Ultrasound-promoted synthesis of novel 2-chloroquinolin-4-pyrimidine carboxylate derivatives as potential antibacterial agents

Article abstract of DOI:10.1007/s11164-012-0715-6

Ultrasound-promoted reaction of substituted 2,4-dichloroquinolines (1) with ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5- carboxylate (2) in the presence of K₂CO₃ as mild base at moderate temperatures leads

Full text of DOI:10.1007/s11164-012-0715-6

Res Chem Intermed (2013) 39:1807–1815
DOI 10.1007/s11164-012-0715-6
Ultrasound-promoted synthesis of novel
2-chloroquinolin-4-pyrimidine carboxylate
derivatives as potential antibacterial agents
•
•
•
G. L. Balaji K. Rajesh Shabana Kouser Ali
V. Vijayakumar
Received: 8 May 2012 / Accepted: 2 July 2012 / Published online: 19 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Ultrasound-promoted reaction of substituted 2,4-dichloroquinolines (1)
with ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (2) in the presence of K2CO3 as mild base at moderate temperatures
leads to 2-chloroquinolin-4-pyrimidine carboxylate derivatives (3) with high regi-
oselectivity. All the compounds synthesized were characterized by use of spectral
data and screened for their antibacterial activity against two Gram-positive
(Staphylococcus aureus, Bacillus cereus) and two Gram-negative (Escherichia coli
and Pseudomonas aeruginosa) bacteria. Activity was moderate.
Keywords 2,4-Dichloroquinolines ꢀ Pyrimidone ꢀ Sonication ꢀ
Antibacterial activity
Introduction
Quinolines and their annelated derivatives are important compounds because of
their presence in numerous natural products and their wide range of biological
applications, for example antimalarial and anticancer. In particular, chloroquine has
long been used for treatment of malaria [1, 2]. Correlation of the structure of
Electronic supplementary material The online version of this article
(doi:10.1007/s11164-012-0715-6) contains supplementary material, which is available
to authorized users.
G. L. Balaji ꢀ K. Rajesh ꢀ V. Vijayakumar (&)
Synthetic Organic Chemistry Research Laboratory, Organic Chemistry Division, School
of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: kvpsvijayakumar@gmail.com
S. Kouser Ali
School of Biosciences and Technology, VIT University, Vellore 632 014, Tamil Nadu, India
123

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G. L. Balaji et al.
O
O
N
HN
O
HN
NH
HN
NH
Cl
N
Cl
Cl
N
Cl
Cl
N
C
H
O
N
Chloroquine
Metaquine
3f
Fig. 1 Structural correlation of compound 3f with known drugs
2,7-dichloroquinolin-4-pyrimidine carboxylate with those of commercial antimalarial
drugs reveals that the molecules share the same basic heterocyclic skeleton (Fig. 1).
Some quinoline derivatives, and their salts and esters, can be used in the
prophylaxis or treatment of arthritis, cardiovascular diseases, diabetes, renal failure,
and, in particular, eating disorders and obesity [3]. 2-Chloroquinoline derivatives
have recently been reported to be carcinogenic in rats [4]. 2,4-Disubstituted
quinolines with additional substituents at positions 5 and 8 have anthelmintic
properties and are also active against drug-resistant nematodes [5, 6]. From the
perspective of the diversity of quinolines, 2,4-dichloro quinolines can be used as key
intermediates in the synthesis of 2,4-disubstituted quinolines by stepwise substi-
tution at the C4 and C2 positions, thereby introducing a new C–O bonding between
the two heterocyclic nuclei; this leads to a wide range of new structures with
biological or other interesting properties. This prompted us to conduct this work, in
which one of the chlorine atoms in 2,4-dichloroquinolines is selectively replaced by
a pyrimidine carboxylate moiety, chosen on the basis of our continuing interest in
quinolines [7–9] and their applications in medicinal chemistry [10–12].
Ultrasonic irradiation is an efficient and innocuous technique for reagent
activation in the synthesis of organic compounds. With heterocyclic compounds,
in particular, it has been used with success to achieve higher yields under milder
reaction conditions than by use of classical methods [13–16]. Ultrasound-promoted
synthesis has attracted much attention in recent decades. One advantage of using
cavitation as an energy source to promote organic reactions includes shorter reaction
times. This procedure is regarded as a clean and useful procedure in organic
synthesis compared with traditional methods; it is also, usually, more convenient.
Experimental
Chemicals were purchased from Sigma–Aldrich and Merck, and used without
additional purification. All reactions were monitored by thin-layer chromatography
(TLC). Melting points were recorded on an Elchem digital melting-point apparatus
in open capillaries and are uncorrected. The ultrasound for sonochemical synthesis
was generated by use of an E-chrom (Taiwan) instrument (diameter of titanium tip
of horn 1.3 9 10-2 m, surface area of ultrasound irradiating face 1.32 9 10-4 m2)
1
with an operating frequency of 22 KHz and rated output power 800 W. H NMR
spectroscopy was performed with a Bruker Avance 400-MHz instrument at room
123

