Synthesis and free radical scavenging property of some quinoline derivatives

Article abstract of DOI:10.4067/S0717-97072010000300008

In the present work synthesis of 2-chloroquinoline-3-carbaldehydes (1a-g), 2-chloro-3-(1, 3-dioxolan-2-yl)quinolines (2a-g) and antioxidant activity using the DPPH assays is reported. The results showed that the compounds 1b, 1c, 2b, 2e, 2f possessed 84.6

Full text of DOI:10.4067/S0717-97072010000300008

J. Chil. Chem. Soc., 55, Nº 3 (2010)
SYNTHESIS AND FREE RADICAL SCAVENGING PROPERTY OF SOME QUINOLINE DERIVATIVES
R. SUBASHINI, S. MOHANA ROOPAN, F. NAWAZ KHAN*
* Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences,
VIT University, Vellore 632 014, Tamil Nadu, India.
(Received: June 10, 2009 - Accepted: November 23, 2009)
ABSTRACT
In the present work synthesis of 2-chloroquinoline-3-carbaldehydes (1a-g), 2-chloro-3-(1, 3-dioxolan-2-yl)quinolines (2a-g) and antioxidant activity using the
DPPH assays is reported. The results showed that the compounds 1b, 1c, 2b, 2e, 2f possessed 84.65 to 85.75 % radical scavenging activity where as compound
1g showing 92.96% radical scavenging activity.
Keywords: Quinoline derivatives, antioxidant, DPPH method
J=8 Hz, CH), 8.09-8.07 (1H, d, J=8 Hz, CH), 8.77 (1H, s, CH), 10.57 (1H, s,
CHO). ESI-MS m/z: 191(M+), Calcd for C10H6ClNO: 191.01.
INTRODUCTION
2-Chloro-8-methylquinoline-3-carbaldehyde12 (1b): Pale yellow
powder, 77% yield, mp 136-138°C (Lit.137°C). IR (KBr) cm-1: 3050,
2919(Aromatic C-H), 2869(aldehyde C-H), 1683(C=O), 1586(C=N), 772(C-
Cl). 1H NMR (CDCl3, 300MHz) d: 2.48 (3H, s, CH3), 7.64-7.60 (2H, m, CH),
7.89-7.85 (1H, m, CH), 8.56 (1H, s, CH), 10.45 (1H, s, CHO). ESI-MS m/z:
205, Calcd for C11H8ClNO: 205.64.
Consumption of fruits and vegetables by human beings, shown lower
risk of chronic diseases such as cancer, cardiovascular disease and stroke1 and
positive health effects2 due to high contents of certain phenolic compounds
in plant-derived foods. Recently, phytochemicals and their effects on human
health have been intensively studied. In particular, a search for antioxidants3,
hypoglycemic agents4, and anticancer agents5 in vegetables, fruits, tea, spices
and medicinal herbs has attracted great attention. Naturally occurring plant
phenolics include several groups of compounds that have health promoting
properties. Phenolics may act as antioxidants, thereby reducing the risk of
atherosclerosis and coronary heart disease, which can be caused by oxidation
of low-density lipoproteins. They also may protect against some forms of
cancer6. Quinoline moiety is mostly present in a medicinal plant whose
tubers possesses cardiovascular, anti-inflammatory and antiparasitic effects
and has been used for the treatment of hepatitis, rheumatism and diarrhea7.
The importance of quinoline and its annulated derivatives is well recognized
by synthetic and biological chemists8. Quinoline is substantial molecular
fragments of camptothecin are known to possess carcinogenic activity9.
In continuation of our work10, we undertook the comparative antioxidant
activity of 2-chloroquinoline-3-carbaldehydes (1a-g) and 2-chloro-3-(1,
3-dioxolan-2-yl)quinolines (2a-g). (Fig 1).
2-Chloro-7-methylquinoline-3-carbaldehyde12 (1c):Paleyellowpowder,
86% yield, mp 144-146°C (Lit.146°C). IR (KBr) cm-1: 3045, 2921(Aromatic
C-H), 2868(aldehyde C-H), 1689(C=O), 1579(C=N), 811(C-Cl).
2-Chloro-6-methylquinoline-3-carbaldehyde12 (1d): Pale yellow
powder, 80% yield, mp 122-123°C (Lit.123°C). IR (KBr)cm-1: 3050,
2921(Aromatic C-H), 2875(aldehyde C-H), 1691(C=O), 1579(C=N), 821(C-
Cl). 1H NMR (CDCl 400MHz) d: 2.56 (3H, s, CH3), 7.26 (1H, s, CH), 7.74-
7.70 (1H, d, J=10.6 3H, z, CH), 7.97-7.95(1H, d, J=8.4 Hz, CH), 8.66 (1H, s,
CH), 10.55 (1H, s, CHO). ESI-MS m/z: 205, Calcd for C H8ClNO: 205.64.
