Synthesis and anticancer evaluation of 3-substituted quinolin-4-ones and 2,3-dihydroquinolin-4-ones

Article abstract of DOI:10.1016/j.bmc.2013.11.047

A series of 3-aryl-5,7-dimethoxyquinolin-4-ones 8 and 3-aryl-5,7-dimethoxy- 2,3-dihydroquinolin-4-ones 13 were synthesized in good yields. Demethylation under a range of conditions afforded the corresponding 5-hydroxy and 5,7-dihydroxy derivatives. Biolog

Full text of DOI:10.1016/j.bmc.2013.11.047

Bioorganic & Medicinal Chemistry 22 (2014) 105–115
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and anticancer evaluation of 3-substituted quinolin-4-ones
and 2,3-dihydroquinolin-4-ones
Santosh Rajput a, Christopher R. Gardner a, Timothy W. Failes b, Greg M. Arndt b, David StC. Black a,
Naresh Kumar a,
⇑
a School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
b ACRF Drug Discovery Centre for Childhood Cancer, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre,
The University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-aryl-5,7-dimethoxyquinolin-4-ones 8 and 3-aryl-5,7-dimethoxy-2,3-dihydroquinolin-4-
ones 13 were synthesized in good yields. Demethylation under a range of conditions afforded the corre-
sponding 5-hydroxy and 5,7-dihydroxy derivatives. Biological evaluation against a range of cancer cells
lines showed that the quinolin-4-one scaffold was more cytotoxic than the reduced 2,3-dihydroquino-
lin-4-one scaffold. The most active monohydroxy compound 15f demonstrated 85.9–99% reduction in
cell viability against the cell lines tested.
Received 29 September 2013
Revised 14 November 2013
Accepted 23 November 2013
Available online 4 December 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Quinolin-4-one
Dihydroquinolin-4-one
Anticancer
1. Introduction
As part of an ongoing research project into the development of
isoflavones with potent anticancer activity, it was of interest to
Isoflavones are a group of naturally occurring phytochemicals
that are found predominantly in legume plants (Leguminosae).
examine the synthesis and biological activity of 3-aryl-quinolin-
4-ones and 3-aryl-2,3-dihydroquinolin-4-ones bearing a similar
oxygenation pattern to the most active isoflavones.
They have been reported to exhibit
a variety of biological
properties including anti-inflammatory, neuroprotective function,
anti-osteoporotic, antiplatelet, antibacterial and antitumor activi-
ties.1–7 Isoflavones also play a role in the prevention of cancers,
coronary heart diseases, menopausal symptoms and osteoporo-
sis.8–13
2. Results and discussion
2.1. Synthesis of 3-aryl-quinolin-4-ones
Replacement of the pyran oxygen with a nitrogen atom in the
isoflavone nucleus gives rise to the corresponding 3-phenyl quino-
lone scaffold. Due to their structural similarity, 3-phenyl quino-
lones might be anticipated to possess similar biological
properties to isoflavones. For example, isobavachalcone 1 and the
quinolone analogues of isoflavones 2 have been found to exhibit
strong inhibitory effects on platelet aggregation (Fig. 1).14,15 Fur-
thermore, when compared with the corresponding isoflavones,
the 3-aryl-1H-quinolin-4-one analogues showed greater anti-pro-
liferative activity and a more specific mechanism of action.15
It has been well established that the presence and position of
hydroxyl and methoxy substituents plays an important role in
determining the biological activity of isoflavanones.16–18 Generally,
analogues with substituents at positions 5 and 7 are the most
active.