Ultrasound-promoted synthesis
1809
temperature. Spectra of *0.03 M solutions in CDCl3 were acquired; TMS was used
as internal reference. The accuracy of the 1H shifts is believed to be 0.02 ppm. The
coupling constants J are in Hz. Mass spectra were obtained by ESI mass
spectrometry.
General procedure for preparation of ethyl 4-(3-(2-chloroquinolin-4-
yloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
derivatives 3a–3i
Conventional method
The substituted 2,4-dichloroquinolines 1a–1i were prepared in accordance with a
literature method [11]. Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (5 mmol) and K2CO3 (15 mmol) were added to a
solution of the appropriate 2,4-dichloroquinoline (5 mmol) in 20 mL DMF, and the
mixture was heated under reflux at 60 °C for 15 h. After completion of the reaction,
the mixture was poured into ice-cold water and the product was collected by
filtration and recrystallized from ethanol.
Ultrasonic irradiation method
Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbox-
ylate (5 mmol) and K2CO3 (15 mmol) were added to a solution of the appropriate
2,4-dichloroquinoline (5 mmol) in 20 mL DMF, and the mixture was subjected to
ultrasonic irradiation at 60 °C for 20 min. After completion of the reaction, the
mixture was poured into ice cold water and the product was collected by filtration
and recrystallized from ethanol.
All the compounds synthesized characterized by use of NMR spectroscopy,
ESI–MS, and elemental analysis.
Ethyl 4-(3-(2-chloro-6-methylquinolin-4-yloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (3a) Mp. 224–226 °C; 1H NMR (400 MHz,
CDCl3) dH: 1.19 (t, 3H, J = 7.1 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3),
2.56 (s, 3H, –CH3 at quinoline C-6), 4.14 (q, 2H, J = 7.1 Hz, –CH3CH2), 5.43 (s,
1H, –CHNH), 5.46 (s, 1H, –CHNH), 6.43 (s, 1H, quinoline H-3), 6.70 (s, 1H,
–NHCO), 7.11 (d, 1H, J = 7.8 Hz), 7.16 (s, 1H, ArH), 7.32 (d, 1H, J = 7.8 Hz,
ArH), 7.46 (t, 1H, J = 7.8 Hz, ArH), 7.60 (d, 1H, J = 8.6 Hz, quinoline H-7), 7.89
(d, 1H, J = 8.6 Hz, quinoline H-8), 8.07 (s, 1H, quinoline H-5); ES–MS: m/z 452.1
(M ? 1); Anal. Calcd. for C24H22ClN3O4: C, 63.79; H, 4.91; N, 9.30. Found: C,
63.71; H, 4.96; N, 9.40.
Ethyl 4-(3-(2-chloro-7-methylquinolin-4-yloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (3b) Mp. 244–246 °C; 1H NMR (400 MHz,
CDCl3) dH: 1.17 (t, 3H, J = 6.7 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3),
2.90 (s, 3H, –CH3 at quinoline C-7), 4.12 (q, 2H, J = 6.7 Hz, –CH3CH2), 5.46
123

