An Expedient Approach for the Synthesis of Bioactive Pyrazole, Isoxazole and Benzodiazepine-Substituted Quinolin-2(1H)-one Derivatives

Article abstract of DOI:10.1002/jhet.2192

A sequence of functionalized pyrazole, isoxazole and benzodiazepine-substituted quinolone derivatives were synthesized in good yield starting from readily available starting precursors. These approaches lead to the synthesis of hitherto unknown compounds with a varied substitution pattern by both conventional and microwave-assisted method. A good number of analogues were evaluated for their in vitro cytotoxicity against human cervical and colon cancer cell lines by MTT protocol. Almost all the selected compounds showed remarkable cytotoxic activities. Among them, compound 4g and 4i emerged as the most promising scaffolds. These scaffolds will be used for further molecular level studies.

Full text of DOI:10.1002/jhet.2192

Month 2014 An Expedient Approach for the Synthesis of Bioactive Pyrazole, Isoxazole
and Benzodiazepine-Substituted Quinolin-2(1H)-one Derivatives
Mathan Sankaran, Chokkalingam Uvarani, Kumarasamy Chandraprakash, Mani Umamaheswari
*
and Palathurai Subramaniam Mohan
School of Chemical Sciences, Bharathiar University, Coimbatore, Tamilnadu, 641046, India
*
E-mail: ps_mohan_in@yahoo.com
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Received July 9, 2013
DOI 10.1002/jhet.2192
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A sequence of functionalized pyrazole, isoxazole and benzodiazepine-substituted quinolone derivatives
were synthesized in good yield starting from readily available starting precursors. These approaches lead
to the synthesis of hitherto unknown compounds with a varied substitution pattern by both conventional
and microwave-assisted method. A good number of analogues were evaluated for their in vitro cytotoxicity
against human cervical and colon cancer cell lines by MTT protocol. Almost all the selected compounds
showed remarkable cytotoxic activities. Among them, compound 4g and 4i emerged as the most promising
scaffolds. These scaffolds will be used for further molecular level studies.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
study, 3-acetyl-4-hydroxyquinolin-2-one has been used as
a lead precursor to synthesize fused pyrimidine and
pyrazoloquinolone derivatives as antioxidants [16]. In
continuation of our earlier work on the synthesis and
antioxidant activities of quinolone-based heterocycles,
we herein report the synthesis of 3-acetyl-4-methyl/
phenyl-substituted quinolin-2-one systems as a lead for
the synthesis of a library of pyrazole-substituted and
isoxazole-substituted quinolones by microwave-assisted
approach, and evaluation of their cytotoxicity for three
human cancer cells have been investigated and presented.
The recent literatures are enriched with progressive
findings about the synthesis and pharmacological action
of substituted and fused heterocycles [1,2]. Among them,
quinolines are one of the important nitrogen heterocycles
that have shown extensive applications in pharmaceuticals
[3,4] and found to have widespread occurrences in natural
products [5]. Moreover, pyrazole-substituted moieties are
found to be a core unit of numerous drug candidates
[6,7], including Celebrex [8], Viagra [9], zaleplon [10],
and allopurino [11–13]. In recent times, pyrazole-bearing
quinoline systems have attracted great interest for their
well-known biological activities including high-affinity
interleukin [14], antioxidants [15,16], acetyl cholinesterase
[17], anticancer [18,19], and DNA gyrase inhibitors [20]. In
addition, the aforementioned activities of dihydroquinolone
derivatives have also been reported to have central
nervous system disorders [21,22], antimicrobial agents [23],
and so on. Moreover, quinolone-substituted pyrazoline
and isoxazoline analogues are found to have a good
molluscicidal activities [24] with LC50 = 0.7876 and
LC50 = 0.7765, and NMDA receptor antagonist [25] for
the treatment of neurological condition makes this class
of molecule distinctive among medicinal chemists and
made them attractive targets for synthesis. In our previous
RESULTS AND DISCUSSION
The starting precursor 3-acetylquinolin-2-one 1a–d was
achieved by the route as depicted by the literature method
[26,27]. In fact, various aromatic aldehydes 2a–f reacted
smoothly with the solution of 3-acetylquinolin-2(1H)-one
1a–d in the presence of sodium hydroxide at room
temperature for 7–10 h to afford the corresponding
quinolone-based α,β-unsaturated systems (3a–l) in excel-
lent yield (Scheme 1; Table 1). The synthetic pathway used
to achieve the target compounds that have been delineated
in Schemes 2 and 3 resulted in poor to moderate yield of
the desired cyclized products (4a–p, 5a–d, 6a–e), probably
© 2014 HeteroCorporation

M. Sankaran, C. Uvarani, K. Chandraprakash, M. Umamaheswari, and P. S. Mohan
Vol 000
Scheme 1. Synthesis of quinolone-based α,β-unsaturated carbonyl systems 3a–l. [Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
Table 1
reaction time to 5–10 min compared with the conventional
heating protocol to afford the desired compound (Table 2).
So, the obtained quinolin-2(1H)-one-based α,β-unsaturated
systems 3 were prepared from 4-substituted 3-acetyl-
quinolin-2(1H)-one with various aromatic aldehydes and
were then treated with phenyl hydrazine/hydrazine hydrate
and hydroxylamine hydrochloride in the presence of
catalytic amount of acetic acid or ethanol in a micro-
wave-assisted, one-pot protocol to give the titled
compound in good yield. The microwave reaction was
carried out in Biotage initiator, and the absorption level
was kept high with a prestirring of 20–30 s. Initially, the
power was kept zero, followed by a gradual increase, and
then the reaction proceeded at a constant power of 360 W
with temperature of 120°C. Almost all the compounds
were isolated with excellent yield by this method, and most
of them were pure enough for further analysis without
going for column chromatography. Therefore, the micro-
wave-assisted method was chosen to be an ideal technique
for preparing libraries in terms of greener approach compared
Synthesis of quinolone-based α,β-unsaturated carbonyl compounds 3a–l.
Product
R
R1
R2
p-Br
p-OCH3
o-Cl
p-Cl
p-Cl
H
p-Cl
p-OCH3
o-Cl
p-CH3
H
Yield in 10–12 h (%)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH3
CH3
C6H5
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
Cl
H
Cl
Cl
NO2
Cl
H
79
90
84
86
78
86
77
84
75
78
82
86
3j
3k
3l
H
H
H
p-OCH3
aIsolated yield from the conventional method.
because of the low neucleophilicity or poor solubility. In
light of these findings, it was decided to perform the reac-
tion, a trial under microwave irradiation. The effort not
only improved the yield dramatically but also reduced the
Scheme 2. Synthesis of pyrazole-substituted quinolone analogues 4a–p and 5a–d. [Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Convenient Approach for the Synthesis of Pyrazole, Isoxazole
and Benzodiazepine Based Quinolines
Scheme 3. Synthesis of isoxazole-substituted quinolone analogues 6a–e. [Color figure can be viewed in the online issue, which is available at www.
interscience.wiley.com.]
Table 2
Conventional and microwave-assisted approach toward the synthesis of analogues 4a–p, 5a–d, and 6a–e.
Method Aa yield
Method Bb yield
Product
R
R1
R2
R3
8–10 h (%)
7–10 min (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH3
CH3
CH3
CH3
H
H
H
H
4-OCH3
4-Br
4-Br
2-Cl
4-CH3
4-Cl
H
2-Cl
4-OCH3
4-CH3
H
H
4-F
4-Cl
H
H
3-NO2
4-F
H
H
3-NO2
H
H
H
H
3-NO2
H
55
46
48
52
50
55
44
56
52
40
58
42
57
45
52
55
45
54
48
55
67
58
62
66
60
75
78
72
84
79
82
80
74
76
68
80
75
78
86
85
78
75
74
71
74
70
75
83
78
75
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
C6H5
CH3
C6H5
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
Cl
Cl
Cl
H
H
H
Cl
H
Cl
H
NO2
H
Cl
H
4j
4k
4l
H
H
4m
4n
4o
4p
5a
5b
5c
5d
6a
6b
6c
6d
6e
4-OCH3
4-Br
4-Cl
4-Br
4-OCH3
4-Br
4-CH3
4-Br
H
—
—
—
—
—
—
—
—
H
Cl
Cl
Cl
H
4-OCH3
4-Cl
4-F
H
—
aIsolated yield from the conventional method.
bIsolated yield from the microwave-assisted approach.
with the conventional way of synthesis. To the best of our
knowledge, the synthesis of 4-phenyl/4-methyl pyrazole-
substituted and isoxazole-substituted quinolin-2(1H)-one
derivative has been described scarcely in the literature.
doublet of doublet at δ 6.94–6.97 attributed to the olefinic
(CH═CH) group with coupling constant 16.5 and 9.0 Hz.
The coupling constant J = 16.5 Hz indicated the E configu-
ration of α,β-unsaturated compounds. In the 13C NMR, the
signal at δ 195.8 was due to the carbonyl carbon adjacent
to olefinic bond, and the signal near 161.9 was due to the
amide-C═O function. The signals around δ 15.99 and
55.84 were attributed to the methyl and methoxy functions,
respectively. In the IR spectra, the stretching frequency of
olefin and amide carbonyl functions appeared at 1597
and 1658 cmꢀ1, respectively. Elemental analyses and
spectral data of 3a–l are consistent with the proposed
structures. The 1H NMR spectrum of 4a (Scheme 2)
showed multiple of signals around δ 3.9 and 3.1 assignable
A library of 25 compounds has been synthesized as sum-
marized in Table 2 including 12 intermediates, and as is
evident, the presence of electron-withdrawing/electron-
donating substitutions did not seem to have any significant
limitation on the overall reactivity, giving the desired
product in quantitative yields. Both analytical and spectral
data (1H, 13C NMR, and mass spectra) of all the synthe-
sized compounds were in full agreement with the proposed
structures. For instance, the 1H NMR spectrum of 3b
in deuterated dimethyl sulfoxide (Scheme 1) furnished
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Sankaran, C. Uvarani, K. Chandraprakash, M. Umamaheswari, and P. S. Mohan
Vol 000
to methylene protons, and the signal at δ 5.35 was due to
the ―CH proton of the pyrazole moiety. The singlet peak
that appeared at δ 3.7 and 2.6 were due to the “OCH3”
and “CH3” function groups, respectively. The signals that
appeared around δ 6.7–7.8 were attributed to the aromatic
protons of 4a. Another singlet peak around δ 11.84 was
due to the “NH” function of 4a. The same was factual for
all other compounds of the series. In the 13C NMR, the
signal that appeared at δ 62.5 was due to the methylene
proton of the pyrazole motif, and the disappearance of
the peak due to the unsaturated ―C═O function in 4a
confirmed the formation of the pyrazole motif. In the IR
spectra, the carbonyl stretching frequency was absent be-
cause of the cyclization as confirmed in the formation of
4a. The mass spectrum shows the M+ ion peak at 410.2
and was in consistent with the proposed structure. Simi-
larly, compounds 5a–d (Scheme 2) and 6a–e (Scheme 3)
were well characterized by the straightforward method,
which is highlighted in Supporting Information.
