Regioselective synthesis and biological evaluation of novel bis(2-chloroquinolines)

Article abstract of DOI:10.1007/s11164-012-0942-x

Reaction of substituted 2,4-dichloroquinolines with bisphenol A in the presence of K₂CO₃ leads to novel bis(2-chloroquinolines) with high regioselectivity. All the synthesized compounds were characterized by use of spectral data. Pre

Full text of DOI:10.1007/s11164-012-0942-x

Res Chem Intermed
DOI 10.1007/s11164-012-0942-x
Regioselective synthesis and biological evaluation
of novel bis(2-chloroquinolines)
•
•
•
K. Rajesh B. Palakshi Reddy S. Sarveswari
V. Vijayakumar
Received: 11 August 2012 / Accepted: 20 November 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract Reaction of substituted 2,4-dichloroquinolines with bisphenol A in the
presence of K2CO3 leads to novel bis(2-chloroquinolines) with high regioselec-
tivity. All the synthesized compounds were characterized by use of spectral data.
Preliminary evaluation of in-vitro antibacterial activity against a variety of
Gram-positive and Gram-negative organisms was also conducted.
Keywords Bis(2-chloroquinolines) ꢀ 2,4-Dichloroquinolines ꢀ Bisphenol A ꢀ
Anti-bacterial activity
Introduction
Synthesis of the quinoline ring system is of major interest in the chemistry of fused
five and six-membered heterocycles, because it has many applications in pharma-
ceuticals [1] and occurs widely in alkaloids, therapeutics, and synthetic analogues
with interesting activity [2–4], and because quinoline compounds have antimalarial
[5], antiasthmatic [6], and anti-inflammatory [7] activity and function as inhibitors of
platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK) [8]. Some
quinoline derivatives, their salts, and esters are used in the prophylaxis or treatment
of arthritis, cardiovascular diseases, diabetes, renal failure, and, particularly, eating
disorders and obesity [9]. 2,4-Disubstituted quinolines with additional substituents at
positions 5 and 8 have anthelmintic properties and are also found to be active against
drug-resistant nematodes [10, 11]. Similarly bisphenol A (BPA) is widely used as a
Electronic supplementary material The online version of this article (doi:10.1007/s
11164-012-0942-x) contains supplementary material, which is available to authorized users.
K. Rajesh ꢀ B. Palakshi Reddy ꢀ S. Sarveswari ꢀ V. Vijayakumar (&)
Centre for Organic and Medicinal Chemistry, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: kvpsvijayakumar@gmail.com
123