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G. L. Balaji et al.
(s, 1H, –CHNH), 5.56 (s, 1H, –CHNH), 6.44 (s, 1H, quinoline H-3), 7.07 (d, 1H,
J = 7.7 Hz, ArH), 7.12 (s, 1H, –NHCO), 7.17 (s, 1H, ArH), 7.31 (d, 1H,
J = 7.7 Hz, ArH), 7.32 (s, 1H, quinoline H-8), 7.44 (d, 1H, J = 8.1 Hz, quinoline
H-6), 7.60 (t, 1H, J = 7.9 Hz, ArH), 7.83 (d, 1H, J = 8.1 Hz, quinoline H-5); ES–
MS: m/z 452.0 (M ? 1); Anal. Calcd. for C24H22ClN3O4: C, 63.79; H, 4.91; N, 9.30.
Found: C, 63.69; H, 4.87; N, 9.47.
Ethyl 4-(3-(2-chloro-8-methylquinolin-4-yloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (3c) Mp. 162–164 °C; 1H NMR (400 MHz,
CDCl3) dH: 1.18 (t, 3H, J = 7.1 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3), 2.76
(s, 3H, –CH3 at quinoline C-8), 4.12 (q, 2H, J = 7.1 Hz, –CH3CH2), 5.46 (s, 1H,
–CHNH), 5.53 (s, 1H, –CHNH), 6.45 (s, 1H, quinoline H-3), 7.04 (s, 1H, –NHCO),
7.10 (d, 1H, J = 8.0 Hz, ArH) 7.16 (s, 1H, ArH), 7.31 (d, 1H, J = 8.0 Hz, ArH),
7.43–7.49 (m, 2H, quinoline H-6 and ArH), 7.62 (d, 1H, J = 8.0 Hz, quinoline H–7),
8.14 (d, 1H, J = 8.2 Hz, quinoline H-5); ES–MS: m/z 451.1 (M ? 1); Anal. Calcd.
for C24H22ClN3O4: C, 63.79; H, 4.91; N, 9.30. Found: C, 63.97; H, 4.78; N, 9.16.
Ethyl 4-(3-(2-chloro-6-methoxyquinolin-4-yloxy) phenyl)-6-methyl-2-oxo-1,2,3,4-
1
tetrahydropyrimidine-5-carboxylate (3d) Mp. 238–240 °C; H NMR (400 MHz,
CDCl3) dH: 1.19 (t, 3H, J = 7.0 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3),
3.96 (s, 3H, –OCH3 at quinoline C-6), 4.12 (q, 2H, J = 7.0 Hz, –CH3CH2), 5.40 (s,
1H, –CHNH), 5.47 (s, 1H, –CHNH), 6.45 (s, 1H, quinoline H-3), 6.58 (s, 1H,
–NHCO), 7.12 (d, 1H, J = 8.0 Hz, ArH), 7.18 (s, 1H, ArH), 7.32 (d, 1H,
J = 8.0 Hz, ArH), 7.40–7.49 (m, 2H, ArH and quinoline H-7), 7.53 (s, 1H, quinoline
H-5), 7.90 (d, 1H, J = 8.1 Hz, quinoline H-8); ES–MS: m/z 468.1 (M ? 1); anal.
calcd. for C24H22ClN3O5: C, 61.61; H, 4.74; N, 8.98. Found: C, 61.92; H, 4.85; N,
8.82.
Ethyl 4-(3-(2-chloro-8-methoxyquinolin-4-yloxy) phenyl)-6-methyl-2-oxo-1,2,3,4-
1
tetrahydropyrimidine-5-carboxylate (3e) Mp. 126–128 °C; H NMR (400 MHz,
CDCl3) dH: 1.18 (t, 3H, J = 7.1 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3),
4.07 (s, 3H, –OCH3 at quinoline C-8), 4.11 (q, 2H, J = 7.1 Hz, –CH3CH2), 5.46
(bs, 2H, –CHNH and –CHNH), 6.49 (s, 1H, quinoline H-3), 6.80 (bs, 1H, –NHCO),
7.10–7.13 (m, 2H, ArH and quinoline H-7), 7.16 (s, 1H, ArH), 7.32 (d, 1H,
J = 7.8 Hz, ArH), 7.46 (t, 1H, J = 8.0 Hz, ArH), 7.51 (t, 1H, J = 8.1 Hz,
quinoline H-6), 7.85 (d, 1H, J = 8.1 Hz, quinoline H-5); ES–MS: m/z 468.1
(M ? 1); anal. calcd. for C24H22ClN3O5: C, 61.61; H, 4.74; N, 8.98. Found: C,
61.85; H, 4.82; N, 8.79.
Ethyl 4-(3-(2,7-dichloroquinolin-4-yloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahy-
1
dropyrimidine-5-carboxylate (3f) Mp. 218–220 °C; H NMR (400 MHz, CDCl3)
dH: 1.19 (t, 3H, J = 7.1 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3), 4.14 (q,
2H, J = 7.1 Hz, –CH3CH2), 5.44 (s, 1H, –CHNH), 5.47 (s, 1H, –CHNH), 6.47 (s,
1H, quinoline H-3), 7.12 (d, 1H, J = 7.9 Hz, ArH), 7.17 (s, 1H, ArH), 7.36 (d, 1H,
J = 7.9 Hz, ArH), 7.48 (t, 1H, J = 7.9 Hz, ArH), 7.71 (d, 1H, J = 8.0 Hz,
123