Figure 1. Ortep view of compound 9e. [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]
BIOLOGICAL EVALUATION
The novel compounds were evaluated for their cytotoxic-
ity against human cancer cell lines through a preliminary
MTT assay [29]. The response parameter (IC50) was calcu-
lated, which corresponds to the compound concentration
causing 50% mortality in net cells. Among the selected com-
pounds, 4g and 4i were found to be promising against three
human cancer cell lines, which could be comparable with
the reference drug adriamycin. Furthermore, compound 4i
was considered to be more potent against human cervical
(HeLa) and colon (HCT-116, HCT-8) cancer cell lines with
the IC50 values of 2.4, 2.2, and 5.6μM (Table 3), followed
by compound 4g that showed a considerable cytotoxicity
against cervical (HeLa) and colon (HCT-116, HCT-8) cancer
cell lines with the IC50 values of 4.14, 8.6, and 7.6 μM, re-
spectively. An interesting change in IC50 values was ob-
served when substituting a hydrogen atom by a fluorine
atom and methoxy function on the compounds belonging
to the series 4 suggesting to be a methoxy group, and the
fluoro function was favored in controlling the growth of
cells. Compared with 4i and 4g, it was observed that com-
pounds 4a, 4b, 4c, 4d, 5a, 5b, 6a, and 6b showed moderate
cytotoxicity against the proliferation of cells. On the other
hand, analogues 4f and 4j displayed less cytotoxicity against
both the cell lines. As a result, from the structural point of
Synthesis and characterization of benzodiazepine-based
quinoline systems. The intermediate (7) and its starting
precursor were synthesized as per the literature method
[28]. In this juncture, Scheme 4 disclosed the synthesis of
benzodiazepine-substituted quinolines 9a–e in good yield,
accomplished from various derivatives of 3-cinnamoyl-4-
hydroxyquinolin-2(1H)-ones (7). For example, the 1H
NMR Spectrum of 9a furnished a singlet at δ 3.70
assignable to the “OCH3” function. The signals at δ 6.2,
5.1, and 4.40 were attributed to the benzodiazepine ring
unit, confirming the formation of 9a. The signals that
appeared around δ 6.8–7.9 was due to the aromatic
protons, and the broad singlet around δ 10.6 and the
sharp singlet at δ 16.2 were attributed to the “NH” and
“OH” functions, respectively. The compound 9a was
further confirmed by their 13C NMR, IR, and elemental
analysis. Compound 9e was unambiguously determined
by single crystal X-ray analysis (Fig. 1). Fascinatingly,
the same reaction could not be performed for the
intermediates (3a–I), which might be because of the
steric hindrance of the phenyl group present at the fourth
position of the quinoline-2-one systems.
Scheme 4. Synthesis of benzodiazepine-substituted quinolone analogues 9a–e. [Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Convenient Approach for the Synthesis of Pyrazole, Isoxazole
and Benzodiazepine Based Quinolines
Table 3
Cytotoxicity expressed by IC50 in μM of compounds for cancer cell lines.
MTT IC50 (μM)
Entry
Product
HeLaa
HCT 116b
HCT-8c
1
2
3
4
5
6
7
8
9
10
11
12
4a
4b
4c
4d
4f
4g
4i
4j
5a
5b
6a
6c
33.26 0.20
22.55 0.40
15.50 0.52
NT
29.2 0.28
18.55 0.20
23.33 0.34
NT
98.5 0.76
8.6 0.16
NT
33.25 0.33
20.20 0.24
22.20 0.28
NT
7.6 0.18
5.6 0.16
NT
NT
NT
18.12 0.44
NT
7.2 0.32
> 100
4.14 0.10
2.4 0.14
87.73 0.85
46.45 0.66
40.11 0.45
15.22 0.22
12.20 0.34
6.3 0.22
2.2 0.12
88.54 0.58
48.23 0.24
40.45 0.30
22.21 0.32
15.05 0.22
8.7 0.20
Adriamycin
NT, not tested.
aData are presented as IC50 values for cervical (HeLa) cancer cells.
bColon HCT-116 cancer cells.
cColon HCT-8 cancer cells.
of Technology, Chennai. Bruker (Advance) 400-MHz instrument
in DMSO-d6 using TMS as internal standard. Chemical shifts are
given in parts per million (δ-scale), and the coupling constants are
given in Hertz. IR spectra were recorded on a JASCO FT IR in-
strument (KBr) pellet in case of solids and CHCl3 in case of vis-
cous liquids. Elemental analyses were performed on a Perkin
Elmer 2400 Series II Elemental CHNS analyzer. Single crystal
X-ray structure was performed in a Bruker APEX-II CCD diffrac-
tometer (crystal type: Monoclinic). Molecular mass of the struc-
tures were performed in Agilent mass spectrometric system.
Organic reactions were performed in Biotage Initiator EXP EU
microwave synthesizer. The human cervical cancer cell line
(HeLa) was obtained from the National Centre for Cell Science
(NCCS), Pune, and grown in Eagles Minimum Essential Medium
containing 10% fetal bovine serum (FBS). All cells were
maintained at 37°C, 5% CO2, 95% air, and 100% relative
humidity. Maintenance of cultures was passaged weekly, and
view, the marked activity seems to be due to the electron-
withdrawing capability of the group attached to the pyrazole
and quinoline ring fragments, as it could make the molecules
more acidic [30,31], whereas quinolinone-bearing isoxazole
ring fragments 6a showed that the IC50 values are 15.22,
22.21, and 18.12μM and 6c showed that the IC50 values
are 12.20 and 15.05μM, which showed reasonable
antiproliferative activity against the aforementioned cell
lines. Our studies obviously suggest that pyrazole-
substituted quinolin-2(1H)-one derivative with an electron-
withdrawing substituent on aryl ring could be an attractive
template for the identification of novel cytotoxic agents.
CONCLUSION
In conclusion, we have synthesized a new series of
pyrazole-substituted, isoxazole-substituted, and benzodiaze-
pine-substituted quinolin-2-(1H)-one analogues. The yield
of the products was enhanced by the microwave-assisted
approach rather than the conventional way of synthesis. The
selected compounds were evaluated for cytotoxicity against
cervical (HeLa) and colon cancer (HCT-116, HCT-8) cell
lines. Most of them were found to be a promise against the
aforementioned cell lines, and these classes of compounds
have scope for further development toward becoming
potential candidates as cytotoxic agents. Overall, the
substituted heterocyclic framework provides a useful basis
for the development of a new class of bioactive compounds.
the culture medium was changed twice a week.
General procedure for the synthesis of quinoline-2(1H)-one
based α,β-unsaturated systems (3a–l). Equimolar amount of
4-phenyl/methyl-3-acetylquinolin-2(1H)-one 1(a–d) (0.01 mmol)
and appropriate aromatic aldehydes 2(a–f) (0.01 mmol) were
dissolved in ethanol, and 0.1 mmol aq. NaOH was added
dropwise over a period of half an hour at 0°C. After the
addition, stirring was continued overnight. Then, the reaction
mixture was poured into 500 g of crushed ice after confirmation
by the TLC. The precipitate thus formed was neutralized with
dil. HCl and filtered off, dried, and chromatographed on a silica
gel column chromatography (8:2) n-hexane:EtOAc to obtain a
1
pale yellow powder, and the products were characterized by H,
13C, and IR spectra.
General procedure for the synthesis of dihydro-1H-pyrazol-
3-yl)-4-quinolin-2(1H)-one or (4a–p)
Conventional method A.
Quinoline-2(1H)-one-based α,β-
EXPERIMENTAL
unsaturated carbonyl compound 3 (0.01 mmol) and substituted
phenyl hydrazine hydrochloride (0.03 mmol) were mixed in
acetic acid and were refluxed over a period of 8–9 h. After the
reaction was over as evidenced by the TLC, the reaction
The melting points were taken using open capillary tubes and
were uncorrected. 1H and 13C NMR spectra were recorded in
Indian Institute of Science (IISC), Bangalore and Indian Institute
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Sankaran, C. Uvarani, K. Chandraprakash, M. Umamaheswari, and P. S. Mohan
Vol 000
mixture was cooled to room temperature. Then, it was poured into
500 g of crushed ice after evaporation of the one-third of the
solvent. The precipitate thus formed was filtered off, washed
with excess of water, and dried; subsequently, the mixture was
chromatographed on a silica gel column chromatography on n-
hexane:EtOAc (7:3) to obtain a reddish yellow powder.