2-Chloro-8-methoxyquinoline-3-carbaldehyde12 1(11e): Pale yellow
powder, 75% yield, mp 190-192°C (Lit. 190°C). IR (KBr) cm-1: 2940(Aromatic
1
(C-H), 2866(aldehyde C-H), 1688(C=O), 1584(C=N), 763(C-Cl). H NMR
(CDCl 400MHz) d: 4.10 (3H, s, CH3), 7.27-7.22 (1H, m, CH), 7.58-7.55 (2H,
m, CH3),, 8.72 (1H, s, CH), 10.57 (1H, s, CHO). ESI-MS m/z: 221, Calcd for
C11H8ClNO2: 221.64.
2-Chloro-6-methoxyquinoline-3-carbaldehyde12 (1f): Pale yellow
powder, 62% yield, mp145-146°C (Lit.146°C). IR (KBr) cm-1: 3051,
ExPERIMENTAL
1
2922(Aromatic C-H), 1680(C=O), 1573(C=N), 814(C-Cl). H NMR (CDCl3,
The materials were purchased from Sigma–Aldrich and Merck and were
used without any additional purification. All reactions were monitored by
thin layer chromatography (TLC). Melting points were determined in open
capillaries using Dalal Melting Point Apparatus (Sunbim) and were corrected
with respect to Benzoic acid. The FT-IR spectrum of samples was recorded
300MHz) d: 3.96 (3H, s, CH3), 7.20-7.19 (1H, d, CH), 7.54-7.50 (1H, m, CH),
7.99-7.95 (1H, d, J=9.24 Hz, CH), 8.65 (1H, s, CH) 10.55 (1H, s, CHO). ESI-
MS m/z: 221, Calcd for C H8ClNO2: 221.64.
2-Chloro-7, 8-dime1t1hylquinoline-3-carbaldehyde (1g): Pale yellow
powder, 83% yield, mp 156 °C. IR (KBr) cm-1: 2924(Aromatic C-H),
1
on AVATAR 330 Thermo Nicolet spectrophotometer. H NMR spectra were
1
2864(aldehyde C-H), 1686(C=O), 1590(C=N), 814(C-Cl). H NMR (CDCl3,
recorded using BRUKER 300 MHz instrument and BRUKER NRC- IISc 400
MHz instrument (with TMS as internal reference). GCMS analyses were
performed with Agilent GCMS- 5973 Inert MSD series.
General procedure for synthesis of 2-chloro-3-(1, 3-dioxolan-2-yl)
quinolines (2a-g)
All the 2-chloroquinoline-3-carbaldehydes (1a-g) were prepared by the
Meth-Cohn method11. A solution of 2-chloroquinoline-3-carbaldehydes 1 (10
mmol) in benzene (50 mL) containing ethylene glycol (1.78 g, 1.6 mL, 28.5
mmol) and a crystal of toluene-p-sulfonic acid was heated under reflux for
5 hours using a Dean-Stark water separator until no more water collected in
the side arm. The cooled solution was treated with saturated aqueous sodium
carbonate (50 mL), Benzene layer separated, dried and evaporated giving 2
which was recrystallised from petroleum ether gave a yellowish white solid.
The product was characterized by NMR, GCMS techniques. Similar proce-
dures were followed for the synthesis of other quinoline derivatives 2a-g and
Table 1.
300MHz) d: 2.54 (3H, s, CH3), 2.72 (3H, s, CH3), 7.46-7.44 (1H, d, J=8.25 Hz,
CH), 7.72-7.69 (1H, d, J=8.25 Hz, CH), 8.65 (1H, s, CH) 10.54 (1H, s, CHO).
ESI-MS m/z: 219, Calcd for C12H10ClNO: 219.67.
2-Chloro-3-(1,3-dioxolan-2-yl)quinoline13 (2a):Paleyellowpowder,65%
yield, mp 60-62 °C. IR (KBr) cm-1: 2899(C-H),1621(C=C), 1567(C=N),1330(-
CH ), 1100(O-C), 755(C-Cl). 1H NMR (CDCl3, 400MHz) d: 4.20-4.13 (4H, m,
CH22 X 2), 6.24 (1H, s, CH), 7.59-7.55 (1H, m, CH), 7.77-7.73 (1H, m, CH),
7.86-7.84 (1H, d, J=8.4 Hz, CH), 8.04-8.02 (1H, d, J=8.8 Hz, CH), 8.40 (1H, s,
CH). ESI-MS m/z: 235, Calcd for C12H10ClNO2: 235.67.
