Synthesis and antibacterial activity of substituted quinoline derivatives

Article abstract of DOI:10.14233/ajchem.2016.19393

An efficient and convenient method is reported for the synthesis of various substituted quinolines through the condensation of o-amino aryl carbonyls with ketones containing an active methylene group in the presence of CuSO₄·5H₂O as

Full text of DOI:10.14233/ajchem.2016.19393

Asian Journal of Chemistry; Vol. 28, No. 9 (2016), 1891-1894
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19393
Synthesis and Antibacterial Activity of Substituted Quinoline Derivatives
1
2,*
S. RAVINDRA and ALKA RANI
1
2
Centre for Chemical Sciences and Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-500085, India
Department of Chemistry, Hindu College, Moradabad-244 001, India
*
Corresponding author: E-mail: alka.c@yahoo.com
Received: 14 November 2015; Accepted: 28 April 2016;
Published online: 1 June 2016;
AJC-17910
An efficient and convenient method is reported for the synthesis of various substituted quinolines through the condensation of o-amino
aryl carbonyls with ketones containing an active methylene group in the presence of CuSO ·5H O as catalyst at room temperature to yeild
4
2
substituted quinolines (3a-l). All the synthesized compounds were fully characterized and screened for their antibacterial activities.
Keywords: Substituted quinolines, Antibacterial activity, o-Aminoarylketone.
conditions, low yields, high temperature, tedious work-up and
the use of stoichiometric and relatively expensive reagents [10-
INTRODUCTION
Quinoline is a common structural unit found in many
15].As a part of our continuing efforts towards the development
natural products with remarkable pharmacological properties.
Members of this family have wide applications in medicinal
chemistry [1-3]. The classical methods for the synthesis of
quinolines, such as Scrup, Doebner-von Miller, Doebner,
Combes, Pfitzinger quinoline syntheses, require harsh reaction
conditions and the yields are unsatisfactory in most cases. The
Friedlander annulations are the simplest, most straightforward
synthetic method for the synthesis of quinoline derivatives,
especially for the highly substituted 3-quinoline carboxylic
esters [4,5]. This method usually involves acid- or base-
catalyzed or thermal (up to 250 °C) condensation between a
of useful synthetic methodologies, we planned to develop a
new method for the synthesis of quinolines and its novel
derivatives via Friedlander annulation approach catalyzed by
copper sulphate. We observed high efficiency of CuSO
4
·5H O
2
(
20 mol %) in sequential condensation/annulation reactions
of o-aminoaryl carbonyls and ketones containing an active
methylene group for the synthesis of substituted quinolines.
EXPERIMENTAL
All the used reactants, reagents and solvents were obtained
from commercial sources and were of analytical grade. Melting
1
2
-aminoaryl ketone or aldehyde and a secondary carbonyl
points were determined by open capillary method. H NMR
1
3
compound possessing a reactive α-methylene group, followed
by cyclodehydration.
(DMSO-d
6
300, 500 MHz) and C NMR (DMSO-d , 300
6
MHz) were recorded on spectrometer TMS as internal standard
(chemical shifts and ppm). Mass spectra were recorded on a
VG micromass70-70H instrument.
General procedure for the synthesis of ethyl 2-methyl-
4-phenylquinoline-3-carboxylate (3a): A mixture of 2-amino-
5-chlorobenzophenone (0.231 g, 1.00 mmol), ethyl 4-chloro-
Friedlander reported quinoline synthesis in 1882 by the
condensation of o-aminobenzaldehyde with acetaldehyde in
the presence of sodium hydroxide. Acid catalysts such as
hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and
phosphoric acids are widely used for this conversion. However,
many of these classical methods require high temperatures,
prolonged reaction times and drastic conditions and the yields
reported are unsatisfactory due to the formation of several side
products [6-9]. Therefore, new catalytic systems are being
continuously explored in search of improved efficiencies and
cost effectiveness. However in recent times iodine, Lewis acids
3-oxobutanoate (0.164 g, 1.00 mmol) and CuSO
4
·5H O
2
(0.049 g, 0.2 mmol, 20 mol %) in ethanol (10 mL) was stirred
at room temperature for 3-4 h. The reaction mixture was
monitored by TLC. After completion of the reaction, the
reaction mixture was concentrated under vacuum. EtOAc (40
mL), was added to the crude product and washed with water
such as ZnCl
e.g., NaAuCl
Even some of these methods also suffer from harsh reaction
2
andAuCl
3
·3H
2
O, a combination of acidic catalysts
(20 mL), dried over anhydrous Na
reduced pressure. The resulting residue was purified by silica
gel column chromatography using EtOAc:hexane (1:10) to
2
SO and concentrated under
4
[
4
, Bi(OTf)
3
, Nd(NO
3
)
3
·6H O] and microwave
2

1
892 Ravindra et al.
Asian J. Chem.