K. Rajesh et al.
reagent for producing epoxy resins and other polymers [12]. Although it has been
widely used for production of plastic products [13], it is regarded as an estrogenic
endocrine-disrupting chemical and affects steroid hormone production in rat ovarian
theca-interstitial and granulosa cells [14, 15]. Bisphenol A has structural resem-
blance to thyroid hormone (TH), and acts as a TH agonist or antagonist by affecting
the release of thyrotropin (TSH) [16].
This prompted us to perform work in which one of the chlorine atoms in
2,4-dichloroquinolines is selectively replaced, under controlled temperature condi-
tions, by the BPA moiety, which was chosen on the basis of our continuing interest
in quinolines [17–19], particularly synthesis of novel substituted quinoline
heterocycles [20], by exploiting the regioselectivity of 2,4-dichloroquinolines.
Although regioselective nucleophilic substitution of 2,4-dichloroquinoline with
4-methoxybenzylalcohol in the presence of sodium hydride [21] is known, it is not
cost effective because of use of catalyst 15-crown-5. Likewise, reaction of
2,4-dichloroquinoline with sodium methoxide gave 2,4-dimethoxyquinoline without
any selectivity [22]. Powdered K2CO3 was therefore used as an effective catalyst to
achieve regioselective synthesis of 2,4-dichloroquinolines under controlled temper-
ature conditions.
Results and discussion
2,4-Dichloroquinolines 1a–j were synthesized, in accordance with our earlier report
[23], by treating malonic acid and different substituted anilines with excess
phosphorus oxychloride. The target molecules 2a–j were synthesized in 66–81 %
yield by reaction of BPA and 2,4-dichloroquinolines 1a–j catalyzed by powdered
K2CO3 in DMF (Table 1). All the synthesized compounds were characterized by
use of spectral data.
Substitution of quinoline at C4 is known to be favored in reactions with powdered
K2CO3 as catalyst. It was also evident from the literature that use of an acid catalyst in
absolute ethanol alone can bring about regioselectivity at C2, and that base-catalyzed
reactions will be driven toward C4 [24]. This is also confirmed by similar reactions; for
example, reaction of 4-chlorobenzenethiol with 2,4-dichloroquinoline at room
temperature in the presence of triethylamine as mild base also leads to the 4-substituted
rather than 2-substituted product [25]. To understand the regioselectivity better, the
azidation reaction of 2,4-dichloro-6-methylquinoline (1b) was also investigated to
check its behavior in nucleophilic substitution at both the a and c positions (Scheme 1).
Reaction of 2,4-dichloro-6-methylquinoline (1b) with sodium azide in the molar
ratio 1:1, in DMF, led regioselectively to 4-azido-2-chloro-6-methylquinoline [26],
the structural conformation of which was determined by single-crystal X-ray
diffraction; this also is indicative of the reactivity of C4 in 2,4-dichloroquinolines.
This result is also confirmed by literature reports of kinetic studies which indicate that
the c-chloro atom of dichloroquinolines is approximately twice as reactive towards
nucleophiles and predominantly an addition–elimination process occurred [27, 28]
The LC–MS spectrum of the crude sample 2b is also indicative of the formation of
mono regio-isomeric product, and hence substitution at C4 was expected to occur
123

Regioselective synthesis and biological evaluation
16
Table 1 Synthesis of bis(2-chloroquinolines) 2a–j
16'
H3C
CH3
14'
13'
13
Cl
12'
15
12
H3C
CH3
14
13
R1
30h
11'
13'
11
+
O
O
4'
K2CO3, DMF
12
12'
5'
5
4
HO
OH R2
N
Cl
R1
R2
R1
R2
9
6
9'
6'
3
3'
2'
R3
2
7'
7
10'
10
1a-j
Cl
N
1'
N
Cl
8
8'
1
R3
R3
2a-j
Compound R1
R2
R3
Yield (%) M.p. (°C)
2a
2b
2c
2d
2e
2f
–H
–H
–H
–H
–H
79
81
77
79
82
76
72
66
69
71
216
222
194
202
212
278
146
254
242
122
–CH3
–H
–H
–CH3
–H
–H
–CH3
–H
–OCH3
–H
–H
–H
–OCH3
–H
2g
2h
2i
–Br
–H
–F
–Cl
–H
–CH3
–H
–CH3
2j
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene) bis(oxy)bis(2-
chlorobenzo[h] quinoline)
N+
Cl
N
N
N-
Cl
H3C
H3
C
H3C
NaN3
DMF
N
N
Cl
N
Cl
N
1b
N
Scheme 1 Synthesis of 4-azido-2-chloro-6-methylquinoline
under the basic conditions used in this work. Better results were obtained with
powdered K2CO3 than with the granular form, because the larger surface area enables
maximum reactivity of 2,4-dichloroquinoline with BPA. A simple monomeric
2-chloro-4,6-dimethoxyquinoline (2k) was also synthesized by treating 2,4-dichloro-
6-methoxyquinoline (1e) with sodium methoxide in the presence of K2CO3 in DMF
(Scheme 2).
Cl
OCH3
H3CO
H3CO
NaOMe
DMF
N
Cl
N
Cl
Scheme 2 Synthesis of 2-chloro-4,6-dimethoxyquinoline (2k)
123

