Synthesis of hetarylquinolines from 4-(4-hydroxy- 2-methylquinolin-3-yl)butan-2-one thiosemicarbazones

Full text of DOI:10.1134/S1070428015070301

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 7, pp. 1046–1049. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © I.L. Aleksanyan, L.P. Ambartsumyan, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 7, pp. 1062–1065.
SHORT
COMMUNICATIONS
Synthesis of Hetarylquinolines from 4-(4-Hydroxy-
2-methylquinolin-3-yl)butan-2-one Thiosemicarbazones
I. L. Aleksanyan and L. P. Ambartsumyan
Yerevan State University, ul. Aleka Manukyana 1, Yerevan, 0025 Armenia
e-mail: ialeksanyan@ysu.am
Received March 17, 2015
DOI: 10.1134/S1070428015070301
Heterocyclic thiosemicarbazones and thiosemicar-
bazides, including quinoline derivatives, are polyfunc-
tional substrates that are widely used in the develop-
ment of methods for the synthesis of biologically
active compounds which may be promising as medi-
cinal agents [1–3]. Increased attention is now given to
the chemistry of quinoline derivatives, in particular
hetarylquinolines, i.e., compounds whose molecules
consist of two heterocyclic fragments, one of which is
quinoline. Compounds exhibiting anticancer, antifun-
gal, antiviral, antibacterial, and immunomodulatory
activity have been found in the series of hetaryl-
quinolines [4–11].
3-(3-oxobutyl)quinolines 1a–1h. Compounds 1a, 1b,
1g, and 1h were synthesized by us previously [12, 13],
while quinolines 1c–1f were not described. Com-
pounds 1a–1h were prepared by hydrolysis of the cor-
responding 3-(3-chlorobut-2-en-1-yl)-4-hydroxy-2-
methylquinolines in sulfuric acid.
Ketones 1a–1h were treated with 1.1 equiv of thio-
semicarbazide in boiling anhydrous ethanol, and thio-
semicarbazones 2a–2h thus obtained were subjected to
heterocyclization by the action of bromoacetophenone
and ethyl bromoacetate. As a result, we isolated thia-
zolidine and thiazolidinone derivatives 3a–3h and
4a–4h, respectively.
Taking into account the above stated, we made
an attempt to synthesize new thiazolidines and thia-
zolidinones from 6(8)-substituted 4-hydroxy-2-methyl-
6(8)-Substituted 4-hydroxy-2-methyl-3-(3-oxo-
butyl)quinolines 1c–1f were synthesized according to
the procedure described in [12, 13] by hydrolysis of
OH
O
OH
Me
S
H
N
NH2
+
Me
H2N
N
N
NH2
R
R
H
S
N
Me
N
Me
1a–1h
2a–2h
OH
Me
PhC(O)CH2Br
N
S
N
R
HN
N
Me
Ph
EtOH, Δ
3a–3h
OH
Me
BrCH2C(O)OEt
N
S
N
R
HN
N
Me
O
4a–4h
R = H (a), 6-Me (b), 8-Me (c), 6-OMe (d), 8-OMe (e), 6-OEt (f), 6-Br (g), 6-COOH (h).
1046

SYNTHESIS OF HETARYLQUINOLINES FROM 4-(4-HYDROXY-2-METHYL...
1047
0.01 mol of the corresponding 3-(3-chlorobut-2-en-1-
yl)-4-hydroxy-2-methylquinolines in 85% H2SO4.
ethanol, 0.082 g (0.001 mol) of anhydrous sodium
acetate, and 0.199 g (1 mmol) of bromoacetophenone
was heated for 4–5 h under reflux with stirring. The
mixture was cooled, and the precipitate was filtered
off, washed with ethanol, and recrystallized from
ethanol.
4-(4-Hydroxy-2,8-dimethylquinolin-3-yl)butan-
2-one (1c). Yield 2.13 g (93%), mp 203–204°C,
Rf 0.58 (ethanol–toluene, 1:3). Found, %: C 73.86;
H 6.82; N 5.55. C15H17NO2. Calculated, %: C 74.07;
H 7.00; N 5.76.