afford the pure product 3a as a pale yellow coloured solid
3.57 (s, 3H), 7.30-7.37 (m, 2H), 7.45-7.57 (m, 4H), 7.61-7.68
1
13
(
0.294 g, 82 %). m.p. 100-103 °C; H NMR (300 MHz, CDCl
3
):
(m, 1H), 8.00 (d, 1H, J = 8.92 Hz); C NMR (75 MHz, CDCl
3
):
δ 0.95 (t, 3H, J = 6.79 Hz), 2.79 (s, 3H), 4.07 (q, 2H, J = 6.79
Hz), 7.33-7.53 (m, 6H), 7.59 (dd, 1H, J = 8.30 Hz, J = 1.51
δ 23.61, 52.16, 125.12, 125.73, 127.91, 128.38, 128.69,
129.02, 130.41, 131.08, 132.27, 134.81, 145.43, 145.98,
13
+
Hz), 7.67-7.78 (m, 1H), 8.08 (d, 1H, J = 8.30 r Hz); C NMR
300 MHz, CDCl ): δ 13.5, 23.7, 61.2, 125.0, 126.3, 126.4,
27.3, 128.1, 128.3, 128.7, 129.2, 130.1, 135.6, 146.1, 147.6,
154.79, 168.52; ESI-MS: m/z 312 (M +H); HRMS calculated
+
(
3
for C18
H
15
O
2
NCl (M +H) 312.0785, found 312.0799.
1
1
1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)ethanone
+
1
54.5, 168.3; ESI-MS: m/z 292 (M +H); HRMS calculated
(3h): m.p. 150-152 °C; H NMR (500 MHz, CDCl ): δ 2.00
3
+
for C19
H17NO
2
(M +H) 292.1332, found 292.1323.
(s, 3H), 2.68 (s, 3H), 7.30-7.40 (m, 2H), 7.49-7.61 (m, 4H),
9
-Phenyl-3,4-dihydroacridin-l(2H)-one (3b): m.p. 152-
7.66 (dd, 1H, J = 9-06 Hz, J = 2.26 Hz), 8.02 (d, 1H, J = 9.06
1
13
1
2
2
54 °C; H NMR (500 MHz, CDCl
3
): δ 2.20-2.30 (m, 2H),
Hz); C NMR (75 MHz, CDCl
3
): δ 23.81, 31.86, 124.98,
.70 (t, 2H, J = 5.99 Hz), 3.38 (t, 2H, J = 5.99 Hz), 8.12 (d,
H, J = 5.99 Hz), 7.36-7.57 (m, 5H), 7.71-7.81 (m, 1H), 8.06
126.08, 126.44, 128.64, 128.82, 129.98, 134.77, 135.15,
+
143.85, 147.48, 153-47, 205.56; ESI-MS: m/z 296 (M +H);
13
+
(
3
1
d, 1H, J = 8.99 Hz); C NMR (300 MHz, CDCl
3
): δ 21.31,
4.53, 40.57, 126.37, 127.42, 127.48, 127.94, 128.02, 128.17,
28.37, 131.69, 137.57, 148.57, 151.39, 162.18, 197.94; ESI-
HRMS (ESI) calculated for C18
found 296.0847.
H
15ONC1 (M +H) 296.0836,
1
Ethyl 2,4-dimethylquinoline-3-carboxylate (3i): H
+
+
MS: m/z 296 (M +Na), 274 (M +H); HRMS (ESI) calculated
for C19
3
NMR (300 MHz, CDCl ): δ 1.44 (t, 3H, J = 7.17 Hz), 2.65 (s,
+
H
16NO (M +H) 274.1226, found 274.1227.