The synthesis of the target compounds was accomplished
through slight modification of previously reported methods
(Scheme 1).19 Treating of ethyl arylacetates 3 with ethyl formate
4 in the presence of sodium hydride yielded
a-aryl-b-ketoesters
5. Subsequent reaction with 3,5-dimethoxyaniline 6 at reflux in
toluene afforded enamines 7 as the Z isomer only. Alternatively,
a mixture of both Z and E isomers was produced when the reaction
was performed in ethanol at room temperature. The two isomers
were not separated as it was found that both isomers could suc-
cessfully undergo cyclisation. Initial attempts to cyclise enamines
7 at 250 °C in Dowtherm for 1.5 h19 resulted in poor yields of the
target 3-aryl-quinolin-4-ones 8. Higher yields were obtained by
heating enamines 7 at 250 °C for 15–20 min in diphenyl ether/
biphenyl (4:1). The products could be obtained in high purity by
trituration with light petroleum and filtration of the residue
(Table 1).
⇑
Corresponding author. Tel.: +61 293854698; fax: +61 293856141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.11.047

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S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
Figure 1. Isobavachalcone 1 and isoflavone derivatives 2.
Scheme 2. Reagents and conditions: (a) NaBH3CN, MeOH, reflux, 8 h; (b) ethyl
chloroformate, pyridine, CH2Cl2, rt, 5 h; (c) 1 N NaOH, MeOH, rt, overnight; (d) PPA,
70 °C, 30 min; (e) 5% NaOH, MeOH, rt, 3 h.
Initial attempts to cyclise acids 11 with H2SO4 or trifluoroacetic
anhydride (TFAA) were unsuccessful, leading only to the recovery
of the starting material along with baseline impurities. Encourag-
ingly, cyclisation with polyphosphoric acid (PPA) at 70 °C for
30 min under N2 successfully gave the desired 3-aryl-2,3-dihydro-
quinolin-8-one esters 12 in 75–85% yield.20 Higher temperatures
or prolonged heating lowered reaction yields and increased the
formation of baseline impurities. The protecting group was cleaved
using 5% NaOH in methanol to generate the corresponding
5,7-dimethoxy-2,3-dihydroquinolin-4-(1H)-ones 13 in good yield
(Table 2). The 1H NMR spectrum of 5,7-dimethoxy-3-aryl-2,3-dihy-
droquinolin-4-(1H)-one 13b showed two methoxy resonances at d
3.78 and 3.82, doublets at d 5.81 and 5.71 (J = 3 Hz) corresponding
to H6 and H8, respectively, and the NH proton resonance at d 4.68.
Further structural confirmation of analogue 13 was obtained by
X-ray crystallography (Fig. 2).
Scheme 1. Reagents and conditions: (a) NaH, anhydrous Et2O, 40 °C, 4 h; (b)
toluene, reflux, 20 h; (c) diphenyl ether/biphenyl (4:1), 250 °C, 20 min.
2.2. Synthesis of 3-aryl-2,3-dihydroquinolin-8-ones
Direct reduction of 3-aryl-quinolin-4-ones 8 was examined as
the most efficient manner of preparing the corresponding
dihydroquinolone derivatives. However, treatment of 3-aryl-quin-
olin-4-ones 8 with reducing agents such as NaBH4, LiAlH4, or
hydrogenation in the presence of Pd/C in EtOH led only to recovery
of the starting materials. Probable reason for the inertness of the
compound 8 towards reduction is its insolubility.
In an alternate strategy, the targeted 2,3-dihydroquinolin-4-
(1H)-ones were prepared in five steps from 3,5-dimethoxyaniline
3. Demethylation of 3-aryl-quinolin-4-ones and 3-aryl-2,3-
dihydroquinolin-4-ones
6 and
a-aryl-b-ketoesters 5 (Scheme 2). Condensation of 3,5-dime-
thoxyaniline 6 and
a
-aryl-b-ketoesters 5 was attempted with var-
Hydroxy substituted flavones are typically more potent than
their methoxy counterparts.16–18 Demethylation of the synthesized
5,7-dimethoxyquinolin-4-ones 8 and 5,7-dimethoxy-2,3-dihydro-
quinolin-4-ones 13 was therefore investigated.