Ultrasound-promoted synthesis
1811
quinoline H-6), 7.93 (d, 1H, J = 8.0 Hz, quinoline H-5), 8.28 (s, 1H, quinoline
H-8); ES–MS: m/z 472.0 (M ? 1); anal. calcd. for C23H19Cl2N3O4: C, 58.49; H,
4.05; N, 8.90. Found: C, 58.62; H, 3.94; N, 8.73.
Ethyl 4-(3-(6-bromo-2-chloroquinolin-4-yloxy) phenyl)-6-methyl-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (3g) Mp. 210–212 °C; 1H NMR (400 MHz,
CDCl3) dH: 1.19 (t, 3H, J = 7.1 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3),
4.13 (q, 2H, J = 7.1 Hz, –CH3CH2), 5.47 (s, 1H, –CHNH), 5.50 (s, 1H, –CHNH),
6.47 (s, 1H, quinoline H-3), 6.88 (s, 1H, –NHCO), 7.11 (d, 1H, J = 7.5 Hz, ArH),
7.17–7.18 (m, 1H, ArH), 7.34 (d, 1H, J = 7.5 Hz, ArH), 7.47 (t, 1H, J = 7.5 Hz,
ArH), 7.84–7.85 (m, 2H, quinoline H-7,8), 8.47 (s, 1H, quinoline H-5); ES–MS:
m/z 515.9 (M ? 1); anal. calcd. for C23H19BrClN3O4: C, 53.46; H, 3.71; N, 8.13.
Found: C, 53.75; H, 3.59; N, 7.98.
Ethyl 4-(3-(2-chloro-6,8-dimethylquinolin-4-yloxy) phenyl)-6-methyl-2-oxo-1,2,3,4-
1
tetrahydropyrimidine-5-carboxylate (3h) Mp. 182–184 °C; H NMR (400 MHz,
CDCl3) dH: 1.17 (t, 3H, J = 7.3 Hz, –CH3CH2), 2.37 (s, 3H, pyrimidone –CH3),
2.50 (s, 3H, –CH3 at quinoline C-8), 2.72 (s, 3H, –CH3 at quinoline C-6), 4.12 (q,
2H, J = 7.3 Hz, –CH3CH2), 5.45 (s, 1H, –CHNH), 5.60 (s, 1H, –CHNH), 6.43 (s,
1H, quinoline H-3), 7.08 (d, 1H, J = 7.6 Hz, ArH), 7.15 (s, 1H, quinoline H-7),
7.28–7.33 (m, 2H, ArH), 7.41–7.45 (m, 2H, –NH and ArH), 7.90 (s, 1H, quinoline
H-5); ES–MS: m/z 466.1 (M ? 1); anal. calcd. for C25H24ClN3O4: C, 64.44; H,
5.91; N, 9.02. Found: C, 64.30; H, 5.08; N, 8.91.
Ethyl 4-(3-(2-chlorobenzo[h]quinolin-4-yloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate (3i) Mp. 164–166 °C; 1H NMR (400 MHz,
CDCl3) dH: 1.15 (t, 3H, J = 7.1 Hz, –CH3CH2), 2.36 (s, 3H, pyrimidone –CH3),
4.13 (q, 2H, J = 7.1 Hz, –CH3CH2), 5.46 (s, 1H, –CHNH), 5.71 (s, 1H, –CHNH),
6.64 (s, 1H, quinoline H-3), 7.12 (d, 1H, J = 8.0 Hz, ArH), 7.19 (s, 1H, ArH), 7.31
(d, 1H, J = 8.0 Hz, ArH), 7.45 (t, 1H, J = 8.0 Hz, ArH), 7.48 (bs, 1H, –NHCO),
7.71–7.74 (m, 2H, quinoline H-700, 800), 7.86 (d, 1H, J = 8.5 Hz, quinoline H-6),
7.92 (d, 1H, J = 8.4 Hz, quinoline H-70), 8.16 (d, 1H, J = 8.5 Hz, quinoline H-5),
9.25 (d, 1H, J = 8.4 Hz, quinoline H-80); ES–MS: m/z 488.1 (M ? 1); anal. calcd.
for C27H22ClN3O4: C, 66.46; H, 4.54; N, 8.61. Found: C, 66.60; H, 4.63; N, 8.52.
Antibacterial activity
Sterile nutrient broth was prepared, inoculated with different species of bacteria (S.
aureus, B. cereus, E. coli, or P. aeruginosa), and incubated at 37 °C overnight.
From this overnight culture, 1 % stock culture was prepared (99 mL sterile nutrient
broth ? 1 mL overnight culture). Nutrient agar (25 mL) was poured into sterile
Petri plates and left to cool. Each agar plate was inoculated with bacterial culture
and spread by use of a spreader. Using a sterile cork borer, 6-mm-diameter holes
were made in the solidified agar plates containing 1 % of the respective bacterial
culture. A total volume of 20 lL of test sample 3a–3i, concentration 250 lg/mL,
123