K. Rajesh et al.
Results (Table 2) from evaluation of in-vitro antibacterial activity against a
variety of Gram-positive and Gram-negative organisms revealed that most of the
derivatives had mild to good activity against Staphylococcus aureus, Escherichia
coli, Bacillus subtilis, and Pseudomonas aeruginosa. Compounds 2b, 2d, 2j, and 2k
had high MIC values (MIC = 750–1,000 lg/mL) and the other compounds had
moderate MIC values (MIC = 500–750 lg/mL) except for 2h, for which the MIC
was low (MIC = 250–500 lg/mL).
Experimental
Materials were purchased from Sigma–Aldrich and Merck and were 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. Infrared (IR) spectra were recorded at room
temperature from 4,000 cm-1 as KBr pellets at a resolution of 4 cm-1, by use of an
Avatar 330 equipped with DTGS detector. Most of the vibrational bands of the IR
spectrum were identified by comparison with those available in literature. 1H NMR
spectroscopy of *0.03 M solutions in CDCl3, with TMS as internal reference, was
performed with a Bruker Avance-200 MHz instrument at room temperature, using
X-WIN NMR version 1.3 cn drx software. The accuracy of the 1H shifts is believed
to be 0.02 ppm. The coupling constants J are in Hertz. Mass spectra were obtained
by use of ESI mass spectrometry.
General procedure for synthesis of bis(2-chloroquinolines) 2a–j
A mixture of substituted 2,4-dichloroquinoline (1a–j) (1 mol), powdered K2CO3
(1 mol), and BPA (0.5 mol) in DMF was stirred at 80 °C for 30 h. Progress of
reaction was monitored by TLC. After completion of the reaction, the reaction
mixture was poured into a beaker containing ice-cold water and stirred well. The
solid which separated was filtered to dryness and purified by column chromatog-
raphy on silica gel (60–120 mesh) with pet. ether–ethyl acetate 8:2 as eluent. This
afforded the white solid products 2a–j in the pure form. The products were
characterized by IR, NMR, and mass spectrometry. The spectral data for compounds
2a–j are given below.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloroquinoline)
(2a)
IR (KBr), m, cm-1: 3057, 2966, 1617, 1579, 1497, 1416, 1363, 1313, 1233, 1213,
1174, 1143, 1070, 1014, 920, 855, 763. 1H NMR (200 MHz, CDCl3), d, ppm
(J, Hz): 1.81 (s, 6H, H-16, 160); 6.56 (s, 2H, H-3, 30); 7.16 (d, J = 10.0, 4H, H-13,
130); 7.42 (d, J = 10.0, 4H, H-12, 120); 7.59 (t, J = 8.0, 2H, H-6, 60); 7.78 (t,
J = 8.0, 2H, H-7, 70); 8.00 (d, J = 8.0, 2H, H-8, 80); 8.32 (d, J = 8.0, 2H, H-5, 50).
ESI–MS m/z: 551.36 [M ? 1]. Anal. calcd for C33H24Cl2N2O2, %: C, 71.87; H,
4.39; N, 5.08; Found: C, 71.79; H, 4.52; N, 4.98.
123