Heating 5,7-dimethoxyquinolin-4-ones 8 with HBr in AcOH for
3 days or refluxing with AlCl3 in chlorobenzene, afforded a com-
plex mixture of inseparable products. On the other hand, demeth-
ylation of 5,7-dimethoxy-2,3-dihydroquinolin-4-ones 13 with
AlCl3 in chlorobenzene at reflux produced the corresponding
dihydroxy analogues 14 in yields of 15%. The reaction yields were
increased to 45–50% when conducted using 5 equiv of BBr3 in
dichloromethane (Scheme 3, Table 3).
ious reducing agents, yielding mixed results. Reduction with
NaBH(OAc)3 afforded ethyl 3-(3,5-dimethoxyphenylamino)-2-aryl-
acrylate 7 instead of the desired ethyl 3-(3,5-dimethoxyphenyla-
mino)-2-arylpropanoate 9. On the other hand, the use of NaBH4
generated products 7 and 9 in 20% and 50% yield, respectively.
The reaction was finally optimized through use of NaBH3CN, which
gave the desired 3-(3,5-dimethoxyphenylamino)-2-arylpropano-
ates 9 in 65–70% yield. The –NH group was protected using ethyl
chloroformate in the presence of pyridine, and the resulting esters
10 were subjected to base hydrolysis to afford the corresponding
acids 11.
Table 1
Yields of 3-aryl-quinolin-4-ones
Table 2
Compound
R
Yield (%)
Yields of 3-aryl-2,3-dihydroquinolin-4-ones
8a
8b
8c
8d
8e
8f
4-Br
4-F
4-Me
4-OMe
H
59
59
51
58
70
55
48
Compound
R
Yield (%)
13a
13b
13c
13d
13e
4-Br
4-F
4-Me
4-OMe
H
59
59
51
58
70
3-Br
2,5-OMe
8g

S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
107
Table 5
Average cell viability of the treated cell lines (concentration of 25
l
M)
MCF7e
Entry
H460a
DU145b
A-431c
HT-29d
8a
8b
8c
33.5 0.4
86 1.1
74.8 2.3
88.7 4.5
76.6 3.1
71.8 5.1
91.1 0.9
95.4 1.0
83.1 1.4
73.5 1.0
43.4 1.7
85.1 1.2
10.0 1.0
105.7 1.7
81.6 2.5
69.1 0.4
103.1 1.3
89.9 0.0
66.5 2.3
89.6 1.8
98.3 4.1
98.5 0.8
104.1 3.0
71.4 5.6
76.5 1.4
1.0 1.5
26.2 1.0
113.6 4.2
101.7 1.9
37.8 0.8
105.7 1.0
98.8 1.6
98.5 0.8
29.2 1.7
31.2 0.5
29.6 1.4
14.1 0.3
97.3 0.9
90.8 1.9
35.3 2.0
53.8 0.8
43.9 0.8
94.3 4.2
87.6 2.7
74.5 2.0
65.5 3.4
38.9 2.7
50.7 1.1
2.0 0.3
8f
13d
13e
14e
15a
15b
15c
15f
16d
16e
85.1 4.8
83.6 5.7
121.3 3.1
52.6 0.5
Figure 2. ORTEP diagram of quinolin-4-one 13b.21
94.1 2.2
78.0 1.6
107.7 3.1
90.8 1.9
85.7 2.8
83.2 3.5
Cell viability is a measure of the% of metabolically active cells. A value of 0% is
indicative of total cell growth inhibition.
a
Lung carcinoma
Prostate carcinoma
Skin (epidermoid) carcinoma
Colon adenocarcinoma
b
c
d
e
Scheme 3. Reagents and conditions: (a) BBr3, CH2Cl2, rt, overnight.
Breast adenocarcinoma
4. Biological activity
Table 3
Yields of targeted 3-aryl-5,7-dihydroxy-2,3-dihydroquinolin-4-ones
Selected quinolin-4-ones and 2,3-dihydroquinolin-4-ones were
screened for anticancer activity (Table 5). In vitro growth inhibi-
tion assays were performed at a fixed concentration of 25 lM in
Compound
R
Yield (%)
14a
14d
14e
4-Br
4-OMe
H
48
45
44
a range of cancer cell lines, including H460 lung carcinoma,
DU145 prostate carcinoma, A-431 skin (epidermoid) carcinoma,
HT-29 colon adenocarcinoma and MCF7 breast adenocarcinoma.