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G. L. Balaji et al.
was poured into the well. Streptomycin (250 lg/mL) was poured into one well and
incubated at 37 °C for 24 h. After incubation for 24 h the zone of Inhibition was
measured in mm.
Results and discussion
The reactivity of the halogen atoms in quinolines varies substantially. Kinetic
studies indicate that the chlorine at C4 of 2,4-dichloro quinolines is approximately
twice as reactive toward nucleophiles as chlorine in other positions. Its reaction is
predominantly via an addition elimination mechanism [18–20]. Although regiose-
lective nucleophilic substitution at C4 of 2,4-dichloroquinoline by 4-methoxybenzyl
alcohol in the presence of sodium hydride [21] is known, it is a costly procedure
because of the use of 15-crown-5 as catalyst. Reaction of 2,4-dichloroquinoline with
sodium methoxide affords 2,4-dimethoxyquinoline with no selectivity [22].
We hypothesized that K2CO3 could act as a mild and effective base for selective
replacement of one of the chlorine atoms in 2,4-dichloroquinoline at moderate
temperature. Reaction of 2,4-dichloro-6-methylquinoline (1a) with sodium azide at
a molar ratio of 1:1 in DMF at 60 °C leads to regioselective formation of 4-azido-2-
chloro-6-methylquinoline [23], which is also indicative of the high reactivity of
chlorine at C4 of 2,4-dichloro quinolines (although the long reaction time with
strong heating leads to formation of the 2,4-disubstituted compound).
On the basis of these results, 2,4-dichloroquinoline (1a) was successfully
converted into 4-(3-(2-chloroquinolin-4-yloxy)phenyl)-6-methyl-2-oxo-1,2,3,4-tetra
hydropyrimidine-5-carboxylate (3a) by reaction of 1a with ethyl 4-(3-hydroxy-
phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2), in the
presence of K2CO3 as mild base in benzene, with conventional heating at 60 °C
for 12 h (Scheme 1). The reaction was then optimized, considering compound 3a as
representative, by varying the solvent. The results are listed in Table 1, which
clearly shows that DMF is suitable. (In previous work we used THF and benzene
which gave low yields [24]). After finding a suitable solvent, the temperature was
optimized as 60 °C, on the basis of previous experience.
The prerequisite 2,4-dichloroquinolines 1a–1i were synthesized by reaction of
malonic acid and the corresponding anilines and excess phosphorus oxychloride
(POCl3), under reflux, in accordance with our earlier work [17]. These compounds
were, in turn, converted into 4-(3-(2-chloroquinolin-4-yloxy)phenyl)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 3a–3i by the reaction
with ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (2), in the presence of K2CO3 as mild base, with DMF as solvent and
with conventional heating at 60 °C, which required 12 h to afford the desired
products in 66–81 % yield. The same reaction was performed under ultrasonic
irradiation for 20 min at 60 °C to afford the products with 80–94 % yield. This
clearly revealed that the ultrasound-promoted synthesis is a better approach to
synthesis of 2-chloroquinolin-4-pyrimidine carboxylate derivatives 3a–3i (Table 2).
Use of K2CO3 under these mild experimental conditions greatly suppressed
formation of the disubstituted products and the constitutional isomers; as a result,
123