2-Methyl-3-{3-[4-phenyl-1,3-thiazol-2(3H)-yli-
denehydrazinylidene]butyl}quinolin-4-ol (3a). Yield
0.38 g (95%), mp 262–263°C, Rf 0.65 (ethanol–tolu-
4-(4-Hydroxy-6-methoxy-2-methylquinolin-3-
yl)butan-2-one (1d). Yield 2.35 g (96%), mp 255–
256°C, Rf 0.52 (ethanol–toluene, 1:2). Found, %:
C 69.75; H 6.36; N 5.58. C15H17NO3. Calculated, %:
C 69.50; H 6.56; N 5.41.
1
ene, 1 :3). H NMR spectrum, δ, ppm: 2.17 br.s (3H,
CH3), 2.43–2.58 m (7H, CH3, CH2), 7.01 s (1H, =CH),
7.12 d.d (1H, Harom, J = 9.13, 2.78 Hz), 7.26–7.35 m
(2H, Harom), 7.45 t (1H, Harom, J = 7.54 Hz), 7.58 br.s
(2H, Harom), 7.68–7.95 m (3H, Harom), 10.13–10.76 m
(1H, NH), 11.59–12.31 m (1H, OH). Found, %:
C 68.48; H 5.26; N 14.06; S 8.13. C23H22N4OS. Calcu-
lated, %: C 68.66; H 5.47; N 13.93; S 7.96.
4-(4-Hydroxy-8-methoxy-2-methylquinolin-3-
yl)butane-2-one (1e). Yield 2.35 g (96%), mp 185–
186°C, Rf 0.56 (ethanol–toluene, 1:2). Found, %:
C 69.32; H 6.68; N 5.29. C15H17NO3. Calculated, %:
C 69.50; H 6.56; N 5.41.
2,6-Dimethyl-3-{3-[4-phenyl-1,3-thiazol-2(3H)-
ylidenehydrazinylidene]butyl}quinolin-4-ol (3b).
Yield 0.39 g (93%), mp 275–276°C, Rf 0.50 (ethanol–
4-(6-Ethoxy-4-hydroxy-2-methylquinolin-3-yl)-
butan-2-one (1f). Yield 2.43 g (94%), mp 240–241°C,
Rf 0.52 (ethanol–toluene, 1:2). Found, %: C 71.62;
H 6.85; N 5.27. C16H19NO3. Calculated, %: C 71.80;
H 6.96; N 5.13.
1
toluene, 1:4). H NMR spectrum, δ, ppm: 1.95–2.11 m
(3H, CH3), 2.33–2.53 m (8H, CH3, CH2), 2.54–2.83 m
(2H, CH2), 6.82–6.93 m (1H, =CH), 7.16–7.27 m (1H,
H
H
arom), 7.27–7.41 m (4H, Harom), 7.75–7.91 m (3H,
arom), 10.98 s (1H, NH), 11.30 s (1H, OH). Found, %:
Thiosemicarbazones 2f–2h were synthesized ac-
cording to the procedure described in [14] from 1.00 g
(0.011 mol) of thiosemicarbazide and 0.01 mol of
ketone 1a–1h.
C 69.39; H 5.67; N 13.28; S 7.85. C24H24N4OS. Cal-
culated, %: C 69.23; H 5.77; N 13.46; S 7.70.
2,8-Dimethyl-3-{3-[4-phenyl-1,3-thiazol-2(3H)-
ylidenehydrazinylidene]butyl}quinolin-4-ol (3c).
Yield 0.38 g (91%), mp 163–164°C, Rf 0.61 (ethanol–
toluene, 1:4). H NMR spectrum, δ, ppm: 1.94 m (3H,
CH3), 2.12 br.s (3H, CH3), 2.54–2.86 m (7H, CH3,
4-(6-Ethoxy-4-hydroxy-2-methylquinolin-3-yl)-
butan-2-one thiosemicarbazone (2f). Yield 3.25 g
(98%), mp 256–257°C, Rf 0.53 (ethanol–toluene, 1:3).
Found, %: C 56.56; H 6.21; N 15.61; S 8.61.
C17H22N4O3S. Calculated, %: C 56.35; H 6.08;
N 15.46; S 8.83.