Among the tested compounds, quinolin-4-ones 15 showed
moderate activity against HT-29 colon adenocarcinoma cell lines
and quinolin-4-one 8a against H460 lung carcinoma, HT-29 colon
adenocarcinoma and MCF7 breast adenocarcinoma. In general,
the monohydroxy analogues 15 demonstrated superior activity to
their dimethoxy counterparts 8, as anticipated. An exception to
this rule was compound 8a, which exhibited 33.5%, 69.1% and
35.3% greater cell growth inhibition in H460 lung carcinoma,
A-431 skin carcinoma and MCF7 breast adenocarcinoma cell lines,
respectively, when compared to its monohydroxy derivative 15a.
Dimethoxyquinoline 8c was also 8.5% more potent than its mono-
hydroxy analogue 15c in the DU145 prostate carcinoma cell line.
Compound 15f showed the greatest reduction (85.9–99.0%) in
cell viability across the cell lines tested. This could potentially be
attributed to the change from a para to a meta substitution pattern
in ring B, potentially leading to more favourable steric interactions
at the active sites. By comparison, the corresponding para deriva-
tive 15a showed much weaker activity against the same cell lines.
A dose–response study was subsequently performed for com-
pound 15f against the selected cell lines in order to better under-
stand its level of activity. Compound 15f was the most active
against the HT-29 colon adenocarcinoma and A-431 skin carci-
Scheme 4. Reagents and conditions: (a) CeCl3ꢀ7H2O-NaI, CH3CN, 100 °C, 8 h.
Table 4
Yields of 3-aryl-5-hydroxy-7-methoxyquinolin-4-ones 15 and 2,3-dihydroquinolin-4-
ones 16
Compound
R
Yield (%)
15a
15b
15c
15d
15e
15f
16a
16c
16d
16e
4-Br
4-F
4-Me
4-OMe
H
3-Br
4-Br
4-Me
4-OMe
H
89
86
86
81
84
79
89
86
81
84
noma cell lines, with IC50 values of 3.6 0.2 and 5.5 0.6
respectively. The compound exhibited similar activity against
H460 lung carcinoma (IC50 = 9.2 0.8 M) and DU145 prostate car-
cinoma (IC50 = 9.5 2.7 M) cell lines, but was least effective in the
MCF7 breast adenocarcinoma cell line, with an IC50 value of
21.9 1.9 M. Furthermore, quinolone 15f was found to have an
IC50 value of 6.7 1.2 M against MRC-5 normal human lung fibro-
blasts, demonstrating a significant difference (p < 0.05) compared
to the HT-29 colon adenocarcinoma cell line. This difference sug-
gests potential for the development of such compounds as possible
therapeutics for colon adenocarcinomas.
lM,
Due to the difficulties associated with the demethylation of
5,7-dimethoxyquinolin-4-ones 8 under harsh conditions, atten-
tion turned to selective demethylation of C5 using milder condi-
tions. Chemoselective cleavage of the C5-methoxy group was
achieved by treating quinolin-4-ones 8 with cerium(III) chlo-
ride-NaI at 100 °C in acetonitrile22 to give monohydroxy com-
pounds 15 in 79–89% (Scheme 4, Table 4). Mechanistically, the
reaction proceeds via chelation of the C4-carbonyl and C5-meth-
oxy groups to cerium, which facilitates the selective demethyla-
tion of C5. Similar reaction of 2,3-dihydroquinolin-4-ones 13
afforded the corresponding monohydroxy analogues 16 in high
yields.