3-(5-(2-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-
yl)-4-methylquinolin-2-(1H)-one (4d). Pale yellow solid (77%);
mp 222–225°C; IR(KBr) υmax 3412.42, 2851.24, 1645.95, 1597.73,
1501.31, 1431.89, 1389.46, 1124.3, 873.59, 750.17 cmꢀ1; 1H NMR
(400 MHz, DMSO-d6) δ 11.87 (s, 1H, 1-NH), 7.85 (d, 1H,
J = 8.08 Hz, Ar―H), 7.52–7.57 (m, 3H, Ar―H), 7.41 (s, 1H,
Ar―H), 7.32–7.34 (m, 3H, Ar―H), 7.25 (t, 2H, J = 8 Hz,
Ar―H), 6.86 (d, 2H, J = 7.96Hz, Ar―H), 6.75 (t, 1H, J = 7.2 Hz,
Ar―H), 5.62 (dd, 1H, J1 = 12.28Hz, J2 = 6.72Hz, Pyr-H), 4.07
(dd, 1H, J1 = 17.60Hz, J2 = 12.36 Hz, Pyr-H), 3.11 (dd, 1H,
J1 = 17.76Hz, J2 = 6.88 Hz, Pyr-H), 2.62 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) δ 133, 132.4, 131.4, 130.5, 128.7, 127.9,
127.4, 125.5, 124.6, 123.7, 123.2, 122, 120.2, 119.6, 119.3,
118.8, 115.4, 112.7, 107.2, 62.3, 59.7, 46.2, 20.7, 16.3, 14; MS
m/z 413 (M+): Anal. Calcd for C25H20ClN3O (413) C, 72.55; H,
Microwave-assisted synthesis B.
Quinoline-2(1H)-one-
based α,β-unsaturated carbonyl compound 3 (0.01 mmol) and
phenyl hydrazine hydrochloride (0.03 mmol) were powdered,
mixed with 2–5 drops of AcOH, and introduced in an open
borosil glass vessel. The reaction proceeded at a constant power
of 360 W with temperature of 120°C for 5 min with constant
interval. After completion (TLC), the reaction mixture was
brought to room temperature and poured into 300 g of crushed
ice. The crude product was recrystallized to obtain the title
compound, which was found to be in good purity (TLC) and yield.
3-(5-(4-Methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-
4.87; N, 10.15; Found: C, 72.59; H, 4.84; N, 10.12%.
4-Phenyl-3-(1-phenyl-5-p-tolyl-4,5-dihydro-1H-pyrazol-3-yl)
quinolin-2(1H)-one (4e). White solid (79%) mp 216–218°C;
IR(KBr) υmax 3437.49, 2835.8, 1656.55, 1598.7, 1503.24,
yl)-4-methylquinolin-2(1H)-one (4a).
(75%); mp 222–225°C; IR (KBr) υmax 2847.38, 1740.44,
1645.95, 1501.31, 1389.46, 998.94, 748.24 cmꢀ1 1H NMR
Pale yellow solid
1243.86, 1031.73, 829.24 cmꢀ1 1H NMR (400 MHz, DMSO-
;
;
d6) 11.89 (s, 1H, 1-NH), 8.26 (s, 1H, Ar―H), 8.14 (d, 1H,
J = 7.8 Hz), 7.82–7.88 (m, 3H, Ar―H), 7.67–7.71 (q, 4H,
Ar―H), 7.17 (t, 2H, J = 7.4 Hz, Ar―H), 6.96 (d, 2H,
J = 7.88 Hz, Ar―H), 6.75 (t, 1H, J = 7.24 Hz), 5.65 (dd, 1H,
J1 = 15.50 Hz, J2 = 5.80 Hz, Pyr-H), 4.00 (dd, 1H, J1 = 17.8 Hz,
J2 = 12.32 Hz, Pyr-H), 3.20 (dd, 1H, J1 = 17.60 Hz, J2 = 6.48 Hz,
Pyr-H), 2.63 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ
137.8, 132.8, 131.03, 130.6, 129, 125.7, 123.5, 122.4, 122,
120.9, 119.1, 115.5, 112.9, 62, 46.1, 40.6, 16.3; Anal. Calcd
for C31H25N3O (455) C, 81.73; H, 5.53; N, 9.22; Found: C,
(400 MHz, DMSO-d6) δ 11.84 (s, 1H, 1-NH), 7.85 (d, 1H,
J = 8.04 Hz, ArH), 7.53 (t, 1H, J = 7.84 Hz, Ar―H), 7.23–7.36
(m, 4H, Ar―H), 7.13 (t, 2H, J = 7.8 Hz, Ar―H), 6.91–6.95 (m,
4H, Ar―H), 6.71 (t, 1H, J = 7.28, Hz, ArH), 5.35 (dd, 1H,
J1 = 6.86 Hz, J2 = 12.12 Hz, Pyr-H), 3.91 (dd, 1H, J1 = 17.8 Hz,
J2 = 12.2 Hz, Pyr-H), 3.72 (s, 3H, ―OCH3), 3.11 (dd, 1H,
J1 = 17.68 Hz, J2 = 6.86 Hz, Pyr-H), 2.62 (s, 3H, ―CH3). 13C
NMR (100 MHz, DMSO-d6) δ 160.6, 158.4, 146.7, 144.7,
137.8, 134.6, 130.6, 128.8, 127.2, 125.6, 123.9, 112, 119.6,
118.5, 115.3, 114.2, 112.9, 62.5, 55.0, 46.4, 16.3; MS m/z
409.5 (M+). Anal. Calcd for C26H23N3O2 (409) C, 76.26; H,
81.78; H, 5; N, 9.15%.
6-Chloro-3-(5-(4-chlorophenyl)-1-(3-nitrophenyl)-4,5-dihydro-
5.66; N, 10.26; Found: C, 76.28; H, 5.59; N, 10.21%.
3-(5-(4-Bromophenyl)-1-(4-fluorophenyl)-4,5-dihydro-1H-
1H-pyrazol-3-yl)-4-phenyl quinolin-2(1H)-one (4f).
solid (82%) mp 218–220°C; IR (KBr) υmax 3302.5, 3146.29,
2852.2, 1644.98, 1388.5, 1209.15, 1090.55, 818.63cmꢀ1 1H
White
pyrazol-3-yl)-4-methylquinolin-2 (1H)-one (4b). Orange solid
(78%); mp 215–218°C; IR (KBr) υmax 2857.24, 1656.55,
;
1508.06, 1218.79, 821.53, 752.10, 640.25cmꢀ1
;
1H NMR
NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H, 1-NH), 7.62 (d, 1H,
J = 8.76 Hz, ArH), 7.54 (d, 2H, J = 7.44 Hz, Ar―H), 7.43–7.50
(m, 5H, Ar―H), 7.37 (s, 1H, Ar―H), 7.24–7.30 (m, 4H,
Ar―H), 6.91 (d, 2H, J = 9.44 Hz, Ar―H), 6.86 (d, 1H,
J = 7.6 Hz, ArH), 5.49 (dd, 1H, J1 = 12.2Hz, J2 = 4.76 Hz, Pyr-H),
3.96 (dd, 1H, J1 = 7.96 Hz, J2 = 12.6Hz, Pyr-H), 2.94 (dd, 1H,
J1 = 18.08 Hz, J2 = 4.92 Hz, Pyr-H); 13C NMR (100MHz,
DMSO-d6) δ 160.8, 149.9, 148.9, 147.8, 144.6, 140.6, 137.5,
135.8, 132.6, 131.4, 130.3, 130.21, 129.3, 128.9, 128.2, 126.5,
126.4, 125.2, 121.4, 118.7, 117.9, 113.1, 107.2, 61.8, 46.8; Anal.
Calcd for C30H20Cl2N4O3 (554) C, 64.87; H, 3.63; N, 10.09;
(400MHz, DMSO-d6) δ 11.85 (s, 1H, 1-NH), 7.83 (d, 1H,
J = 8 Hz, ArH), 7.69 (d, 1H, J = 6.3 Hz, Ar―H), 7.54 (t, 3H,
J = 8 Hz, Ar―H), 7.34 (d, 3H, J = 8 Hz, Ar―H), 7.23 (t, 1H,
J = 6.8 Hz, Ar―H), 7.00 (t, 1H, J = 8.56 Hz, Ar―H), 6.92 (t, 2H,
J = 7.44Hz, Ar―H) 5.38 (dd, 1H, J1 = 12.00Hz, J2 = 8.56Hz,
Pyr-H), 3.94 (dd, 1H, J1 = 15.72 Hz, J2 = 12.00Hz, Pyr-H), 3.16
(dd, 1H, J1 = 17.76 Hz, J2 = 8.56 Hz, Pyr-H), 2.60 (s, 3H, CH3).
13C NMR (100 MHz, DMSO-d6) δ 161.2, 157.4, 155.4, 147.6,
46.8, 142.4, 141.8, 138.3, 132.3, 131.7, 131.0, 128.9, 126.1,
124.1, 122.5, 122.5, 120.9, 120; Anal. Calcd for C25H19BrFN3O
(475) C, 63.04; H, 4.02; N, 8.82; Found: C, 63.10; H, 4.06; N,
Found: C, 64.80; H, 3.65; N, 10.12%.
6-Chloro-3-(1-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-
8.85%.
3-(5-(4-Bromophenyl)-1-(4-chlorophenyl)-4,5-dihydro-1H-
pyrazol-3-yl)-4-phenylquinolin-2 (1H)-one (4g).
yellow solid (80%) mp 225–227°C; IR (KBr) υmax 3155.11,
3022.87, 2854.13, 1659.45, 1509.03, 1209.15 cmꢀ1 1H
Pale
pyrazol-3-yl)-4-methylquinolin-2(1H)-one (4c).
solid (72%) mp 217–220°C; IR (KBr) υmax 2850.27, 1658.48,
1596.77, 1496.49, 1007.62, 819.59, 753.06 cmꢀ1 1H NMR
Orange
;
;
NMR (400 MHz, DMSO-d6). δ 11.55 (s, 1H, 1-NH), 7.62 (m,
2H, Ar―H), 7.45 (t, 1H, J = 9.6 Hz, Ar―H), 7.36 (d, 2H,
J = 7.68 Hz, Ar―H), 6.93–7.32 (m, 8H, Ar―H), 6.83 (t, 2H,
J = 9.5 Hz, Ar―H), 6.53 (d, 2H, J = 7.56 Hz, Ar―H), 5.17
(dd, 1H, J1 = 19.76 Hz, J2 = 9.60 Hz, Pyr-H), 3.89 (dd, 1H,
J1 = 18.64 Hz, J2 = 15.36 Hz, Pyr-H), 2.88 (dd, J1 = 18.80 Hz,
J2 = 6.76 Hz Pyr-H); 13C NMR (100 MHz, DMSO-d6) δ 160.9,
159.9, 157.48, 154.9, 149.1, 147.4, 146.4, 145.1, 142.8,
141.2, 138.2, 136.1, 134.1, 133.1, 131.3, 130.9, 129.2, 128.8,
128.6, 127.8, 127.6, 126.5, 125.8, 121.5, 121, 118.1, 117.8,
115.3, 114.4, 63.5, 47; Anal. Calcd for C30H21ClFN3O (493)
C, 72.95; H, 4.29; N, 8.51. Found: C, 72.92; H, 4.35; N, 8.52%.