1
CH2), 6.97 s (1H, =CH), 7.23 d.d (1H, Harom, J = 9.13,
2.78 Hz), 7.09–7.23 m (1H, Harom), 7.36 t (1H, Harom
J = 7.54 Hz), 7.53 br.s (2H, Harom), 7.68–7.91 m (3H,
arom), 10.08–10.89 m (1H, NH), 11.62–12.25 m
,
4-(6-Bromo-4-hydroxy-2-methylquinolin-3-yl)-
butan-2-one thiosemicarbazone (2g). Yield 3.41 g
(93%), mp 262–263°C (decomp.), Rf 0.51 (ethanol–
toluene, 1:2). Found, %: C 47.31; H 4.29; N 14.52;
S 8.54. C15H17BrN4OS. Calculated, %: C 47.24;
H 4.46; N 14.70; S 8.40.
H
(1H, OH). Found, %: C 69.01; H 5.90; 13.52; S 7.58.
C24H24N4OS. Calculated, %: C 69.23; H 5.77; N 13.46;
S 7.70.
6-Methoxy-2-methyl-3-{3-[4-phenyl-1,3-thiazol-
2(3H)-ylidenehydrazinylidene]butyl}quinolin-4-ol
(3d). Yield 0.37 g (86%), mp 253–254°C, Rf 0.60
(ethanol–toluene, 1:3). Found, %: C 66.81; H 5.46;
N 12.78; S 7.63. C24H24N4O2S. Calculated, %:
C 66.67; H 5.56; N 12.96; S 7.41.
3-[3-(Carbamothioylhydrazinylidene)butyl]-
4-hydroxy-2-methylquinoine-6-carboxylic acid (2h).
Yield 3.29 g (99%), mp 350°C (decomp.), Rf 0.63
(ethanol). Found, %: C 55.37; H 5.29; N 16.01; S 9.42.
C16H18N4O3S. Calculated, %: C 55.49; H 5.10;
N 16.18; S 9.25.
8-Methoxy-2-methyl-3-{3-[4-phenyl-1,3-thiazol-
2(3H)-ylidenehydrazinylidene]butyl}quinolin-4-ol
(3e). Yield 0.40 g (93%), mp 143–144°C, Rf 0.6
6(8)-Substituted 2-methyl-3-{3-[4-phenyl-1,3-
thiazol-2(3H)-ylidenehydrazinylidene]butyl}quino-
lin-4-ols 3a–3h (general procedure). A mixture of
1 mmol of compound 2a–2h, 4–5 mL of anhydrous
1
(ethanol–toluene, 1:3). H NMR spectrum, δ, ppm:
1.56–1.98 m (3H, CH3), 2.08–2.25 m (3H, OCH3),
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ALEKSANYAN, AMBARTSUMYAN
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2.43–2.64 m (5H, CH3, CH2), 2.68–2.91 m (2H, CH2),
7.02–7.21 m (1H, =CH), 7.45–7.57 m (1H, Harom),
7.63–7.79 m (4H, Harom), 7.86–7.97 m (3H, Harom),
11.02 s (1H, NH), 11.34 s (1H, OH). Found, %:
C 66.83; H 5.46; N 12.83; S 7.60. C24H24N4O2S. Cal-
culated, %: C 66.67; H 5.56; N 12.96; S 7.41.
1.91–2.15 m (3H, CH3), 2.35–2.48 m (3H, CH3), 2.52–
2.84 m (4H, CH2), 3.48–3.79 m (2H, CH2), 7.16 t (1H,
H
arom, J = 7.14 Hz), 7.34–7.56 m (2H, Harom), 7.96–
8.17 m (1H, Harom), 11.13 br.s (2H, NH, OH). Found,
%: C 59.78; H 5.52; N 16.12; S 9.58. C17H18N4O2S.
Calculated, %: C 59.65; H 5.26; N 16.36; S 9.36.
6-Ethoxy-2-methyl-3-{3-[4-phenyl-1,3-thiazol-
2(3H)-ylidenehydrazinylidene]butyl}quinolin-4-ol
(3f). Yield 0.42 g (94%), mp 256–257°C, Rf 0.68
2-{[4-(4-Hydroxy-2,6-dimethylquinolin-3-yl)-
butan-2-ylidene]hydrazinylidene}-1,3-thiazolidin-4-
one (4b). Yield 0.32 g (91%), mp 275–276°C, Rf 0.58
1
1
(ethanol–toluene, 1:3). H NMR spectrum, δ, ppm:
(ethanol–toluene, 1:2.5). H NMR spectrum, δ, ppm:
1.46 t (3H, CH3CH2, J = 6.75 Hz), 2.03 br.s (3H, CH3),
2.45–2.90 m (7H, CH3, CH2), 4.04–4.25 m (2H,
OCH2), 6.90 s (1H, =CH), 7.14 d.d (1H, Harom, J =
9.13, 2.78 Hz), 7.18–7.27 m (1H, Harom), 7.34 t (1H,
1.91–2.04 m (3H, CH3), 2.31–2.45 m (8H, CH3, CH2),
2.53–2.81 m (2H, CH2), 3.63–3.82 m (2H, CH2), 7.31–
7.47 m (2H, Harom), 7.84 s (1H, Harom), 11.29 br.s (1H,
OH), 11.64 br.s (1H, NH). Found, %: C 60.46; H 5.48;
N 15.89; S 8.75. C18H20N4O2S. Calculated, %:
C 60.67; H 5.62; N 15.73; S 8.99.