l
l
l
l
In contrast to the quinolin-4-ones, the tested 2,3-dihydroquin-
olin-4-ones 13, 14 and 16 did not show any significant anticancer

108
S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
activity. Furthermore, no consistent trend was observed between
the biological activity and the number of hydroxyl substituents
on the compounds. The activity of the 3-phenyl analogues against
H460 lung carcinoma cells increased in the order 13e < 16e < 14e
as the degree of demethylation increased. On the other hand, the
monohydroxy derivative 16e was the most active analogue against
DU145, A-431 and HT-29 cell lines while the dihydroxy compound
14e was the most active against the MCF7 breast adenocarcinoma
cell line. Additionally, the dimethoxy 3-(4-methoxyphenyl) ana-
logue 13d was more active against DU145 and A-431 cell lines
while the corresponding monohydroxy compound 16d was more
active against the HT-29 cell line. However, the two compounds
displayed similar activity in the H460 and MCF7 cell lines.
followed by the addition of ethyl 2-arylacetate 3 (41.1 mmol) at
room temperature. The reaction mixture was stirred at 40 °C for
4 h, quenched with water (100 mL), and the ethereal layer was sep-
arated. The aqueous layer was washed with ether (100 mL), acidi-
fied with 10% HCl (8 mL), and extracted with ethyl acetate
(3 ꢁ 150 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure to give ethyl 2-formyl-2-
aryl acetate 5 as colourless oil. The compound was used in subse-
quent reactions without further purification.
6.2.2. (Z)-Ethyl 2-aryl-3-((3,5-dimethoxyphenyl)amino)acrylate
(7a–g)
A mixture of 3,5-dimethoxyaniline 6 (36.9 mmol) and ethyl
2-formyl-2-aryl acetate 5 (36.9 mmol) in toluene (100 mL) was
heated at reflux for 20 h. On cooling, the reaction mixture was di-
luted with toluene (50 mL) and washed with water (100 mL). The
organic phase was dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude mixture was purified using
column chromatography (2% ethyl acetate in n-hexane) to give
the title compound 7 as a white solid.
5. Conclusion
A series of 3-aryl-5,7-dimethoxyquinolin-4-ones 8 and 3-aryl-
5,7-dimethoxy-2,3-dihydroquinolin-4-ones 13 were synthesized
in good yields. Chemoselective cleavage of the C5-methoxy group
using cerium(III) chloride and sodium iodide in acetonitrile suc-
cessfully afforded the corresponding monohydroxy derivatives 15
and 16 in high yields. The dihydroxy derivatives 3-aryl-5,7-dihy-
droxy-2,3-dihydroquinolin-4-ones 14 were obtained by demethyl-
ation with BBr3 in dichloromethane.
Anticancer screening of selected compounds showed that
the quinolin-4-one scaffold was more active than the reduced
2,3-dihydroquinolin-4-one scaffold. The monohydroxy compound
15 were generally more potent than their dimethoxy counterparts
13 in the tested cell lines. Overall, the most active analogue was
compound 15f, which demonstrated 85.9–99.0% reduction in cell
viability across all the cell lines tested.
6.2.3. (Z)-3-Aryl-5,7-dimethoxyquinolin-4(1H)-one (8a–g)
(Z)-Ethyl-3-((3,5-dimethoxyphenyl)amino)-2-aryl acrylate
7
(4.9 mmol) was added in portions to a mixture of biphenyl and di-
phenyl ether (1:4) and the resulting solution was heated at 250 °C
for 20 min. On cooling, the title compound 8 precipitated out of the
reaction mixture. The product was collected by filtration and then
washed with n-hexane as a pale yellow solid.
6.2.4. Ethyl 3-((3,5-dimethoxyphenyl)amino)-2-aryl propanoate
(9a–e)
To a solution of 3,5-dimethoxyaniline 6 (36.9 mmol) and ethyl
2-formyl-2-aryl acetate 5 (36.9 mmol) in methanol (100 mL) was
added sodium cyanoborohydride (73.8 mmol). After the bubbling
subsided, the mixture was heated to reflux for 8 h and the reaction
was monitored using TLC. After completion, the methanol was con-
centrated under reduced pressure and the resulting oil was taken
up in ethyl acetate and washed with water (100 mL). The organic
layer was dried over anhydrous Na2SO4 and concentrated under re-
duced pressure to give a yellow oil. The crude oil was purified
using column chromatography (2% ethyl acetate in n-hexane) to
yield the title compound 9 as a yellow oil.