(400 MHz, DMSO-d6) δ 11.89 (s, 1H, 1-NH), 7.85 (d, 1H,
J = 8.4 Hz, Ar―H), 7.53–7.57 (m, 3H, Ar―H), 7.30–7.35 (m,
3H, Ar―H), 7.25 (t, 1H, J = 7.6 Hz, Ar―H), 7.20 (d, 2H,
J = 8.8 Hz, Ar―H), 6.91 (d, 2H, J = 9.2, Hz, Ar―H), 5.46
(dd, 1H, J1 = 12.00Hz, J2 = 6.4 Hz, Pyr-H), 3.95 (dd, 1H,
J1 = 22.40 Hz, J2 = 11.00Hz, pyr-H), 3.15 (dd, 1H, J1 = 17.60 Hz,
J2 = 6.40Hz, Pyr-H), 2.60 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6) δ 161.1, 148.4, 146.8, 142.1, 138.3, 132.3, 131.7,
131.2, 128.8, 126.2, 124, 122.6, 121, 120, 115.8, 114.8, 62.7,
46.8, 16.9; Anal. Calcd for C25H19BrClN3O (491) C, 60.93; H,
3.89; N, 8.53; Found: C, 60.98; H, 3.86; N, 8.49%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Convenient Approach for the Synthesis of Pyrazole, Isoxazole
and Benzodiazepine Based Quinolines
142.6, 138.2, 136.1, 130.7, 129.7, 128.7, 128.5, 128.1,
127.9, 127.2, 125.8, 124.2, 122.1, 119.7, 118.2, 115.3,
112.6, 62.3, 46.4; Anal. Calcd for C30H23N3O (441) C,
6-Chloro-3-(5-(2-chlorophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-phenylquinolin-2(1H)-one (4h). Pale yellow
solid (74%) mp 214–216°C; IR (KBr) υmax 3437.49, 3151.11,
81.61; H, 5.25; N, 9.52; Found: C, 81.56; H, 5.29; N, 9.50%.
3022.87, 2853.17, 1651.73, 1597.73, 1501.31, 1394.28,
1213.97 cmꢀ1 1H NMR (400MHz, DMSO-d6) δ 12.29 (s, 1H,
;
6-Chloro-3-(1,5-diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-
phenylquinolin-2(1H)-one (4l).
White solid (75%) mp
1-NH), 7.59 (d, 1H, J = 6.32 Hz, ArH), 7.33–7.55 (m, 6H,
Ar―H), 7.26 (t, 1H, J = 7.56 Hz, Ar―H), 7.12–7.20 (m, 3H,
Ar―H), 7.04 (q, 2H, Ar―H), 6.90 (d, 1H, J = 2.36 Hz, Ar―H),
6.65 (t, 1H, J = 7.36 Hz, Ar―H), 6.47 (d, 2H, J = 7.72Hz,
Ar―H), 5.65 (dd, 1H, J1 = 16.28 Hz, J2 = 5.12Hz, Pyr-H), 3.98
(dd, 1H, J1 = 14.00Hz, J2 = 5.24 Hz, Pyr-H), 2.81 (dd, 1H,
J1 = 15.5Hz, J2 = 12.24 Hz, Ar―H). 13C NMR (100 MHz,
DMSO-d6) δ 160.4, 148.8, 144.7, 138.5, 136.9, 135.5, 130.6,
129.6, 129, 128.7, 128.3, 127.6, 127, 125.9, 125.1, 121.1, 117.4,
112.3, 79.1, 59.5, 44.8; MS m/z 510.2 (M+). Anal. Calcd for
C30H21Cl2N3O (509) C, 70.59; H, 4.15; N, 8.23; Found: C,
218–222°C; IR (KBr) υmax 3153.04, 2917.77, 1650.77, 1597.73,
1500.35, 1393.32, 828.27, 748.24cmꢀ1;1H NMR (400MHz,
DMSO-d6) δ 12.24 (s, 1H, 1-NH), 7.42–7.62 (m, 6H, Ar―H),
7.39 (t, 2H, J = 7.6Hz, ArH), 7.17–7.24 (m, 4H, Ar―H), 6.99 (t,
2H, J = 7.6Hz, ArH), 6.89–6.90 (m, 3H, Ar―H), 6.60 (d, 1H,
J = 7.2 Hz, ArH), 6.55 (d, 2H, J = 8Hz, ArH), 5.26 (dd, 1H,
J1 = 15.88 Hz, J2 =6.24 Hz, Pyr-H), 3.86 (dd, 1H, J1 = 12.16 Hz,
J2 = 7.52 Hz, Pyr-H), 2.82 (dd, 1H, J1 = 14.00 Hz, J2 =5.42 Hz,
Pyr-H); 13CNMR(100 MHz, DMSO-d6) δ 160.5, 148.8, 144.4,
143.8, 142.4, 136.9, 135.5, 130.5, 129.7, 128.4, 127.2, 125.9,
125.4, 121.1, 118.3, 117.4, 112.6, 62.3, 46.3; Anal. Calcd for
C30H22ClN3O (475) C, 75.70; H, 4.66; N, 8.83; Found: C, 75.72;
70.54; H, 4.19; N, 8.28%.
3-(5-(4-Methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-
H, 4.61; N, 8.80%.
yl)-4-phenylquinolin-2(1H)-one (4i). Orange solid (76%); mp
225–228°C; IR (KBr) υmax 3437.49, 2835.8, 1656.55, 1598.7,
3-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-methylquinolin-
2(1H)-one (4m). Off white solid (78%) mp 222–225°C; IR (KBr)
υmax 3155.94, 2847.38, 1655.59, 1597.73, 1500.35, 1387.53,
1503.24, 1243.86, 1031.73, 829.24, 752.10, 611.32 cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H, 1-NH), 7.44–7.52
(m, 5H, Ar―H), 7.34 (d, 1H, J = 8.5 Hz, ArH), 7.22–7.25 (m,
2H, Ar―H), 7.07–7.14 (m, 3H, Ar―H), 6.96 (t, 2H, J = 6.5 Hz,
Ar―H), 6.80 (t, 1H, J = 10 Hz, Ar―H), 6.73 (d, 2H, J = 6 Hz,
Ar―H), 6.70 (d, 1H, J = 7 Hz, Ar―H), 5.13 (dd, 1H,
J1 = 12.50 Hz, J2 = 6.50 Hz, Pyr-H), 3.96 (dd, 1H, J1 = 17.50 Hz,
J2 = 12.50 Hz, Pyr-H), 3.79 (s, 3H, OCH3), 2.97 (dd, 1H,
J1 = 17.5 Hz, J2 = 12.00 Hz, Pyr-H); 13C NMR (100 MHz,
DMSO-d6) 160.1, 158.7, 149.2, 144.5, 137.8, 133.5, 132.1,
131.4, 120.1, 124.5, 124.5, 122.3, 121, 119.6, 118.1, 114.1,
111.6, 61.1, 45.1, 44.6, 15.1; Anal. Calcd for C31H25N3O2
(471) C, 78.96; H, 5.10; N, 8.24 Found: C, 78.91; H, 5.15; N,
1
997.98 cmꢀ1; H NMR (400MHz, DMSO-d6) δ 11.83 (s, 1H, 1-
NH), 7.84 (d, 1H, J=8Hz, Ar―H), 7.51 (d, 1H, J=8Hz, Ar―H),
7.24–7.37 (m, 7H, Ar―H), 7.13 (t, 2H, J= 8.8 Hz, ArH), 6.92
(d, 2H, J=8Hz, Ar―H), 6.71 (t, 1H, J=7.2Hz, Ar―H), 5.36
(dd, 1H, J1 = 12.40 Hz, J2 = 5.50 Hz, Pyr-H), 3.95 (dd, 1H,
J1 =17.80Hz, J2 = 12.00 Hz, Pyr-H), 3.12 (dd, 1H, J1 = 17.80 Hz,
J2 = 7.20 Hz, Pyr-H), 2.61 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 134.1, 133.1, 132.4, 130.1, 128.7, 127.9, 128.4,
126.3, 125.3, 124.5, 122.1, 122.1, 120.1, 119.6, 118.2, 115.2,
111.6, 106.1, 62.2, 58.2, 47, 20.7, 16.3; Anal. Calcd for C25H21N3O
(379) C, 79.13; H, 5.58; N, 10.56; Found: C, 79.15; H, 5.58; N,
10.51%.
8.28%.
6-Chloro-3-(5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-
3-(1-(3-Nitrophenyl)-5-p-tolyl-4,5-dihydro-1H-pyrazol-3-yl)-
pyrazol-3-yl)-4-phenylquinolin-2(1H)-one (4n). Orange solid:
(85%) mp 228–232°C; (KBr) υmax 4011.46, 3155.94, 2923.56,
1653.66, 1596.77, 1501.31, 1247.72, 1034.62, 829.24, 746.32,
4-phenylquinolin-2(1H)-one (4j).