Regioselective synthesis and biological evaluation
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloro-
6-methylquinoline) (2b)
IR (KBr), m, cm-1: 3050, 2962, 2920, 1566, 1501, 1433, 1320, 1299, 1217, 1167,
1
1097, 1066, 1013, 930, 837. H NMR (200 MHz, CDCl3), d, ppm (J, Hz): 1.80
(s, 6H, H-16, 160); 2.56 (s, 6H, –CH3 at 6, 60); 6.53 (s, 2H, H-3, 30); 7.14 (d, 4H,
J = 8.0, H-13, 130); 7.40 (d, 4H, J = 8.0, H-12, 120); 7.60 (dd, J = 8.0, 2H, H-7,
70); 7.89 (d, J = 8.0, 2H, H-8, 80); 8.08 (s, 2H, H-5, 50). ESI–MS m/z: 579 [M ? 1].
Anal. calcd for C35H28Cl2N2O2, %: C, 72.54; H, 4.87; N, 4.83; Found: C, 72.39; H,
4.90; N, 4.90.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloro-7-
methylquinoline) (2c)
IR (KBr), m, cm-1: 2968, 2930, 1625, 1578, 1496, 1420, 1374, 1339, 1299, 1212,
1
1173, 1136, 1074, 1015, 916, 855, 831, 768. H NMR (200 MHz, CDCl3), d, ppm
(J, Hz): 1.80 (s, 6H, H-16, 160); 2.57 (s, 3H, –CH3 at 7); 2.92 (s, 3H –CH3 at 70);
6.50 (s, 1H, H-3); 6.55 (s, 1H, H-30); 7.09–7.16 (m, 4H, J = 8.0, H-13,130); 7.30-
7.42 (m, 6H); 7.55-7.63 (m, 1H); 7.82 (t, J = 9.0, 2H, H-6, 60); 8.19 (d, J = 8.0,
1H). ESI–MS m/z: 579.16 [M ? 1]. Anal. calcd for C35H28Cl2N2O2, %: C, 72.54;
H, 4.87; N, 4.83; Found: C, 73.28; H, 4.83; N, 4.80.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloro-8-
methylquinoline) (2d)
IR (KBr), m, cm-1: 2967, 2920, 1612, 1578, 1496, 1445, 1402, 1322, 1300, 1227,
1
1210, 1168, 1108, 1015, 942, 882, 838, 761. H NMR (200 MHz, CDCl3), d, ppm
(J, Hz): 1.80 (s, 6H, H-16, 160); 2.77 (s, 6H, –CH3 at 8, 80); 6.56 (s, 2H, H-3, 30);
7.14 (d, J = 10.0, 4H, H-13, 130); 7.40 (d, J = 10.0, 4H, H-12, 120); 7.46–7.50
(m, 2H, H-6, 60); 7.62 (d, 2H, J = 8.0, H-7, 70); 8.16 (d, J = 8.0, 2H, H-5, 50).
ESI–MS m/z: 579.20 [M ? 1]. Anal. calcd for C35H28Cl2N2O2, %: C, 72.54; H,
4.87; N, 4.83; Found: C, 72.56; H, 4.71; N, 4.88.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloro-6-
methoxyquinoline) (2e)
1
IR (KBr), m, cm-1: 2965, 2924, 1577, 1499, 1227, 1170, 1098, 1027, 916, 827. H
NMR (200 MHz, CDCl3), d, ppm (J, Hz): 1.81 (s, 6H, H-16, 160); 3.95 (s, 6H,
–OCH3 at 6, 60); 6.55 (s, 2H, H-3, 30); 7.16 (d, J = 10.0, 4H, H-13, 130); 7.39–7.43
(m, 6H, H-12, 120, 7, 70); 7.54 (s, 2H, H-5, 50); 7.91 (d, 2H, J = 10.0, H-8, 80).
ESI–MS m/z: 611 [M ? 1]. Anal. calcd for C35H28Cl2N2O4, %: C, 68.74; H, 4.62;
N, 4.58; Found: C, 68.80; H, 4.66; N, 4.47.
123