Harom, J = 7.54 Hz), 7.57 br.s (2H, Harom), 7.71–7.94 m
(3H, Harom), 10.08–10.94 m (1H, NH), 11.61–12.33 m
(1H, OH). Found, %: C 67.54; H 5.71; N 12.28;
S 7.39. C25H26N4O2S. Calculated, %: C 67.26; H 5.83;
N 12.56; S 7.17.
2-{[4-(4-Hydroxy-2,8-dimethylquinolin-3-yl)-
butan-2-ylidene]hydrazinylidene}-1,3-thiazolidin-4-
one (4c). Yield 0.33 g (92%), mp 321–322°C, Rf 0.65
(ethanol–toluene, 1:3). Found, %: C 60.55; H 5.82;
N 15.56; S 9.14. C18H20N4O2S. Calculated, %:
C 60.67; H 5.62; N 15.73; S 8.99.
6-Bromo-2-methyl-3-{3-[4-phenyl-1,3-thiazol-
2(3H)-ylidenehydrazinylidene]butyl}quinolin-4-ol
(3g). Yield 0.45 g (94%), mp 287–288°C, Rf 0.61
1
(ethanol–toluene, 1:4). H NMR spectrum, δ, ppm:
2-{[4-(4-Hydroxy-6-methoxy-2-methylquinolin-
3-yl)butan-2-ylidene]hydrazinylidene}-1,3-thiazoli-
din-4-one (4d). Yield 0.35 g (93%), mp 308–309°C,
1.96–2.13 m (3H, CH3), 2.32–2.50 m (5H, CH3, CH2),
2.62–2.82 m (2H, CH2), 6.89 s (1H, =CH), 7.16–
7.27 m (1H, Harom), 7.27–7.48 m (3H, Harom), 7.50–
7.63 m (1H, Harom), 7.72–7.90 m (2H, Harom), 8.24 s
(1H, Harom), 10.27–11.17 m (1H, NH), 11.17–11.70 m
(1H, OH). Found, %: C 57.21; H 4.23; N 11.86;
S 6.52. C23H21BrN4OS. Calculated, %: C 57.38;
H 4.37; N 11.64; S 6.65.
1
Rf 0.58 (ethanol–toluene, 1:2). H NMR spectrum, δ,
ppm: 1.86–1.99 m (3H, CH3), 2.06–2.14 br.s (3H,
OCH3), 2.27–2.34 m (5H, CH3, CH2), 2.61–2.87 m
(2H, CH2), 3.58–3.78 m (2H, CH2), 7.41–7.53 m
(2Harom), 7.85 s (1Harom), 11.18 br.s (1H, OH),
11.59 br.s (1H, NH). Found, %: C 58.23; H 5.21;
N 15.26; S 8.46. C18H20N4O3S. Calculated, %:
C 58.06; H 5.38; N 15.05; S 8.60.
4-Hydroxy-2-methyl-3-{3-[4-phenyl-1,3-thiazol-
2(3H)-ylidenehydrazinylidene]butyl}quinoline-6-
carboxylic acid (3h). Yield 0.40 g (90%), mp 273–
274°C, Rf 0.60 (ethanol–toluene, 1:3). Found, %:
C 64.29; H 4.82; N 12.74; S 7.52. C24H22N4O3S. Cal-
culated, %: C 64.56; H 4.93; N 12.55; S 7.18.