211–212°C; IR (KBr) υmax: 3846.33, 3079.76, 2888.84,
1651.73, 1523.49, 114.65, 1006.66, 808.03, 702.92 cmꢀ1 1H
Orange solid (68%); mp
;
1
702.92 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1H, 1-
NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H, 1-NH), 7.40–7.53
(m, 8H, Ar―H), 7.24 (d, 2H J = 8.8 Hz, Ar―H), 7.09 (t, 1H,
J = 8.76 Hz, Ar―H), 7.04 (d, 3H, J = 7.36 Hz, Ar―H), 6.87 (d,
1H, J = 7.96 Hz, Ar―H), 6.81 (d, 2H, J = 5.6 Hz, Ar―H), 5.32
(dd, 1H, J1 = 12.36 Hz, J2 = 4.80 Hz, Pyr-H), 3.97 (dd, 1H,
J1 = 19.16 Hz, J2 = 12.00 Hz, Pyr-H), 2.91 (dd, 1H,
J1 = 17.16 Hz, J2 = 4.8 Hz, Pyr-H), 2.21 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) δ 161, 148.8, 145.1, 137.1, 136.5, 130.2,
129.9, 128.9, 128.3, 127.8, 126.3, 124.1, 122.5, 118.7, 115.8,
112.6, 107.1, 62.4, 47.1, 21.1; Anal. Calcd for C31H24N4O3
(500) C, 74.38; H, 4.83; N, 11.19; Found: C, 74.41; H, 4.85; N,
NH), 7.56 (d, 1H, J = 8.8 Hz, Ar―H), 7.40–7.52 (m, 4H,
Ar―H), 7.36 (s, 1H, Ar–H), 7.24 (d, 1H, J = 7.2 Hz, Ar―H),
6.98 (q, 2H, Ar―H), 6.90 (d, 1H, J = 2.4 Hz, Ar―H),
6.75–6.83 (m, 4H, Ar―H) 6.56 (d, 3H, J = 8 Hz, Ar―H), 5.18
(dd, 1H, J1 = 12.40 Hz, J2 = 5.60 Hz, Pyr-H), 3.84 (dd,1H,
J1 = 21.80 Hz, J2 = 12.40 Hz, Pyr-H), 3.69 (s, 3H, ―OCH3),
2.79 (dd, 1H, J1 = 16.00 Hz, J2 = 7;.60 Hz, Pyr-H); 13C NMR
(100 MHz, DMSO-d6) δ 161, 158.7, 149.2, 144.3, 137.4, 136.8,
132.4, 131, 130.7, 128.9, 128.6, 127.5, 126.3, 124.5, 122.3,
121, 118.6, 117, 114.1, 112,4, 62, 46.1, 44.6, 16.5; Anal. Calcd
for C31H24ClN3O2 (505) C, 73.58; H, 4.78; N, 8.30; Found: C,
11.23%.
73.57; H, 4.76; N, 8.32%.
3-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-phenylquinolin-
3-(5-(4-Bromophenyl)-1-(3-nitrophenyl)-4,5-dihydro-1H-
2(1H)-one (4k).
(KBr) υmax 3154.97, 2935.13, 2846.42, 1660.41, 1597.73, 1500.35,
1389.46, 1306.54, 1214.93, 1123.3 cmꢀ1 1H NMR
Pale yellow solid (80%); mp 220–222°C; IR
pyrazol-3-yl)-4-methylquinolin-2(1H)-one (4o).
Orange
solid (87%); mp 224–226°C; IR (KBr) υmax 2857.24,
1654.55, 1508.23,1277.79, 825.53, 750.10, 645.25 cmꢀ1; H
1
;
(400 MHz, DMSO-d6) δ 12.09 (s, 1H, 1-NH), 7.43–7.50
(m, 5H, Ar―H), 7.39 (d, 1H, J = 7.6 Hz, Ar―H), 7.15–7.24
(m, 4H, Ar―H), 7.10 (t, 1H, J = 8 Hz, Ar―H), 6.99–7.02
(m, 3H, Ar―H), 6.91 (d, 2H, J = 6.8 Hz, Ar―H), 6.58
(t, 3H, J = 7.6 Hz, Ar―H), 5.20 (dd, 1H, J1 = 12.80 Hz,
J2 = 6.00 Hz, Pyr-H), 3.88 (dd, J1 = 17.8 Hz, J2 = 12.40 Hz,
Pyr-H), 2.81 (dd, 1H, J1 = 6 Hz, J2 = 17.6 Hz, Pyr-H); 13C
NMR (100 MHz, DMSO-d6) δ 160.7, 150.1, 144.9, 144.1,
NMR (400MHz, DMSO-d6) δ 11.89 (s,1H, 1-NH), 7.85 (d,1H,
J = 8.4 Hz, ArH), 7.49–7.62 (m, 3H, Ar―H), 7.34 (d, 3H,
J = 10.2Hz, Ar―H), 7.25 (t, 1H, J = 7.6 Hz, Ar―H), 7.20 (d, 2H,
J = 8.8Hz, Ar―H), 6.91 (d, 2H, J = 9.2Hz, Ar―H), 5.46 (dd, 1H,
J1 = 12Hz, J2 = 6.40 Hz, Pyr-H), 3.95 (dd,1H, J1 = 20.40 Hz,
J2 = 11.00 Hz, Pyr-H), 3.15 (dd,1H, J1 = 17.60 Hz, J2 = 6.40 Hz,
Pyr-H), 2.60 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ
161. 2, 157.4, 155.4, 147.6, 146.8, 142.4, 141.8, 138.2, 132.3,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Sankaran, C. Uvarani, K. Chandraprakash, M. Umamaheswari, and P. S. Mohan
Vol 000
131.7, 131.1, 128.9, 126.1, 124.1, 122.5, 122.5, 120.9, 120.1; Anal.
Calcd for C25H19BrN4O3 (503) C, 59.65; H, 3.80; N, 11.13; Found:
12.24 (s, 1H, Q-NH), 7.47–7.58 (m, 4H, Ar―H), 7.40 (d, 1H,
J = 8.96 Hz, Ar―H), 7.32 (d, 1H, J = 6.0 Hz, Ar―H),7.28 (d,
2H, J = 8.92 Hz, Ar―H), 7.20 (d, 2H, J = 8.32 Hz, Ar―H), 6.88
(d, 1H, J = 3.56 Hz, Ar―H), 4.58 (t, 1H, J = 10.72 Hz, Pyr-H),
3.25 (dd, 1H, J1 = 17.28 Hz, J2 = 10.72 Hz, Pyr-H), 2.52 (dd,
1H, J1 = 16.80 Hz, J2 = 9.56 Hz, Pyr-H); 13C NMR (400 MHz,
DMSO-d6) δ 161.1, 149.2, 146.1, 143.1, 137.5, 135.8, 131.8,
130.8, 128.3, 127, 125.3, 121.3, 118.9, 117, 63.2, 61.8, 46.5,
45.1, 43.8; Anal. Calcd for C24H18ClN3O (399), C, 72.09; H,
C, 59.60; H, 3.83; N, 11.10%.
3-(5-(4-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-
yl)-6-nitro-4-phenylquinolin-2(1H)-one (4p).
Orange solid
(72%); mp 218–223°C; IR (KBr) υmax 3299.61, 3152.08,
2993.94, 1906.29, 1646.91, 1528.31, 1489.74, 1335.46,
1095.37, 831.16, 754.03, 696.17 cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6) δ 12.35 (s, 1H, 1-NH), 8.26 (d, 1H, J = 6.8 Hz,
ArH), 8.09 (s, 1H, H-NO2), 7.39–7.49 (m, 4H, ArH), 7.34 (d,
1H, J = 8.9 Hz, ArH), 7.16–7.20 (m, 3H, ArH), 7.04 (t, 2H,
J = 7.8 Hz, ArH), 6.88 (d, 2H, J = 8.35 Hz, ArH), 6.70 (t, 1H,
J = 7.3 Hz, ArH), 6.62 (d, 2H, J = 7.95 Hz, ArH), 5.13 (dd, 1H,
J1 = 12.40 Hz, J2 = 5.55 Hz, Pyr-H), 3.85 (dd, 1H, J1 = 17.00 Hz
J2 = 12.50 Hz, Pyr-H), 2.86 (dd, 1H, J1 = 7.45 Hz, J2 = 5.65 Hz,
Pyr-H); 13C NMR (100 MHz, DMSO-d6) δ 160.2, 150, 147.8,
147.2, 143.7, 140.1, 138.8, 135.1, 131.7, 130.1, 129.3, 128.2,
126.5, 125.4, 121.5, 118.7, 116.9, 107.1, 61.8, 46.8; Anal.
Calcd for C30H21ClN4O3 (520) C, 69.48; H, 4.06; N, 10.75;
Found: C, 69.46; H, 3.98; N, 10.71%.
4.54; N, 10.51 Found: C, 72.05; H, 4.58; N, 10.49%.
3-(5-(4-Bromophenyl)-4, 5-dihydro-1H-pyrazol-3-yl)-4-phenyl
quinolin-2(1H)-one (5c). Orange solid (80%); mp 231–232°C;
IR (KBr) υmax 2994.91, 2850.27, 1644.02, 1431.89, 1376.93,
1
1270.86 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H,
Q-NH), 7.45–7.51 (m, 4H, ArH), 7.39 (d, 1H, J = 8.6 Hz, ArH),
7.31 (d, 1H, J = 6.88 Hz, ArH), 7.20 (s, 1H, ArH), 7.01–7.09
(m, 5H, ArH), 6.97 (t, 2H, J = 6.88 Hz, ArH), 4.52 (t, 1H,
J = 9.68 Hz, Pyr-H), 3.40 (dd, 1H, J1 = 20.24 Hz, J2 = 12.52 Hz,
Pyr-H), 3.19 (dd, 1H, J1 = 16.36 Hz, J2 = 11.40 Hz, Pyr-H); 13C
NMR (100 MHz, DMSO-d6) δ 134.8, 134.7, 133.9, 133.8,
133.2, 132.9, 132.4, 132.3, 131.3, 131.3, 130.7, 127.9, 127.8,
126.3, 126.2, 120.7, 120.5, 67.5, 49.8, 45.3, 25.3; Anal. Calcd
for C24H18BrN3O (443) C, 64.88; H, 4.08; N, 9.46. Found: C,
General procedure for the synthesis of 4,5-dihydro-1H-
pyrazol-3-yl)quinolin-2(1H)-one (5a–d)
Conventional method A.
Substituted α,β-unsaturated
carbonyl compounds 3 (0.01 mmol) and hydrazine hydrate
(0.03 mmol) were taken in ethanol and were refluxed over a
period of 6–7 h. After the reaction was over as evidenced by the
TLC, the reaction mixture was cooled to room temperature.