3H), 2.71 (s, 3H), 4.48 (q, 2H, J = 7.17 Hz), 7.47-7.62 (m,
13
1
-(2-Methyl-4-phenylquinolin-3-yl)ethanone (3c): m.p.
1H), 7.65-7.79 (m, 1H), 7.93-8.11 (m, 2H); C NMR (75 MHz,
CDCl ): δ 14.17, 15.57, 23.69, 61.56, 123.89, 125.71, 126.21,
1
110-112 °C; H NMR (500 MHz, CDCl
3
): δ 1.95 (s, 3H), 2.67
3
13
(
s, 3H), 7.31-7.71 (m, 8H), 8.03 (d, 1H, J = 9.06 Hz);
C
127.93, 129.20, 129.93, 141.33, 147.05, 154.25, 169.09; ESI-
+
NMR (75 MHz, CDCl
1
1
3
): δ 23.81, 31.86, 124.98, 126.08,
MS: m/z 230 (M +H); HRMS (ESI) calculated for
+
26.44, 128.64, 128.82, 129.98, 134.77, 135.15, 143.85,
C
14
H
15NO
2
Na (M +Na) 252.0995, found 252.1008, C14
H
16NO
2
+
+
47.48, 153.47, 205.56; ESI-MS: m/z 284 (M +Na), 262
(M +H) calculated 230.1175 found 230.1182, 179.0176,
157.0357.
+
(
M+H); HRMS (ESI) calculated for C18
H
15NONa (M +Na)
1
2
84.1045, found 284.1055 and calculated for C18
H
16NO
Methyl 2,4-dimethylquinoline-3-carboxylate (3j): H
+
(
M +H) 262.1226, found 262.1235.
Ethyl 2-(chloromethyl)-4-phenylquinoline-3-carboxylate
3
NMR (300 MHz, CDCl ): δ 2.63 (s, 3H), 2.70 (s, 3H), 4.00 (s,
3H), 7.49-7.60 (m, 1H), 7.67-7.78 (m, 1H), 7.94-8.90 (m, 2H);
1
13
(
3d): m.p. 105-106 °C; H NMR (300 MHz, CDCl
3
): δ 0.92
C NMR (75 MHz, CDCl ): δ 15.73, 23.73, 52.42, 123.93,
3
(
7
7
t, 3H, J = 7.17 Hz), 4.05 (q, 2H, J = 7.17 Hz), 5.03 (s, 2H),
126.61, 126.25, 127.62, 129.13, 130.03, 141.61, 147.02,
+
.32-7.42 (m, 2H), 7.44-7.58 (m, 4H), 7.60-7.68 (m, 1H), 7.73-
154.27, 169.60; ESI-MS: m/z 216 (M +H); HRMS calculated
13
+
.83 (m, 1H), 8.15 (d, 1H, J = 8.30 Hz); C NMR (75 MHz,
): δ 13.38, 45.64, 61.67, 125.31, 126.95, 128.44, 128.64,
28.83, 129.10, 131.14, 131.66, 133.79, 134.89, 145.63,
for C13
H
13NO
2
+
Na (M +Na) 238.0838, found 238.0846,
CDCl
1
1
(
3
3
C
13
H
14NO
2
(M +H) calculated 216.1019 found 216.1026,
179.0177.
+
1
47.29, 153.31, 167.25; ESIMS: m/z 348 (M +Na), 326
1-(2,4-Dimethylquinolin-3-yl)ethanone (3k): H NMR
+
+
M +H); HRMS calculated for C19
48.0761, found 348.0777.
,3-Dimethyl-9-phenyl-3,4-dihydroacridin-l(2H)-one
H
16NO
2
Cl Na (M +Na)
3
(300 MHz, CDCl ): δ 2.54 (s, 3H), 2.57 (s, 3H), 2.62 (s, 3H),
7.46-7.58 (m, 1H), 7.63-7.74 (m, 1H), 7.88-7.97 (m, 1H), 8.01
13
3
(d, 1H, J = 8.30 Hz); C NMR (75 MHz, CDCl ): δ 15.02,
3
1
(
(
3e): m.p. 192-194 °C; H NMR (300 MHz, CDCl
s, 6H), 2.58 (s, 2H), 3.28 (s, 2H), 7.13-7.24 (m, 2H), 7.35-
.61 (m, 5H), 7.71-7.82 (m, 1H), 8.07 (d, 1H, J = 8.30 Hz);
3
): δ 1.16
23.21, 32.44, 123.43, 125.68, 126.17, 128.85, 129.61, 135.43,
+
138.48, 146.53, 152.33, 206.44; ESI-MS: m/z 200 (M +H).
