found, %: C 63.78; H 4.41; N 9.43;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

SYNTHESIS OF SUBSTITUTED IN BENZENE RING
727
4-[(2-Mercaptophenyl)amino]-2-methyl-8-
REFERENCES
chloroquinoline (VIg). Yield 2.67 g (89%), mp 216–
217°C, Rf 0.68 (ethanol–toluene, 1:3). 1H NMR spectrum,
δ, ppm: 2.50 s (3H, NCCH3), 6.40–8.20 m (8Harom),
5.10 s (1H, NH). Found, %: C 63.95; H 4.29; N 9.40;
S 10.55. C17H13ClN2S. Calculated, %: C 63.89; H 4.33;
N 9.32; S 10.65.
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3. Beilst., H, vol. 20, p. 392.
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