Then, it was poured into 300 g of crushed ice after evaporation
of the one-third of the solvent. The precipitate thus formed was
filtered off, washed with excess of water, and dried, and then
the mixture was chromatographed on a silica gel column
chromatography on n-hexane:EtOAc (7:3) to obtain a pale
yellow powder.
64.85; H, 4.01; N, 9.41%.
4-Phenyl-3-(5-p-tolyl-4,5-dihydro-1H-pyrazol-3-yl)quinolin-
2(1H)-one (5d). Pale yellow powder (74%); mp 218–222°C;
IR (KBr) υmax 3359.39, 2848.35, 1648.84, 1512.88, 1345.11,
855.27, 758.85, 701.96, 607.46 cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6) δ 12.10 (s, 1H, Q-NH), 8.10 (d, 2H, J = 11.24 Hz,
ArH), 7.45–7.54 (m, 5H, ArH), 7.39 (d, 1H, J = 7.88 Hz, ArH),
7.33–7.35 (m, 4H, ArH), 7.19 (d, 1H, J = 6.0 Hz, ArH),7.09(t,
1H J = 9 Hz, ArH), 7.99 (d, 1H, J = 10.12 Hz, ArH), 4.73 (t,
1H, J = 7.88 Hz, Pyr-H), 4.03 (dd, 1H, J1 = 16.08 Hz,
J2 = 9.68 Hz, Pyr-H), 3.16 (dd, 1H, J1 = 16.44 Hz, J2 = 9.76 Hz,
Pyr-H), 2.08 (s, 1H, CH3); 13C NMR (100 MHz, DMSO-d6) δ
152.7, 150.6, 147.2, 138.8, 136.3, 131.9, 130.6, 129.8, 129,
128.3, 127.7, 127.4, 126.6, 123, 121.6, 119.7, 116.9, 114.8,
63.5, 61.4, 46.8, 45.5, 43.6; Anal. Calcd for C25H21N3O (379),
C, 79.13; H, 5.58; N, 11.07. Found: C,79.11; H, 5.55; N,
11.05%.
Microwave-assisted synthesis B.
Quinoline-2(1H)-one-
based α,β-unsaturated carbonyl compound 3 (0.01 mmol) and
phenyl hydrazine hydrochloride (0.03 mmol) were powdered,
mixed with two to five drops of EtOH, and introduced in an
open borosil glass vessel. The reaction proceeded at a constant
power of 360 W with temperature 120°C for 5 min with
constant interval. After completion (TLC), the reaction mixture
was brought to room temperature and poured into 300 g of
crushed ice after evaporation of the one-third of the solvent.
The crude product was recrystallized to obtain the title
compound, which was found to be in good purity (TLC) and
General procedure for the synthesis of 4,5-dihydroisoxazol-3-
yl)quinolin-2(1H)-one (6a–e)
Conventional method A. Various substituted α,β-unsaturated
carbonyl compounds
3
(0.01 mmol) and hydroxylamine
yield (Table 2).
3-(5-(4-Bromophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-methyl
hydrochloride (0.03 mmol) were taken in ethanol and were
refluxed over a period of 7–8 h. After the reaction was over as
evidenced by the TLC, the reaction mixture was cooled to room
temperature. Then, it was poured into 500g of crushed ice after
evaporation of the one-third of the solvent. The precipitate thus
formed was filtered off, washed with excess of water, and dried,
and then the mixture was chromatographed on a silica gel
column chromatography on n-hexane:EtOAc (8:2) to obtain a
reddish yellow powder.
quinolin-2(1H)-one (5a). Yellow solid (75%) mp 225–226°C;
IR (KBr) υmax 3324.68, 3158.83, 2843.52, 1663.30, 1486.85,
1428.03, 1263.15 cmꢀ1 1H NMR (400 MHz, DMSO-d6) δ
;
11.55 (s, 1H, 1-NH), 7.23 (d, 1H, J = 7.76 Hz, Ar―H), 7.34 (s,
1H, Pyr-NH), 7.45–7.52 (m, 3H, Ar―H), 7.33 (d, 2H,
J = 9.46 Hz, Ar―H), 7.87 (d, 1H, J = 8.9 Hz, Ar―H), 7.14 (t,
1H, J = 8.00 Hz, Ar―H), 4.82 (t, 1H, J = 9.28 Hz, Pyr-H), 2.87
(dd, 1H, J1 = 17.88 Hz, J2 = 9.28 Hz, Pyr-H), 2.04 (dd, 1H,
J1 = 18.44 Hz, J2 = 8.80 Hz, Pyr-H); 13C NMR (100 MHz,
DMSO-d6) δ 161.4, 148.8, 146.2, 142.8, 138.1, 131.6, 130.3,
128.6, 126.7, 123.2, 121.7, 120.2, 116.5, 114.8, 64.1, 62.5,
45.8; Anal. Calcd for C18H14ClN3O2 (339) C, 63.63; H, 4.15;
Microwave-assisted synthesis B.
Equimolar amount of
quinolin-2(1H)-one-based α,β-unsaturated carbonyl compound
3 (0.01 mmol) and hydroxylamine hydrochloride (0.03 mmol)
were powdered, mixed with 2-5 drops of EtOH, and introduced
in an open borosil glass vessel. The reaction proceeded at a
constant power of 360 W with temperature of 120°C for 5 min
with constant interval. After completion (TLC), the reaction
mixture was brought to room temperature and poured into
300 g of crushed ice. The crude product was recrystallized to
N, 12.37 Found: C, 63.60; H, 4.17; N, 12.33%.
6-Chloro-4-phenyl-3-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)
quinolin-2(1H)-one (5b). White solid (74%) mp 228–230°C;
IR (KBr) υmax 3313.11, 3149.19, 2992.98, 1652.70, 1486.85,
1404.89, 1088.62 cmꢀ1 1H NMR (400 MHz, DMSO-d6) δ
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Convenient Approach for the Synthesis of Pyrazole, Isoxazole
and Benzodiazepine Based Quinolines
obtain the title compound, which was found to be in good purity
130.7, 129.7, 128.1, 128.2, 126.6, 125.3, 122, 120.2, 117.1, 82.6,
(TLC) and yield (Table 2).
46.5; Anal. Calcd For C24H17ClN2O2 (400) C, 71.91; H, 4.27; N,
3-(5-(4-Bromophenyl)-4,5-dihydroisoxazol-3-yl)-6-chloro-4-
6.99; Found: C, 71.88; H, 4.22; N, 7.02%.
phenylquinolin-2(1H)-one (6a). Pale green solid (82%); mp
216–220°C; IR (KBr) υmax 3304.43, 3150.15, 2827.13,
1900.50, 1646.91, 1482.99, 1262.18, 1084.76, 893.84,
3-(5-(4-Fluorophenyl)-4,5-dihydroisoxazol-3-yl)-4-phenylquinolin-
2(1H)-one (6e).
Pale green solid (75%); mp 210–215°C; IR
(KBr) υmax 3201.43, 2727.20, 1915.50, 1646.65, 1326.10,
1075.55, 895.80, 703.11 cmꢀ1; 1H NMR (400 MHz, DMSO-d6) δ
12.25 (s, 1H, 1-NH), 7.52 (dd, 1H, J1 = 8.56Hz, J2 = 2.50Hz,
ArH), 7.49–7.58 (m, 2H, ArH), 7.39–7.43 (m, 2H, ArH), 7.16 (d,
2H, J = 6.90Hz, ArH), 6.61 (d, 2H, J = 7.25 Hz, ArH), 6.43 (d,
1H, J = 2.50 Hz, ArH), 5.78 (dd, 1H, J1 = 11.72 Hz, J2 = 7.67Hz,
CH―H), 4.05 (dd, 1H, J1 = 17.12Hz, J2 = 9.45Hz, CH2―H),
2.97 (dd, 1H, J1 = 10.39 Hz, J2 = 7.41 Hz, CH2―H); 13C NMR
(100 MHz, DMSO-d6) δ 161.5, 154.2, 149.1, 142.2, 134.1, 133.9,
131.1, 129.9, 128.1, 125.5, 124.3, 121.1, 116.1, 83.6, 47.2; Anal.
Calcd For C24H17FN2O2 (384) C, 74.99; H, 4.46; N, 7.29; Found:
703.89 cmꢀ1 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H,
;
1-NH), 7.61 (dd, 1H, J1 = 8.26 Hz, J2 = 2.84 Hz, ArH), 7.54–
7.56 (m, 2H, ArH), 7.43–7.45 (m, 2H, ArH), 7.32 (d, 2H,
J = 8.56 Hz, ArH), 7.25 (d, 1H, J = 7.40 Hz, ArH), 6.96 (d, 2H,
J = 8.00 Hz, ArH), 6.90 (d, 1H, J = 2.84 Hz, ArH), 5.54 (dd,
1H, J1 = 11.72 Hz, J2 = 6.88 Hz, CH―H), 3.70 (dd, 1H,
J1 = 17.12 Hz, J2 = 11.44 Hz, CH2―H), 2.91 (dd, 1H,
J1 = 13.84 Hz, J2 = 7.44 Hz, CH2―H); 13C NMR (100 MHz,
DMSO-d6) δ 160.7, 153.5, 150.7, 140.9, 138.1, 134.9, 132.9,
131.7, 129.7, 129.1, 128.9, 128.9, 128.8, 128.2, 126.6, 126.3,
123, 121, 118.1, 80.8, 46.56; Anal. Calcd For C24H16BrClN2O2
(479) C, 60.08; H, 3.36; N, 5.84; Found: C, 60.12; H, 3.40; N,
C, C, 75.05; H, 4.41; N, 7.32%.
General procedure for the synthesis of benzo[b][1,4]
diazepin-4-yl)quinolin-2(1H)-one (9a–e). Equimolar amount
5.82%.