2-{[4-(4-Hydroxy-8-methoxy-2-methylquinolin-
3-yl)butan-2-ylidene]hydrazinylidene}-1,3-thiazoli-
din-4-one (4e). Yield 0.36 g (96%), mp 248–249°C,
1
Rf 0.55 (ethanol–toluene, 1:3). H NMR spectrum, δ,
2-{[4-(4-Hydroxy-2-methylquinolin-3-yl)butan-
2-ylidene]hydrazinylidene}-1,3-thiazolidin-4-ones
4a–4h (general procedure). A mixture of 1 mmol of
compound 2a–2h, 4–5 mL of anhydrous ethanol,
0.082 g (1 mmol) of anhydrous sodium acetate, and
0.22 g (0.15 mL, 1.3 mmol) of ethyl bromoacetate was
heated for 4–5 h under reflux with stirring. The mix-
ture was cooled, and the precipitate was filtered off,
washed with ethanol, and recrystallized from ethanol.
ppm: 2.04–2.16 m (3H, CH3), 2.19–2.21 br.s (3H,
OCH3), 2.27–2.30 m (5H, CH3, CH2), 2.67–2.87 m
(2H, CH2), 3.45–3.69 m (2H, CH2), 7.49–7.55 m
(2H, Harom), 7.79 s (1H, Harom), 11.09 br.s (1H, OH),
11.53 br.s (1H, NH). Found, %: C 58.26; H 5.62;
N 14.86; S 8.79. C18H20N4O3S. Calculated, %: C 58.06;
H 5.38; N 15.05; S 8.60.
2-{[4-(6-Ethoxy-4-hydroxy-2-methylquinolin-
3-yl)butan-2-ylidene]hydrazinylidene}-1,3-thiazoli-
din-4-one (4f). Yield 0.38 g (96%), mp 309–311°C,
2-{[4-(4-Hydroxy-2-methylquinolin-3-yl)butan-
2-ylidene]hydrazinylidene}-1,3-thiazolidin-4-one
(4a). Yield 0.33 g (96%), mp 306–307°C, Rf 0.50
1
Rf 0.56 (ethanol–toluene, 1:3). H NMR spectrum, δ,
ppm: 1.56 t (3H, CH3CH2, J = 6.72 Hz), 2.10 br.s (3H,
CH3), 2.46–2.89 m (5H, CH3, CH2), 4.11–4.26 m (2H,
1
(ethanol–toluene, 1:3). H NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 7 2015

SYNTHESIS OF HETARYLQUINOLINES FROM 4-(4-HYDROXY-2-METHYL...
1049
2. Saad, H.A., Osman, N.A., and Moustafa, A.H.,
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OCH2), 2.65–2.88 m (2H, CH2), 3.61–3.75 m (2H,
CH2), 7.46–7.60 m (2H, Harom), 7.84 s (1Harom),
11.22 br.s (1H, OH), 11.57 br.s (1H, NH). Found, %:
C 59.28; H 5.61; N 14.65; S 8.19. C19H22N4O3S. Cal-
culated, %: C 59.08; H 5.70; N 14.51; S 8.29.
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2-{[4-(6-Bromo-4-hydroxy-2-methylquinolin-
3-yl)butan-2-ylidene]hydrazinylidene}-1,3-thiazoli-
din-4-one (4g). Yield 0.41 g (97%), mp 329–331°C,
1
Rf 0.67 (ethanol–toluene, 1:4). H NMR spectrum, δ,
ppm: 2.10–2.16 m (3H, CH3), 2.29–2.32 m (5H, CH3,
CH2), 2.65–2.85 m (2H, CH2), 3.63–3.81 m (2H, CH2),
7.39–7.51 m (2H, Harom), 7.68 s (1H, Harom), 11.34 br.s
(1H, OH), 11.62 br.s (1H, NH). Found, %: C 48.65;
H 4.21; N 13.19; S 7.43. C17H17BrN4O2S. Calculated,
%: C 48.46; H 4.04; N 13.30; S 7.60.
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4-Hydroxy-2-methyl-3-{3-[(4-oxo-1,3-thiazoli-
din-2-ylidene)hydrazinylidene]butyl}quinoline-
6-carboxylic acid (4h). Yield 0.37 g (96%), mp 361–
362°C, Rf 0.44 (ethanol–toluene, 3:1). Found, %:
C 55.81; H 4.41; N 14.72; S 8.42. C18H18N4O4S. Cal-
culated, %: C 55.96; H 4.66; N 14.51; S 8.29.
1
The H NMR spectra were recorded from solutions
in DMSO-d6 on a Varian Mercury-300 spectrometer
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