K. Rajesh et al.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloro-8-
methoxyquinoline) (2f)
IR (KBr), m, cm-1: 3036, 2970, 1614, 1573, 1495, 1405, 1326, 1308, 1265, 1211,
1171, 1105, 1062, 1014, 951, 840, 748. 1H NMR (200 MHz, CDCl3), d, ppm
(J, Hz): 1.80 (s, 6H, H-16,160); 4.08 (s, 6H, –OCH3 at 8, 80); 6.59 (s, 2H, H-3, 30);
7.14 (d, J = 8.0, 6H, H-13, 130, 7, 70); 7.4 (d, J = 8.0, 4H, H-12, 120); 7.51 (t, 2H,
J = 9.0, H-6, 60); 7.87 (d, 2H, J = 8.0, H-5, 50). ESI–MS m/z: 611.37 [M ? 1].
Anal. calcd for C35H28Cl2N2O4, %: C, 68.74; H, 4.62; N, 4.58; Found: C, 68.56; H,
4.72; N, 4.49.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloro-6-
bromoquinoline) (2g)
IR (KBr), m, cm-1: 2967, 1575, 1490, 1435, 1390, 1318, 1224, 1172, 1077, 1015,
924, 868, 827. 1H NMR (200 MHz, CDCl3), d, ppm (J, Hz): 1.81 (s, 6H, H-16, 160);
6.57 (s, 2H, H-3, 30); 7.14 (d, J = 8.0, 4H, H-13, 130); 7.42 (d, J = 10.0, 4H, H-12,
120); 7.85 (bs, 4H, H-7, 70, 8, 80); 8.48 (s, 2H, H-5, 50). ESI–MS m/z: 708 [M?2],
709 [M?3], 710 [M?4]. Anal. calcd for C33H22Br2Cl2N2O2, %: C, 55.88; H, 3.13;
N, 3.95; Found: C, 55.73; H, 3.16; N, 3.88.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2,7-dichloro-
6-fluoroquinoline) (2h)
IR (KBr), m, cm-1: 3062, 2969, 1575, 1498, 1448, 1324, 1213, 1171, 1116, 1070,
1
1015, 932, 827. H NMR (200 MHz, CDCl3), d, ppm (J, Hz): 1.81 (s, 6H, H-16,
160); 6.57 (s, 1H, H-3); 6.68 (s, 1H, H-30); 7.14 (d, J = 8.0, 4H, H-13, 130); 7.42
(d, J = 10.0, 4H, H-12, 120); 7.59 (t, J = 9.0, 1H, H-5); 7.89–8.09 (m, 3H, H-50, 7,
70). ESI–MS m/z: 656 [M?2], 657 [M?3]. Anal. calcd for C33H20Cl4F2N2O2, %:
C, 60.39; H, 3.07; N, 4.27; Found: C, 60.26; H, 3.11; N, 4.33.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis(2-chloro-
6,8-dimethylquinoline) (2i)
IR (KBr), m, cm-1: 3058, 2967, 2919, 1578, 1495, 1448, 1319, 1235, 1172, 1100,
1015, 942, 893, 858. 1H NMR (200 MHz, CDCl3), d, ppm (J, Hz): 1.80 (s, 6H, H-16,
160); 2.52 (s, 6H, –CH3 at 6, 60); 2.74 (s, 6H, –CH3 at 8, 80); 6.54 (s, 2H, H-3, 30); 7.13
(d, J = 8.0, 4H, H-13, 130); 7.40 (d, 4H, J = 10.0, H-12, 120); 7.47 (s, 2H, H-7, 70);
7.94 (s, 2H, H-5, 50). ESI–MS m/z: 607.52 [M ? 1]. Anal. calcd for C37H32Cl2N2O2,
%: C, 73.14; H, 5.31; N, 4.61; Found: C, 73.39; H, 5.37; N, 4.52.
4,40-(4,40-(propane-2,2-diyl)bis(4,1-phenylene)bis(oxy)bis
(2-chlorobenzo[h]quinoline) (2j)
IR (KBr), m, cm-1: 3051, 2967, 1621, 1580, 1491, 1440, 1399, 1316, 1258, 1214,
1174, 1108, 1015, 956, 825, 756. 1H NMR (200 MHz, CDCl3), d, ppm (J, Hz): 1.83
123