6-Chloro-4-phenyl-3-(5-phenyl-4, 5-dihydroisoxazol-3-yl)quinolin-2
of substituted 3-cinnamoyl-4-hydroxyquinolin-2(1H)-one
7
(1H)-one (6b). Pale green solid (82%); mp 205–210°C; IR (KBr)
υmax 3301.54, 3148.22, 2829.06, 1642.09, 1481.06, 1370.18,
(0.01 mmol) and o-phenylenediamine 8 (0.03 mmol) was taken
in acetic acid and was refluxed over a period of 8–9 h. After the
reaction was over as evidenced by the TLC, the reaction
mixture was cooled to room temperature. Then, it was poured
into 300 g of crushed ice after evaporation of the one-third of
the solvent. The precipitate thus formed was filtered off, washed
with excess of water, and dried, and then the mixture was
chromatographed on a silica gel column chromatography on
hexane:ethyl acetate (8:2) to obtain a pale green yellow powder.
4-Hydroxy-3-(2-(4-methoxyphenyl)-2,3-dihydro-1H-benzo[b]
1258.32, 1258.32, 888.05, 759.81 cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6) δ 12.31 (s, 1H, NH), 7.61 (dd, 1H, J1 = 9.12Hz,
J2 = 2.40Hz, ArH), 7.55 (t, 2H, J = 4.20 Hz, ArH), 7.44–7.47 (m,
2H, ArH), 7.37 (d, 1H, J = 6.00Hz, ArH), 7.26–7.27 (m, 4H,
ArH), 6.91–6.97 (m, 3H, ArH), 5.50 (dd, 1H, J1 = 11.44 Hz,
J2 = 7.48Hz, CH―H), 3.69 (dd, 1H, J1 = 17.72 Hz, J2 = 10.48 Hz,
CH2―H), 2.94 (dd, 1H, J1 = 18.36Hz, J2 = 9.20Hz, CH―H); 13
C
NMR (100MHz, DMSO-d6) δ 160.4, 153.5, 150.3, 142.2, 138.1,
134.6, 131.6, 129.6, 129.1, 128.9, 128.3, 126.7, 126.5, 126.4,
123, 121.4, 118.2, 81.8, 46.2; Anal. Calcd For C24H17ClN2O2
(400) C, 71.91; H, 4.27; N, 6.99; Found: C, 71.87; H, 4.32; N,
[1,4]diazepin-4-yl)quinolin-2(1H)-one (9a).
Pale green solid
(77%); mp 210–215°C; IR (KBr) υmax 3404.71, 3100.97,
2900.41, 1644.02, 1563.99, 1494.56, 1368.25, 1176.36,
1
1030.77, 753.06 cmꢀ1; H NMR (300 MHz, DMSO-d6) δ 16.20
7.02%.
6-Chloro-3-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)-
(s, 1H, C4-OH), 10.66 (s,1H, C1-NH), 7.95 (d,1H, J = 8.10 Hz,
Ar―H), 7.49 (t,1H, J = 7.80 Hz, Ar―H), 7.28 (d, 2H,
J = 8.42 Hz, Ar―H), 7.14–7.21 (m, 3H, Ar―H), 7.09 (d, 2H,
J = 7.20 Hz, Ar―H), 6.88–6.91(m, 3H, Ar―H), 6.22 (s,1H,
CH―H), 5.13 (d,1H, J = 8.40 Hz, CH―H), 4.40 (s,1H,
CH―H), 3.70 (s,3H, OCH3), 13C NMR (100 MHz, DMSO-d6)
δ 172.4, 159.2, 141.9, 137.8, 133.7, 128.3, 127.4, 125.1, 121.3,
120.1, 114.2, 65.7, 55.5, 37.6; Anal. Calcd for C25H21N3O3
(411): C, 72.98; H, 5.14; N, 10.21; Found: C, 72.95; H, 5.09;
4-phenylquinolin-2(1H)-one (6c). Pale green solid (82%) mp
220–224°C; IR (KBr) υmax 3150.15, 2990.09, 1903.40, 1649.80,
1481.06, 1368.25, 897.70, 702.92, 611.32, 550.57 cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H, NH), 7.63 (t, 2H,
J = 8.48 Hz, ArH), 7.27–7.32 (m, 3H, ArH), 7.19 (d, 2H,
J = 7.04 Hz, ArH), 7.07 (d, 2H, J = 9.00 Hz, ArH), 6.97 (d, 1H,
J = 2.16 Hz, ArH), 6.91 (d, 1H, J = 2.24 Hz, ArH), 6.84 (d, 2H,
J = 8.48 Hz, ArH), 6.69 (d, 1H, J = 9.55 Hz, ArH), 5.45 (dd,
1H, J1 = 14.12 Hz, J2 = 7.08 Hz, CH―H), 3.85 (s, 3H, OCH3),
3.66 (dd, 1H, J1 = 18.36 Hz, J2 = 9.92 Hz, CH―H), 2.91 (dd,
1H, J1 = 16.24 Hz, J2 = 8.48 Hz, CH―H);13C NMR (100 MHz,
DMSO-d6) δ 194.1, 160.4, 159.9, 153.5, 150.4, 147.1, 146.7,
141.4, 138.8, 138.1, 137.6, 134.8, 134.1, 133.1, 132.1, 131.7,
131.3, 129.9, 129.1, 128.9, 126.9, 126.1, 123.2, 121.1, 118.2,
81.4, 46.2; Anal. Calcd for C25H19ClN2O3 (430) C, 69.69; H,
N, 10.23%.
3-(2-(4-Chlorophenyl)-2,3-dihydro-1H-benzo[b][1,4]diazepin-
4-yl)-4-hydroxyquino lin-2(1H)-one (9b).
Pale green solid
(75%); mp 223–225°C; IR (KBr) υmax 3414.35, 2868.59,
1646.91, 1604.48, 1562.06, 1372.10, 1307.50, 882.27,
1
752.10 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ 16.23 (s, 1H, C-
4-OH), 10.66 (s, 1H, C1-NH), 7.94 (d, 1H, J = 8.56 Hz, Ar―H),
7.47 (t, 1H, J = 8.52 Hz, Ar―H),7.05–7.37 (m, 9H, Ar―H),
6.89 (t, 1H, J = 7.88 Hz, Ar―H), 6.32 (s, 1H, CH―H), 5.21 (d,
1H, J = 8.52 Hz, CH―H), 4.17 (s, 1H, CH―H), 13C NMR
(100 MHz, DMSO-d6) δ 172.4, 144.2, 141.7, 133.5, 132.3,
128.7, 128.4, 128.3, 125.2, 121.3, 120.3, 115.5, 65.7, 36.8;
Anal. Calcd for C23H7ClN3O2 (402): C, 68.57; H, 4.25; N,
4.44; N, 6.50; Found: C, 69.58; H, 4.48; N, 6.47%.
3-(5-(4-Chlorophenyl)-4,5-dihydroisoxazol-3-yl)-4-phenylquinolin-
2(1H)-one (6d). Pale green solid (78%); mp 210–215°C; IR
(KBr) υmax 3304.43, 3150.15, 2827.13, 1900.50, 1646.91,
1482.99, 1262.18, 1084.76, 893.84, 703.89 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6) δ 12.30 (s, 1H, 1-NH), 7.55 (dd, 1H,
J1 = 8.12 Hz, J2 = 2.55 Hz, ArH), 7.53–7.58 (m, 2H, ArH),
7.40–7.44 (m, 2H, ArH), 7.22 (d, 2H, J = 7.87 Hz, ArH), 6.66
(d, 2H, J = 7.50 Hz, ArH), 6.57 (d, 1H, J = 2.40 Hz, ArH), 5.48
(dd, 1H, J1 = 10.72 Hz, J2 = 6.76 Hz, CH―H), 3.66 (dd, 1H,
J1 = 16.12 Hz, J2 = 10.20 Hz, CH2―H), 2.88 (dd, 1H,
J1 = 11.84 Hz, J2 = 7.10 Hz, CH2―H); 13C NMR (100 MHz,
DMSO-d6) δ 162.7, 155.2, 148.7, 141.9, 135.1, 133.9, 131.5,
10.43; Found: C, 68.50; H, 4.28; N, 10.39%.
3-(2-(4-Bromophenyl)-2,3-dihydro-1H-benzo[b][1,4]diazepin-
4-yl)-4-hydroxyquinolin-2(1H)-one (9c).
mp 217–220°C; IR (KBr) υmax 3406.64, 2868.59, 1647.88,
1604.48, 1562.06, 1372.10, 883.23, 754.03 cmꢀ1 1H NMR
Green solid (80%);
;
(400 MHz, DMSO-d6) δ 16.25 (s, 1H, C4-OH), 10.62 (s, 1H,
C1-NH), 7.93 (d, 1H, J = 9.40 Hz, Ar―H), 7.46–7.51(m, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Sankaran, C. Uvarani, K. Chandraprakash, M. Umamaheswari, and P. S. Mohan
Vol 000
Ar―H), 7.31 (d, 2H, J = 7.04 Hz, Ar―H), 7.15–7.20 (m, 3H,
Ar―H), 7.05 (d, 2H, J = 6.28 Hz, Ar―H), 6.90 (t, 1H,
J = 8.60 Hz, Ar―H), 6.32 (s, 1H, CH―H), 5.19 (d, 1H,
J = 9.44 Hz, CH―H), 4.18 (s, 1H, CH―H); 13C NMR
(100 MHz, DMSO-d6) δ 172.1, 144.7, 141.2, 133.6, 132.1,
128.9, 126.3, 125.2, 121.3, 120.7, 120.3, 115.5, 65.4, 36.8;
Anal. Calcd for C24H18BrN3O2 (460) C, 62.62; H, 3.94; N, 9.13;
570 nm using a micro plate reader. The percentage of cell
inhibition was determined using the following formula, and a
graph was plotted with the percentage of cell inhibition versus
concentration. From this, the IC50 value was calculated:
% inhibition ¼ ½mean OD of untreated cells ðcontrolÞ=
mean OD of treated cells ðcontrolÞꢁ ꢂ 100:
Found: C, 62.58; H, 3.96; N, 9.07%.
4-Hydroxy-3-(2-phenyl-2, 3-dihydro-1H-benzo[b][1,4]diazepin-
4-yl)quinolin-2(1H)-one (9d).