Ultrasound-promoted synthesis
1813
Step 1:
Cl
N
R1
COOH
COOH
POCl3
R1
R2
H2C
+
NH2
R2
Cl
R3
R3
1(a-i)
OH
Step 2:
O
O
O
O
+
+
+
O
NH4
O-
O
NH
HO
O
N
H
O
R1
N
2
Step 3:
R2
R3
OH
O
Cl
O
R1
R2
K2CO3
O
+
O
NH
Cl
N
Cl
O
NH
DMF, ))))
R3
N
O
N
O
H
H
1(a-i)
2
3(a-i)
Scheme 1 Synthesis of 2-chloroquinolin-4-pyrimidine carboxylate derivatives 3(a–i)
Table 1 Optimization of conditions for synthesis of compound 3a
Entry
Solvent
Time (min)
Temperature
Yield
1
2
3
DMF
20
20
20
60
60
60
94
74
55
THF
Benzene
Table 2 Reaction of 2,4-dichloroquinolines containing different substituents in the presence of K2CO3
under conventional heating conditions and under ultrasonic irradiation
Entry
R1
R2
R3
Yielda (%)
Mp (°C)
Conventional
heating
Ultrasound
3a
3b
3c
3d
3e
3f
3g
3h
3i
–CH3
–H
–H
–H
81
69
73
75
66
73
70
78
74
94
87
89
90
87
80
84
91
85
224–226
225–227
162–164
238–240
126–128
218–220
210–212
182–184
164–166
–CH3
–H
–H
–H
–CH3
–H
–OCH3
–H
–H
–H
–OCH3
–H
–H
–Cl
–H
–Br
–H
–CH3
–H
–CH3
2-chlorobenzo(h)quinoline
Isolated yields
a
123

1814
G. L. Balaji et al.
Table 3 Antibacterial activity of 3a–3i
Name of species
Gram type
Zone of inhibition (mm)
Streptomycin
3a
3b
3c
3d
3e
3f
3g
3h
3i
E. coli
-ve
-ve
?ve
?ve
16
15
17
17
10
8
–
10
8
13
–
13
14
15
15
14
–
–
–
8
–
8
12
10
12
–
8
P. aeruginosa
S. aureus
B. cereus
–
10
10
10
12
–
12
10
10
–
12
11
14
Nutrient agar was used as culture medium; the test concentration of 250 lg/mL was used with DMSO as
solvent
regioselectivity was also increased. Similar reactions, for example reaction of
4-chlorobenzenethiol with 2,4-dichloroquinoline at room temperature in the
presence of triethylamine as mild base also led to the 4-substituted, rather than
2-substituted, product; this also is evidence of a similar effect of the use of
ultrasound [25]. Similar ultrasound-promoted reaction of halogenated quinolines
with alcohols has also been reported [26]. It also evident from the literature that use
of an acid catalyst in absolute ethanol alone can result in regioselectivity at C2 [27].
1
Formation of compound 3a was apparent from H NMR results. A triplet at d
1.19 ppm (J = 7.14 Hz), which integrates for three protons, corresponds to the
–OCH2CH3 methyl; a quartet at d 4.12–4.15 ppm corresponds to the –CH3CH2
protons. Singlets at d 2.37 ppm and d 2.56 ppm arise from the methyl protons on
pyrimidone and on quinoline C-6, respectively. This observation proves formation
of the target molecule. Formation of the desired product was also confirmed by
observation of the m/z peak at 452.1 (M ? 1) in the ESI–MS spectrum. Similarly,
3a–3i were also characterized by use of the spectral data reported in the
Experimental section.
All the synthesized compounds 3a–3i were screened for their in-vitro antibac-
terial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus) and
Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria by use of
the cup-plate method. Table 3 reveals that compounds 3a–3i have moderate activity
against all the species tested. Compound 3d, with methoxy group at the 6 position,
is more active than the other compounds against all the species.
Conclusion
In summary, ultrasonic irradiation was identified as an efficient method for synthesis
of novel 2-chloroquinolin-4-pyrimidinecarboxylate derivatives compared with
conventional heating. K2CO3 proved to be an mild and efficient base for
regioselective synthesis of 2,4-dichloroquinolines, and favored the formation of
the C4-substituted quinoline as the major product of the reaction. Antibacterial
screening of compounds 3a–3i at 250 lg/mL gave moderate inhibition zones.
Because novel chloroquinoline derivatives are in great demand because of increased
resistance of malarial parasites to the anti-malarial drug chloroquine, we believe this
123

Ultrasound-promoted synthesis
1815
method will certainly help to generate a diverse quinoline library for identification
of better anti-malarial agents.
Acknowledgments The authors are thankful to the administration, VIT University, Vellore, India, for
providing facilities to conduct research work, and are also thankful to SAIF, IIT-Madras, and VIT-TBI for
providing NMR, mass, and IR spectral facilities, respectively. The author G.L. Balaji is thankful to the
VIT University for providing a Research Associate.
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