Regioselective synthesis and biological evaluation
(s, 6H, H-16, 160); 6.76 (s, 2H, H-3, 30); 7.18 (d, J = 8.0, H-13, 130; 7.43
(d, J = 8.0, 4H, H-12, 120); 7.72–7.94 (m, 8H); 8.21 (d, J = 10.0, 2H); 9.20–9.24
(m, 2H). ESI–MS m/z: 651 [M ? 1]. Anal. calcd for C41H28Cl2N2O2, %: C, 75.58;
H, 4.33; N, 4.30; Found: C, 76.36; H, 4.26; N, 4.23.
2-chloro-4,6-dimethoxyquinoline (2k)
1
IR (KBr), m, cm-1: 3089, 2921, 2849, 1572, 1494, 1275, 1094, 1027, 829, 786. H
NMR (300 MHz, CDCl3), d, ppm (J, Hz): 3.93 (s, 3H, -OCH3 at C-4); 4.05 (s, 3H,
-OCH3 at C-6); 6.71 (s, 1H, H-3); 7.35 (d, J = 9.0, 1H, H-7); 7.38 (s, 1H, H-5);
7.85 (d, J = 9.0, 1H, H-8). 13C NMR (75 MHz, CDCl3), d, ppm (J, Hz): 55.6
(–OCH3 at C-6); 56.1 (–OCH3 at C-4); 100.1 (C-5); 101.2 (C-3); 121.1 (C-9); 122.0
(C-7); 129.4 (C-8); 143.9 (C-10); 149.0 (C-2); 157.6 (C-6); 162.5 (C-4). ESI–MS m/
z: 224 [M ? 1]. Anal. calcd for C35H28Cl2N2O4, %: C, 59.07; H, 4.51; N, 6.26;
Found: C, 58.98; H, 4.57; N, 6.21.
Antibacterial activity
In-vitro evaluation of the antibacterial activity of compounds 2a–k
The broth microdilution method [29] with Mueller–Hinton agar medium was used
in a preliminary study of the antibacterial activity of synthesized compounds 2a–k
with standard pathological bacterial strains E. coli ATCC 25922, P. aeruginosa
ATCC 25619, S. aureus ATCC 25923, and B. subtilis ATCC 29212. The
antibacterial activity of the test compounds was compared with that of ciproflox-
acin. Twofold serial dilutions of the test compounds and reference drugs were
prepared in Mueller–Hinton broth. Test compounds and the standard drug
ciprofloxacin were dissolved in dimethylsulfoxide (DMSO, 1 mL) and the solution
was diluted with distilled water (9 mL). Further progressive serial dilutions were
performed to obtain the required concentrations from 250 to 1,000 lg/mL. Petri
dishes were inoculated with 5 9 104 colony-forming units (cfu)/mL and incubated
at 37 °C for 24 h. The minimum inhibitory concentration (MIC) was the lowest
concentration of the tested compound that resulted in no visible growth on the plate.
To ensure that the solvent had no effect on bacterial growth, a control was
performed with the test medium supplemented with DMSO at the same dilutions as
used in the experiments. The results of the study are listed in Table 2.
Conclusion
We have described the highly regioselective synthesis of novel bis(2-chloroquin-
olines) by reaction of 2,4-dichloroquinolines with BPA catalyzed by powdered
K2CO3 in DMF. Substitution at C4 of the quinoline is known to be favored, and
substitution at C2 was zero during the course of the reaction. The azidation reaction
of 2,4-dichloro-6-methylquinoline (1b) was also investigated to check its behavior
123

K. Rajesh et al.
Table 2 In-vitro antibacterial
activity (MIC, lg/mL) of bis(2-
chloroquinolines) 2a–k
Compound
S. aureus B. subtilis Acaule
P. aeruginosa
2a
500
1,000
750
500
1,000
750
500
1,000
750
500
1,000
750
2b
2c
2d
1,000
250
1,000
500
1,000
500
1,000
250
2e
2f
250
500
500
500
2g
500
500
500
500
2h
250
250
500
250
2i
500
750
750
750
2j
1,000
750
1,000
1,000
1,000
1,000
750
2k
1,000
12.5
Ciprofloxacin
12.5
12.5
12.5
in nucleophilic substitution with significant c-attack. Preliminary evaluation of the
in-vitro antibacterial activity (MIC lg/mL) of all the synthesized compounds
revealed mild to moderate activity against the organisms tested.
Acknowledgments We are grateful for financial support from the Department of Science and
Technology, Government of India (grant no. SR/FTP/CS-108/2006) and to VIT University, Vellore, for
providing research facilities.
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