7
Ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-
13
1
C NMR (125 MHz, CDCl
3
): δ 28.27, 32.17, 48.30, 54.13,
carboxylate (3l): H NMR (300 MHz, CDCl
3
): δ 0.92 (t, 3H,
1
1
22.61, 126.36, 127.33, 127.44, 127.95, 128.04, 128.18,
28.43, 131.58, 137.50, 148.91, 150.93, 161.07, 197.87; ESI-
J = 7.17 Hz), 4.05 (q, 2H, J = 7.17 Hz), 5.00 (s, 2H), 7.30-
7.41 (m, 2H), 7.47-7.57 (m, 3H), 7.59 (d, 1H, J = 2.07 Hz),
+
+
MS: m/z 324 (M +Na), 302 (M +H); HRMS (ESI) calculated
for C21
C
7.71 (dd, 1H, J = 8.87 Hz, J = 2.26 Hz), 8.09 (d, 1H, J = 8.87
+
13
H
19NONa (M +Na) 324.1358, found 324.1368,
Hz); C NMR (75 MHz, CDCl
3
): δ 13.38, 45.64, 61.67,
+
21
H
20NO (M +H) calculated 302.1539 found 302.1551.
125.31, 126.95, 128.44, 128.64, 128.83, 129.10, 131.14,
131.66, 133.79, 134.89, 145.63, 147.29, 153.31, 167.25; ESI-
Ethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate
1
+
(
3f): m.p. 103-105 °C; H NMR (300 MHz, CDCl
3
): δ 0.95 (t,
H, J = 7.55 Hz), 2.78 (s, 3H), 4.07 (q, 2H, J = 7.55 Hz), 7.32-
.41(m, 2H), 7.45-7.58 (m, 4H), 7.61-7.70 (m, 1H), 8.02 (d,
MS: 360 (M +H).
3
7
1
6
1
RESULTS AND DISCUSSION
13
H, J = 9.06 Hz); C NMR (125 MHz, CDCl ): δ 13.59, 23.67,
1.43, 125.15, 125.90, 128.13, 128.39, 128.71, 129.22, 130.45,
3
Twelve novel compounds (3a-l) in good yields (Table-1)
have been synthesized via 2-amino-5-chloro benzophenones
by employing the reaction sequences as shown in Scheme-I.
The synthesis of substituted qinolines primarily is due to
an appropriate Cu(II) salt as Lewis acid activator and finding
out right conditions that would favour dehydration. To this
end, copper sulfate pentahydrate was considered an attractive
31.07, 132.29, 134.95, 145.36, 146.01, 154.95, 168.03; ESI-
+
MS: m/z 326 (M +H); HRMS (ESI) calculated for
C
C
+
19
H
16
O
2
NClNa (M +Na) 348.07618, found 348.0775,
NCl (M+H) calculated 326.0942 found 326.0957.
Methyl 6-chloro-2-methyl-4-phenylquinoline-3-
19
H
17
O
2
1
carboxylate (3g): H NMR (500 MHz, CDCl ): δ 2.76 (s, 3H),
3

Vol. 28, No. 9 (2016)
Synthesis and Antibacterial Activity of Substituted Quinoline Derivatives 1893
Ph O
O
.