205–210°C; IR (KBr) υmax 3400.85, 2863.77, 1642.09,
Pale green solid (72%); mp
Acknowledgments. The authors thank the Council of Scientific
and Industrial Research CSIR-SRF (Ref No. 09/472(0145)/
2K10–EMR-I) New Delhi, India, for the financial assistance.
We acknowledge Dr Aathirajan, Professor, Cell Culture
Laboratory, KMCH College of Pharmacy, Coimbatore for
evaluating cytotoxicity. The authors thank SAIF, NMR
Research Centre, Bangalore SAIF, IIT Chennai for spectral study.
1604.48, 1555.31, 1464.67, 1367.28, 876.48, 751.13,
487.90 cmꢀ1 1H NMR (400 MHz, DMSO-d6) δ 16.23 (s,1H,
;
C-4-OH), 10.69 (s,1H, C1-NH), 7.94 (d,1H, J = 8.76 Hz,
Ar―H), 7.48 (t,1H, J = 8.76 Hz, Ar―H), 7.25–7.37 (m, 4H,
Ar―H), 7.05–7.23 (m, 6H, Ar―H), 6.89 (t,1H, J = 7.44 Hz,
Ar―H), 6.29 (s,1H, CH―H), 5.18 7.93 (d,1H, J = 10.12 Hz,
CH―H), 4.35 (s,1H, CH―H); 13C NMR (100 MHz, DMSO-
d6) δ 172.4, 145.6, 141.8, 128.8, 128.4, 127.8, 126.3, 125.1,
121.4, 120.2, 115.6, 37.44; Anal. Calcd for C24H19N3O2 (381):
C, 75.57; H, 5.02; N, 11.02; Found: C, 75.60; H, 5.05; N,
REFERENCES AND NOTES
10.98%.
[1] Abbas, H. S.; Hafez, H. N.; El-Gazzar, A. B. A. Eur J Med
Chem 2011, 46, 21–30.
[2] Kumar, S.; Bawa, S.; Gupta, H. Mini Rev Med Chem 2009, 9,
1648–1654.
[3] Leue, S.; Miao, W.; Kanaz, A.; Genisson, Y.; Garcon, S.;
Greene, A. E. J Chem Soc, Perkin Trans 2001, 1, 2903–2905.
[4] Toyota, M.; Komori, C.; Ihara, M. Heterocycles 2002, 56, 101-
103.
[5] Saari, R.; Torma, J. C.; Nevalainen, T. Bioorg Med Chem
2011, 19, 939–950.
[6] Magedov, M.; Van slambrouck S.; Steelant, W. F. A.;
Rozhkova, E.; Przhevalskii, N. M.; Rogelj, S.; Kornienko, A. J Med
Chem, 2007, 50, 5183–5192.
[7] Wu, D.; Jin, F.; Lu, W.; Zhu, J.; Li, C.; Wang, W.; Tang, Y.;
Jiang, H.; Huang, J.; Liu, G.; Li, J. Chem Biol Drug Des 2012, 79,
897–906.
[8] Conti, P.; Pinto, A.; Tamborini, L.; Rizzo, V.; De Micheli, C.
Tetrahedron 2007, 63, 5554–5560.
[9] Wawer, I.; Pisklak, M.; Chilmonczyk, Z. Pharm Biomed Anal
2005, 38, 865–870.
4-Hydroxy-3-(2-p-tolyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-
4-yl)quinolin-2(1H)-one (9e).
225–228°C; IR (KBr) υmax 3325.64, 2913.91, 1645.95, 1602.56,
1565.92, 1460.81, 1360.53, 811.88, 754.03537.07cmꢀ1 1H
Pale green solid (70%); mp
;
NMR (400 MHz, DMSO-d6) δ 16.18 (s, 1H, C-4-OH), 10.67 (s,
1H, C1-NH), 7.94 (d, 1H, J=8.10Hz, Ar―H), 7.49 (t, 1H,
J=7.20Hz, Ar―H), 7.05–7.25 (m, 8H, Ar―H), 6.89 (t, 1H,
J=7.20Hz, Ar―H), 6.26 (s, 1H, CH―H), 5.14 (d, 1H,
J=9.00Hz, CH―H), 4.36 (s, 1H, CH―H), 2.24 (s, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6) δ 172.4, 142.6, 141.8, 136.9, 133.5,
129.4, 128.4, 126.2, 125.1, 121.4, 120.2, 115.7, 66.1, 37.7, 21.1;
Anal. Calcd for C25H21N3O2 (395) C,75.93; H,5.35; N, 10.63;
Found: C, 75.89; H, 5.32; N, 10.57%; CCDC number for 9e:
CCDC 886309. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK. Fax: + 44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
In vitro cytotoxicity assay.
Cytotoxicity studies of the
compounds along with adriamycin were carried out on human
cervical cancer cells (HeLa), colon cancer cells (HCT-116), and
colon cancer cell lines (HCT-8), which were obtained from the
National Centre for Cell Science, Pune, India. Cell viability was
carried out using the MTT assay method. The HeLa, HCT-8,
and HCT-116 cells were grown in Eagles minimum essential
medium containing 10% FBS. For the screening experiment, the
cells were seeded into 96-well plates in 100 μL of the respective
medium containing 10% FBS, at a plating density of 10,000
cells/well, and incubated at 37°C, under conditions of 5% CO2,
95% air, and 100% relative humidity for 24 h prior to the
addition of compounds. The compounds were dissolved in
DMSO and diluted in the respective medium containing 1%
FBS. After 24 h, the medium was replaced with the respective
medium with 1% FBS containing the compounds at various
concentrations and incubated at 37°C under conditions of 5%
CO2, 95% air, and 100% relative humidity for 48 h. Triplication
was maintained, and the medium not containing the compounds
served as the control. After 48 h, 10 μL of MTT (5 mg/mL) in
phosphate buffered saline (PBS) was added to each well and
incubated at 37°C for 4 h. The medium with MTT was then
flicked off, and the formed formazan crystals were dissolved in
100 μL of DMSO. The absorbance was then measured at
[10] Avram, M. J.; Spyker, D. A.; Kehne, J. H.; Cassella, J. V. J
Clin Pharmaco 2013, DOI: 10.1177/0091270011436886.
[11] Anwar, H. F.; Elnagdi, M. H. Arkivoc 2009, i, 198–250.
[12] de Boer, Y. S.; Van Gerven, N. M. F.; de Boer, N. K. H.;
Mulder, C. J. J.; Bouma, G.; Van Nieuwkerk, C. M. J. Aliment Pharmacol
Ther 2013, 37, 640–646,
[13] Adam, A. L.; Galal, A. A.; Menninger, K.; Barna, B. Plant Pa-
thology, 2000, 49, 317–323.
[14] Pli, P. A.; Jung, F.; Ashton, S.; Christine, R.; Brempt, L.;
Morgentin, R.; Pasquet, G.; Taylor, S., Bioorg Med Chem Lett 2012,
22, 3050–3055.
[15] Halehatty, R., Prakash, N.; Halehatty, S.; Ravikumar Naik, B.
T. R.; Naika, H. R.; Gouthamchandra, R.; Riaz, M.; Khadeer Ahamed, B.
M. Eur J Med Chem 2009, 44, 981–989.
[16] Sankaran, M.; Chandraprakash, K.; Uvarani, C.; Mohan, P. S.
Bioorg Med Chem Lett 2010, 20, 7147–7151.
[17] Camps, P.; Formosa, X.; Galdeano, C.; Gomez, T.; Munoz-
Torrero, D.; Ramirez, L.; Viayna, E.; Gomez, E. Chem Biol Interact,
2010, 187, 411–415.
[18] Ghorab, M. M.; Ragab, F. A.; Heiba, H. I.; Arafa, R. K.; El-
Hossary, E. M. Eur J Med Chem 2010, 45, 3677–3684.
[19] Wang, Y.; Ai, J.; Wang, Y.; Chen, Y.; Wang, L.; Liu, G.;
Geng, M.; Zhang, A. J Med Chem 2011, 54, 2127–2142.
[20] Shen, L. L.; Mitscher, L. A.; Sharma, P. N.; Donnel, T. J.;
Chu, D. W. T.; Cooper, C. S.; Rosen, T.; Pernett, A. G. Biochem 1989,
28, 3886–3894.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Convenient Approach for the Synthesis of Pyrazole, Isoxazole
and Benzodiazepine Based Quinolines
[21] Yasuo, O.; Yoji, S.; Seiji, S.; Nobuyuki, K.; Tatsuyoshi, T.;
Tetsuro, K.; Katsura, T.; Tsufumi, U.; Takashi, M.; Takao, N. J Med
Chem 2000, 43, 177–189.
[22] Beatriz, P.; Christian, F. M.; Enrique, R. Tet Lett 2002, 43,
7929–7932.
[23] Sivakumar, P. M.; Ganesan, S.; Doble, P. V. M. Chem Biol
Drug Des 2010, 76, 407–411.
[26] Ukrainets, I. V.; Tkach, A. A.; Yang, L. Y.; A. Chem
Heterocycl Comp 2009, 45, 169–175.
[27] Lekhok, K. C.; Bhuyan, D.; Prajapati, D.; Boruah, R. C. Mol
Divers 2010, 14, 841-846.
[28] Ukrainets, I. V.; Tkach, A. A.; Yang, L. Y. Chem Heterocycl
Comp 2009, 45,169.
[29] Monks, A.; et al. J National Cancer Institute 1991, 83, 757–766.
[30] Boyles, J. R.; Baird, M. C.; Campling, B. G.; Jain, N. J Inorg
Biochem 2001, 84, 159–162.
[24] Toche, R. B.; Kazi, M. A.; Jachak, M. N.; Desai, A. E. J Appl
Sci Res 2009, 6, 637–641.
[25] Stephen, T. F.; Dennis, L. C.; Shelley, M. C.; Sommer, T. M.
patent wo 2010/088408a2.
[31] Seong, B. C.; Yon, K.; Young, M. I.; Byung, Z. A. Arch
Pharm Res 2004, 5, 485–494.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet