New quinoline derivatives on the basis of (4-hydroxy-2-methylquinolin-3-yl) acetic acid

Article abstract of DOI:10.1023/B:RUJO.0000044555.03402.9b

A procedure was developed for the synthesis of (4-hydroxy-2-methylquinolin- 3-yl)acetic acid and the corresponding acyl chloride. Reactions of the latter with o-aminobenzenethiol, o-phenylenediamine, o-aminophenol, anthranilic acid, and thiosemicarbazide gave, respectively, 2-(4-hydroxy-2-methylquinolin-3- ylmethyl)-1,3-benzothiazole, -benzoxazole, -benzimidazole, 2-(4-hydroxy-2- methylquinolin-3-ylmethyl)-4H-3,1-benzoxazin-4-one, and 4-hydroxy-2-methyl-3-(5- sulfanyl-1H-1,2,4-triazol-3-ylmethyl)quinoline.

Full text of DOI:10.1023/B:RUJO.0000044555.03402.9b

Russian Journal of Organic Chemistry, Vol. 40, No. 6, 2004, pp. 889–891. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 6, 2004,
pp. 926–928.
Original Russian Text Copyright © 2004 by Avetisyan, Aleksanyan, Pivazyan.
New Quinoline Derivatives on the Basis
of (4-Hydroxy-2-methylquinolin-3-yl)acetic Acid
A. A. Avetisyan, I. L. Aleksanyan, and A. A. Pivazyan
Erevan State University, ul. A. Manukyana 1, Erevan, 375025 Armenia
e-mail: organkim@sun.ysu.am
Received April 21, 2003
Abstract—A procedure was developed for the synthesis of (4-hydroxy-2-methylquinolin-3-yl)acetic acid
and the corresponding acyl chloride. Reactions of the latter with o-aminobenzenethiol, o-phenylenediamine,
o-aminophenol, anthranilic acid, and thiosemicarbazide gave, respectively, 2-(4-hydroxy-2-methylquinolin-3-
ylmethyl)-1,3-benzothiazole, -benzoxazole, -benzimidazole, 2-(4-hydroxy-2-methylquinolin-3-ylmethyl)-4H-
3,1-benzoxazin-4-one, and 4-hydroxy-2-methyl-3-(5-sulfanyl-1H-1,2,4-triazol-3-ylmethyl)quinoline.
Quinolines are widely spread in nature, and many
biologically active substances include a quinoline
fragment [1–3]. Both natural and synthetic quinoline
derivatives exhibit antiallergic, spasmodic, psycho-
tropic, neurotropic, and antiphlogistic activity, and
they attract interest from the practical viewpoint,
specifically for the preparation of medicines [4, 5].
EXPERIMENTAL
1
The H NMR spectra were obtained on a Varian
Mercury-300 instrument in DMSO-d6. The IR spec-
trum of acid II was recorded on a UR 20 spectrometer
in mineral oil. The purity of the products was checked
by TLC on Silufol UV-254 plates (development with
iodine vapor). The yields and elemental analyses of
compounds I–IX are given in table.
We have developed a convenient procedure for the
synthesis of (4-hydroxy-2-methylquinolin-3-yl)acetic
acid (II) and -acetyl chloride (III). The procedure is
based on thermal cyclization of ethyl α-ethoxycar-
bonylmethyl-β-phenylaminocrotonate which is obtain-
ed by reaction of diethyl acetylsuccinate [6] with
aniline at room temperature. Alkaline hydrolysis of the
cyclization product, ethyl (4-hydroxy-2-methylquino-
lin-3-yl)acetate (I) gave (4-hydroxy-2-methylquino-
lin-3-yl)acetic acid (II). Treatment of the latter with
thionyl chloride in anhydrous benzene in the presence
of DMF afforded acyl chloride hydrochloride III in
almost quantitative yield. We examined reactions of
III with some nucleophilic reagents, in particular
o-aminobenzenethiol, o-phenylenediamine, o-amino-
phenol, anthranilic acid, and thiosemicarbazide. These
reactions smoothly occurred on heating equimolar
amounts of the reactants in anhydrous pyridine on
a water bath, and the yield of the target products
ranged from 68 to 96%. By reaction of III with thio-
semicarbazide we obtained compound VIII which
underwent intramolecular cyclization in acidic or basic
medium, leading to 4-hydroxy-2-methyl-3-(5-sulfanyl-
1H-1,2,4-triazol-3-ylmethyl)quinoline (IX) (Scheme 1).
Ethyl (4-hydroxy-2-methylquinolin-3-yl)acetate
(I). A mixture of 21.6 g (0.1 mol) of diethyl acetyl-
succinate [6] and 9.3 g (0.1 mol) of freshly distilled
aniline was left to stand at room temperature in
a desiccator charged with phosphorus(V) oxide until
a required amount of water (1.8 ml) was separated.
The resulting material was then washed with strongly
dilute hydrochloric acid and with water, dried over
MgSO4, and subjected to heterocyclization. For this
purpose, 14.55 g (0.05 mol) of ethyl α-ethoxycar-
bonylmethyl-β-phenylaminocrotonate was added drop-
wise under vigorous stirring in a stream of nitrogen to
200 ml of mineral oil heated to 250°C. The mixture
was cooled, and the precipitate was filtered off,
washed with benzene, and recrystallized from acetic
acid. 1H NMR spectrum, δ, ppm: 1.3 s (3H, CH3), 2.5 s
(3H, CH3), 3.5 t (2H, CH2), 4.1 s (2H, CH2), 7.2–8.0 m
(4H, Harom), 11.25 s (1H, OH).
(4-Hydroxy-2-methylquinolin-3-yl)acetic acid
(II). A mixture of 2.45 g (0.01 mol) of ethyl ester I,
1.2 g (0.03 mol) of NaOH dissolved in 50 ml of water,
and 30 ml of ethyl alcohol was heated for 4 h on
1070-4280/04/4006-0889 © 2004 MAIK “Nauka/Interperiodica”

AVETISYAN et al.
890
Scheme 1.
OH
OH
OH
CH2COOEt
Me
CH2COOH
CH2COCl
Me
NaOH
NaOH
·HCl
N
N
Me
N
I
II
III
SH
OH
OH
OH
S
O
N
NH2
NH2
N
N
Me
N
Me
IV
VI
III
NH2
NH2
COOH
NH2
OH
OH
H
N
O
N
N
O
H2NNHC(S)NH2
N
Me
N
Me
V
VII
OH
N
S
OH
N
H
N
N
N
NH2
SH
H
O
N
NH
Me
Me
IX
VIII
a water bath. The alcohol was distilled off, the residue
was diluted with 20 ml of cold water, the mixture was
filtered, the filtrate was acidified to pH 4–5, and the
precipitate was filtered off. IR spectrum, ν, cm–1: 1730
left overnight. The precipitate of IV was filtered off,
washed with water, and recrystallized from aqueous
alcohol. 1H NMR spectrum, δ, ppm: 2.45 s (3H, CH3),
3.00 s (2H, CH2), 6.6–8.1 m (8H, Harom), 11.20 s
(1H, OH).
1
(C=O, acid), 2700–3000 (OH, acid). H NMR spec-
trum, δ, ppm: 2.55 s (3H, CH3), 3.60 s (2H, CH2), 7.2–
2-(4-Hydroxy-2-methylquinolin-3-ylmethyl)-1,3-
benzimidazole (V) was synthesized in a similar way
from 0.68 g (0.0025 mol) of compound III and 0.27 g
8.1 m (4H, Harom), 11.15 s (2H, OH).
(4-Hydroxy-2-methylquinolin-3-yl)acetyl chlor-
ide hydrochloride (III). A solution of 9 g (0.075 mol)
of thionyl chloride in a mixture of 20 ml of anhydrous
benzene and 4 ml of DMF was added on cooling to
a solution of 2.17 g (0.05 mol) of acid II in 50 ml of
anhydrous benzene. The mixture was heated for 3 h on
a water bath and cooled, and the precipitate of III was
filtered off and washed with anhydrous benzene.
1
(0.0025 mol) of o-phenylenediamine. H NMR spec-
trum, δ, ppm: 2.51 s (3H, CH3), 2.90 s (2H, CH2), 6.6–
8.0 m (8H, Harom), 9.6 s (1H, NH), 11.05 s (1H, OH).
2-(4-Hydroxy-2-methylquinolin-3-ylmethyl)-1,3-
benzoxazole (VI) was synthesized in a similar way
from 0.68 g (0.0025 mol) of compound III and
1
0.2725 g (0.0025 mol) of o-aminophenol. H NMR
spectrum, δ, ppm: 2.54 s (3H, CH3), 2.9 t (2H,
CH2), 6.6–7.1 m (4H, Harom), 7.4–8.0 m (4H, Harom),
11.2 s (1H, OH).
2-(4-Hydroxy-2-methylquinolin-3-ylmethyl)-1,3-
benzothiazole (IV). A mixture of 0.68 g (0.0025 mol)
of acyl chloride III and 0.3125 g (0.0025 mol) of
o-aminobenzenethiol in 10 ml of anhydrous pyridine
was heated for 5–6 h on a water bath. Pyridine was
distilled off under reduced pressure, 30 ml of cold
water was added to the residue, and the mixture was
2-(4-Hydroxy-2-methylquinolin-3-yl)methyl)-
4H-3,1-benzoxazin-4-one (VII). A mixture of 0.68 g
(0.0025 mol) of compound III and 0.34 g (0.0025 mol)
of anthranilic acid in 15 ml of anhydrous pyridine was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 6 2004