2-Chloro-3-(1,3-dioxolan-2-yl)-8-methylquinoline13 (2b): Pale yellow
powder, 87% yield, mp 86-88°C. IR (KBr) cm-1: 2919(Aromatic C-H),
1
2883(C-H), 1614(C=C), 1597(C=N), 1330(-CH2), 1101(O-C), 765(C-Cl). H
NMR (CDCl3, 400MHz) d: 2.78(3H, s, CH3), 4.22-4.12 (4H, m, CH2 X 2), 6.26
(1H, s, CH), 7.49-7.44 (1H, m, CH), 7.61-7.58 (1H, d, J=7 Hz, CH), 7.70-7.68
(1H, d, J=8.08 Hz, CH), 8.37 (1H, s, CH). LC-MS m/z: 250(M+), Calcd for
C13H12ClNO2: 249.69.
The spectral data of the compounds 1(a-g) & 2(a-g) is given below.
2-Chloroquinoline-3-carbaldehyde12 (1a): Pale yellow powder, 82%
yield, mp 148-150°C (Lit.149°C). IR (KBr) cm-1: 3043, 2923(Aromatic C-H),
2-Chloro-3-(1, 3-dioxolan-2-yl)-7-methylquinoline11 (2c): Pale yellow
powder, 85% yield, mp 72-74°C (Lit. 75-76°C). IR (KBr) cm-1: 2921(Aromatic
1
1
C-H),1626(C=C), 1541(C=N),1330(-CH ), 1101(O-C), 810(C-Cl). H NMR
2871(aldehyde C-H), 1687(C=O), 1579(C=N), 761(C-Cl). H NMR (CDCl3,
(CDCl3, 400MHz) d: 2.58(3H, s, CH3), 4.213-4.23 (4H, m, CH2 X 2), 6.24 (1H,
400MHz) d: 7.68-7.64 (1H, m, CH), 7.92-7.87 (1H, m, CH), 8.00-7.98 (1H, d,
e-mail: nawa2-f@yahoo.cp.in
317

J. Chil. Chem. Soc., 55, Nº 3 (2010)
s, CH), 7.44-7.42 (1H, d,J=8.4Hz, CH), 7.77-7.75 (1H, d, J=8 Hz, CH), 7.83
(1H, s, CH), 8.37 (1H, s, CH). ESI-MS m/z: 250[M+1], Calcd for C13H12ClNO2:
249.69.
Table 1. Synthesis of 2-chloro-3-(1, 3-dioxolan-2-yl)quinoline, 2(a-g)
2-Chloro-3-(1,3-dioxolan-2-yl)-6-methylquinoline13 (2d): Pale yellow
powder, 78% yield, mp 52-54°C. IR (KBr) cm-1: 2894(C-H),1598(C=N),
1
1329(-CH ), 1096(O-C), 823(C-Cl). H NMR (CDCl3, 300MHz) d: 2.54 (3H,
s, CH3), 4.220-4.13 (4H, m, CH2 X 2), 6.23 (1H, s, CH), 7.62-7.57 (2H, m, CH),
7.95-7.92 (1H, d, J=8.55 Hz, CH), 8.32 (1H, s, CH). ESI-MS m/z: 250[M+1],
Calcd for C13H12ClNO2: 249.69.
2-Chloro-3-(1,3-dioxolan-2-yl)-8-methoxyquinoline13 (2e): Pale yellow
powder, 82% yield, mp 119-121°C. 1H NMR (CDCl3, 300MHz) d: 4.10 (3H, s,
OCH3), 4.32-4.20 (4H, m, CH2 X 2), 6.32 (1H, s, CH), 7.27-7.22 (1H, m, CH),
7.58-7.55 (2H, m, CH), 8.72 (1H, s, CH). IR (KBr) cm-1: 1632, 1107, 805. ESI-
MS m/z: 266[M+1], Calcd for C13H12ClNO3: 265.69.
2-Chloro-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline (2f): Pale yellow
powder, 74% yield, mp 93-95 °C. IR (KBr) cm-1: 2930(Aromatic C-H),
1619(C=C),1594(C=N), 1332(-CH ), 1103(O-C), 820(C-Cl). 1H NMR (CDCl3,
300MHz) d: 3.92 (3H, s, OCH ), 24.22-4.10 (4H, m, CH X 2), 6.22 (1H, s,
CH), 7.11-7.10 (1H, d, J=2.43 3Hz, CH), 7.41-7.37 (1H,2 m, CH), 7.94-7.91
(1H, d, J=9.18 Hz, CH), 8.30 (1H, s, CH). ESI-MS m/z: 266[M+1], Calcd for
C13H12ClNO3: 265.69.