O
O
CuSO 5H O
4 2
OEt
Ph
NH2
H C
OEt
3
N
CH3
EtOH, RT
1
a-c
2a-f
3a-l
Reaction conditions: o-Aminoarylketone (1 mmol), -methyleneketone (1 mmol), CuSO
4
·5H O (20 mol %), ethanol 10 mL)
2
Scheme-I: Synthesis of substituted quinolines (3a-l)
catalyst in view of its attenuated Lewis acidity, ability to
coordinate with hydroxy group and excellent performance as
an alcohol dehydration catalyst. Herein, we reveal a simple,
inexpensive, mild and efficient method for the condensation
of o-aminoaryl carbonyls with ketones containing an active
spectrum of ethyl 2-methyl-4-phenylquinoline-3-carboxylate
δ 13.5, 23.7, 61.2, 125.0, 126.3, 126.4, 127.3
Antibacterial activity:All the newly prepared compounds
(3a-l) were screened for the antibacterial activity is performed
according to the paper disc method [16,17]. The antibacterial
screening data showed that almost all the compounds 3a-l are
active and showing moderate to good antibacterial activity.
Among the screened 3b, 3e, 3f, 3j and 3j in which respectively
showed high activity against all the micro-organism employed.
The activities of these compounds are almost equal to the
standards and the remaining compounds showed moderate to
good antibacterial activity (Table-2).
methylene group by using catalytic amount of CuSO
4
·5H O
2
(
20 mol %) at room temperature to afford the polysubstituted
1
quinolines (3a-l) in high yields (Scheme-I). H NMR spectrum
of ethyl 2-methyl-4-phenylquinoline-3-carboxylate 3a δ 0.95
(
t, 3H, J = 6.79 Hz), 2.79 (s, 3H), 4.07 (q, 2H, J = 6.79 Hz),
7
7
.33-7.53 (m, 6H), 7.59 (dd, 1H, J = 8.30 Hz, J = 1.51 Hz),
.67-7.78 (m, 1H), 8.08 (d, 1H, J = 8.30 r Hz) and C NMR
13
TABLE-1
SYNTHESIZED SUBSTITUTED QUINOLINES
S.
No.
o-Amino-
ketone
S.
No.
o-Amino-
ketone
Ketone
Product
Ketone
Product
Ph
O
O
O
Ph
O
O
O
O
O
Cl
Cl
Cl
OEt
CH3
OMe
Ph
Ph
1
H C
OEt
95
7
H3C
OMe
95
3
NH2
O
N
NH2
N
CH3
O
2
a
2f
1
a
1b
3g
3a
O
Ph
O
Ph
O
O
O
O
O
O
Cl
Ph
Ph
CH3
2
3
4
5
6
85
93
82
80
94
8
H C
CH3
OEt
80
95
92
83
85
3
NH2
N
3b
NH2
N
CH3
O
2c
1
1
1
1
a
a
a
a
2b
1b
3h
O
Ph
O
O
CH3
O
O
O
O
Ph
CH3
CH3
OEt
H C
CH3
9
H C
3
3
NH2
N
CH3
NH2
O
N
CH3
2c
2a
2f
3c
1c
1c
1c
3i
O
Ph
O
CH3
O
O
O
O
Ph
OEt
Cl
CH3
OMe
Cl
OEt
10
11
12
H3C
OMe
CH3
OEt
NH2
N
NH2
N
CH3
2d
3d
3j
O
O
Ph
O
O
CH3
O
O
Ph
CH3
NH2
CH3
CH3
CH3
CH3
H C
3
NH2
N
3e
CH3
N
CH3
O
2c
2d
2e
3k
O
Ph
O
O
Ph
O
O
O
O
O
Cl
Cl
Cl
OEt
Ph
OEt
Cl
Ph
NH2
H3C
OEt
Cl
N
CH3
NH2
N
2a
1b
3f
1b
3l

1
894 Ravindra et al.
Asian J. Chem.
TABLE-2
ANTIBACTERIAL ACTIVITY OF SUBSTITUTED QUINOLINES (3a-l)
Escherichia coli (Gram-negative) (conc. µg/mL)
Staphylococcus aureus (Gram-positive) (conc. µg/mL)
Compounds
2
00
100
20
14
13
-
50
200
12
31
-
18
28
23
11
22
13
14
26
3
100
21
24
14
-
50
9
22
7
11
23
22
17
15
17
11
19
8
3
3
a
b
20
12
11
14
18
12
23
11
22
13
14
12
12
8
3
c
3
d
11
30
22
17
17
17
11
11
8
3
e
19
12
19
15
11
-
19
32
19
15
11
-
3
f
3
3
g
h
3
i
3
j
3
k
11
6
29
6
3
l
Ciprofloxacin (100 µg/disc)
20
21
1
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