NEW QUINOLINE DERIVATIVES
891
Yields, melting points, Rf values, and elemental analyses of compounds I–IX
Found,%
Calculated,%
Comp. Yield,
mp, °C Rf
Formula
no.
%
C
H
N
S
–
–
–
C
H
N
S
61
95
88
245
300
–
–
68.40 6.20 05.65
0.7a0 66.50 5.20 06.60
53.20 3.85 05.25
C14H15NO3
C12H11NO3
68.57 6.12 05.71
66.36 5.07 06.45
–
–
–
I
II
–
C12H10ClNO2·HCl 52.94 4.04 05.15
III
IV
V
72
68
96
75
196 0.61b 67.90 4.42 09.54 10.30 C18H14N2OS
68.35 4.57 09.15 10.45
285
240
0.67c 75.05 5.42 14.66
0.44a 74.60 4.72 09.45
300 0.46b 71.20 4.55 08.92
–
–
–
C18H15N3O
C18H14N2O2
C19H14N2O3
74.74 5.19 14.53
74.48 4.82 09.65
71.70 4.40 08.80
–
–
–
VI
VII
75
282
230
–
53.97 4.68 19.12 11.25 C13H14N4O2S
53.79 4.82 19.31 11.03
57.35 4.41 20.58 11.76
VIII
IX
91 (a)
89 (b)
0.40a 57.15 4.66 20.87 11.55 C13H12N4OS
56.90 4.55 20.45
a
b
c
Eluent chloroform–acetone, 10:1.
Eluent benzene–acetone, 6:1.
Eluent benzene–acetone, 3:1.
heated for 8–10 h under reflux. The solvent was dis-
tilled off under reduced pressure, 20 ml of cold water
was added to the residue, and the mixture was acidified
to pH 4 and was left overnight. The precipitate of VII
the mixture was left to stand for 24 h at room
temperature. It was then poured into ice water and
neutralized to pH 5–6, and the precipitate was filtered
off and recrystallized from aqueous alcohol (1:1).
Samples of IX prepared as described in a and b
showed no depression of the melting point on mixing.
1H NMR spectrum, δ, ppm: 2.5 s (3H, CH3), 3.10 s
(2H, CH2), 7.50–7.9 m (4H, Harom), 8.35 s and 8.40 s
(2H, NH), 11.5 s (1H, OH).
1
was filtered off and washed with water. H NMR
spectrum, δ, ppm: 2.45 s (3H, CH3), 2.90 s (2H, CH2),
7.0–8.0 (8H, Harom), 11.20 s (1H, OH).
N1-[(4-Hydroxy-2-methylquinolin-3-yl)acetyl]-
thiosemicarbazide (VIII). A mixture of 0.68 g
(0.0025 mol) of chloride III and 0.228 g (0.0025 mol)
of thiosemicarbazide in 10 ml of anhydrous pyridine
was heated for 9–10 h on a water bath. After cooling,
the precipitate was filtered off and recrystallized from
aqueous alcohol.
REFERENCES
1. Michael, J.P., Nat. Prod. Rep., 1997, vol. 14, p. 11.
2. Bellino, A. and Venturella, P., Heterocycles, 1986,
vol. 24, p. 1821.
4-Hydroxy-2-methyl-3-(5-sulfanyl-1H-1,2,4-
triazol-3-ylmethyl)quinoline (IX). a. A mixture of
0.725 g (0.0025 mol) of thiosemicarbazide VIII and
10 ml of a 20% solution of NaOH was heated on
a water bath until it became homogeneous and was
then heated for an additional 2 h. The solution was
cooled and filtered, and the filtrate was acidified to
pH 5–6. The precipitate was filtered off and recrystal-
lized from aqueous alcohol.
3. Ramesh, C.A. and Selvapalam, N., J. Chem. Res., Synop.,
1998, no. 6, p. 531.
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organicheskikh preparatov, Moscow: Inostrannaya Lite-
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b. Concentrated sulfuric acid, 3 ml, was added to
0.725 g (0.0025 mol) of thiosemicarbazide VIII, and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 6 2004