2-Chloro-3-(1,3-dioxolan-2-yl)-7,8-dimethylquinoline
(2g):
Pale yellow powder, 81% yield, mp 107-109 °C. IR (KBr) cm-1: 3053,
2887(C-H),1606(C=C), 1563(C=N),1360(-CH ), 1108(O-C), 781(C-Cl). 1H
NMR (CDCl 300MHz) d: 2.54 (3H, s, CH ), 2.272 (3H, s, CH3), 4.22-4.10 (4H,
m, CH2 X 2)3,, 6.22 (1H, s, CH), 7.46-7.443(1H, d, J=8.25 Hz, CH), 7.72-7.69
(1H, d, J=8.25 Hz, CH), 8.65 (1H, s, CH). ESI-MS m/z: 264[M+1], Calcd for
C14H14ClNO2: 263.72.
BIOLOGICAL INVESTIGATION
Preparation of stock solution
The synthesized compounds were used to prepare stock using ethanol (0.3
mM). The appropriate concentrations of the compounds were made by serial
dilution.
Invitro antioxidant activity
Antioxidant activity was measured by following methodology assessed by
Roopan et al.,14, 15. For the present study the samples were prepared in different
concentrations i.e. 0.02, 0.05, 0.1, 0.15, 0.2 mM in AR grade ethanol. The
samples (3 mL) of above concentrations were mixed with 1 mL of 0.15 mM of
DPPH prepared in AR grade ethanol and incubated at room temperature for 30
min in dark. The absorbance of the incubated solutions and the blank (with out
sample) were recorded against BHT. The absorbance was measured at 517 nm
using a UV-Visible Spectrophotometer. Radical Scavenging Capacity (RSC)
in percent was calculated by the following equation:
When an antioxidant added to the radicals there is a degree of decolorization
owing to the presence of the antioxidants which reverses the formation of the
DPPH× radical. Bleaching rate of a stable free radical, DPPH× is monitored at
a characteristic wavelength in the presence of the sample. In its radical form,
DPPH× absorbs at 517 nm, but upon reduction by an antioxidant species its
absorption decreases. When the absorption decreases the % inhibition value
will be increase. The absorbance was measured at 517nm. Different derivatives
of quinoline reduced DPPH radicals significantly. Activities of quinoline
(1a-g/2a-g) derivatives were compared with commercial antioxidant butylated
hydroxy toluene, (BHT) (Fig. 1). DPPH is a stable free radical and accepts an
electron or hydrogen radical to become a stable diamagnetic molecule. In the
radical form, this molecule had an absorbance at 517 nm which disappeared
after acceptance of an electron or hydrogen radical from an antioxidant
compound to become a stable diamagnetic molecule. Compound 1g had
relatively high DPPH radical scavenging activity at 0.2 mM concentration. As
shown in Fig. 1, 1b, 1d, 1g & 2b, 2e, 2f, found to have the ability to scavenge
hydroxyl radicals, remaining compounds are inactive.
RSC(%)
=
100 x (Ablank- Asample)/ Ablank
Where
RSC
Ablank
Ablank
=
Radical Scavenging Capacity
Absorbance of blank
Absorbance of sample
=
=
RESULTS AND DISCUSSION
Radical scavenging activity is very important due to the deleterious
role of free radicals in foods and in biological systems. Diverse methods
are currently used to assess the antioxidant activity. Herein is reported a
synthesis of 2-chloro-quinoline-3-carboxaldehydes (1a-g) and 2-chloro-3-(1,
3-dioxolan-2-yl)quinolines (2a-g) as potential antioxidants. Chemical assays
are based on the ability to scavenge synthetic free radicals, using a variety
of radical-generating systems and methods for detection of the oxidation end-
point. DPPH× radical scavenging methods are common spectrophotometric
procedures for determining the antioxidant capacities of components. All the
compounds were fully characterized and screened for biological activity using
DPPH method as per the literature methodology14, 15. These assays have been
applied to determine the antioxidant activity of pure component.
Fig 1. In vitro antioxidant activity of quinoline compounds
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J. Chil. Chem. Soc., 55, Nº 3 (2010)
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In conclusion, we have developed a new anti-oxidative quinoline
derivatives, 1a-g/2a-g. The maximum antioxidant activity was observed with
1g. Compounds 2e, 2f showed good free radical scavenging property and
compounds 1b, 1d exhibited less activity compare to other compounds.
ACKNOWLEDGEMENT
We are grateful for financial support from the Department of Science
and Technology, Government of India (Grant No. SR/FTP/CS-99/2006) and
VIT University, Vellore for providing research facilities. The authors wish
to express their gratitude to Technology Buisness Incubator, VIT University,
Madras Univeristy, Chennai, Indian Institute of Science, Bangalore and
Syngene International Limited, Bangalore for their support of FT-IR, NMR,
LCMS.
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