6. Experimental section
6.1. Materials and methods
Melting points (uncorrected) were measured using a Mel-Temp
melting point apparatus. Microanalyses were performed by the
Microanalysis Unit of the University of Otago, New Zealand. Infrared
spectra were recorded as Nujol mulls on a Perkin-Elmer 298 or a
Perkin-Elmer 580B spectrometer. Ultraviolet-visible spectra were re-
corded in methanol (unless otherwise stated) on a Hitachi UV-3200
spectrometer. 1H and 13C NMR spectra were obtained in the desig-
nated solvents on a Bruker AC300F (300 MHz) spectrometer. 1H
NMR data were recorded as follow: chemical shift measured in parts
per million (ppm) downfield from TMS (d), multiplicity, observed
coupling constant (J) in Hertz (Hz), proton count. Multiplicities are
reported as singlet (s), broad singlet (br s), doublet (d), triplet (t),
quartet (q), quintet (quin) and multiplet (m). 13C NMR chemical
shifts are reported in ppm downfield from TMS and identifiable car-
bons are given. The EI and ES mass spectra were recorded on an AEI
MS 12 mass spectrometer at 70 eV ionizing potential and 8000 V
accelerating voltage with an ion source temperature of 210 °C. Kiesel-
gel 60H (Merck, Art 7736) was employed for flash chromatography
and thin layer chromatography (t.l.c.) was performed on DC Alumin-
ium Foil Kieselgel F254 (Merck, Art 5554). Solvents and reagents were
purified by literature methods. Petroleum ether refers to the hydro-
carbon fraction of boiling range 60–80 °C. compounds were detected
by short and long ultraviolet light and with iodine vapor.
6.2.5. Ethyl 3-((3,5-dimethoxyphenyl)(ethoxycarbonyl)amino)-
2-aryl propanoate (10a–e)
Ethyl chloroformate (38.6 mmol) was added dropwise to a mix-
ture of ethyl 3-((3,5-dimethoxyphenyl)amino)-2-aryl propanoate 9
(25.7 mmol) and pyridine (51.5 mmol) in dichloromethane
(100 mL) at 0 °C under a nitrogen atmosphere. The mixture was
stirred for 5 h and then poured into a mixture of dichloromethane
and water (100 mL, 1:1). The dichloromethane layer was separated
and washed successively with 10% HCl (100 mL), sat. NaHCO3
(100 mL) and saturated aqueous sodium chloride (100 mL). The or-
ganic layer was dried over anhydrous Na2SO4 and concentrated un-
der reduced pressure to give 11 as yellow oil, which was used in
the subsequent step without further purification.
6.2.6. Ethyl 3-((3,5-dimethoxyphenyl)(ethoxycarbonyl)amino)-
2-aryl propanoic acid (11a–e)
Ethyl 3-((3,5-dimethoxyphenyl)(ethoxycarbonyl)amino)-2-aryl
propanoate 10 (20.8 mmol) in aqueous sodium hydroxide (1 N)
and methanol (1:1, 100 mL) was stirred at room temperature over-
night. The reaction mixture was concentrated to about half the vol-
ume under reduced pressure, diluted with water and extracted
with ethyl acetate (100 mL). The aqueous layer was acidified with
10% HCl to pH 2 and extracted with ethyl acetate (3 ꢁ 100 mL).
6.2. General procedure for the preparation of quinolin-4-ones
6.2.1. Ethyl 2-formyl-2-aryl acetate (5a–g)
To a suspension of sodium hydride (49.4 mmol, 60% dispersion
in oil) in anhydrous diethyl ether (150 mL) under a nitrogen
atmosphere was added ethyl formate 4 (61.65 mmol) dropwise,

S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
109
These organic extracts were combined, washed with brine
(100 mL), dried over anhydrous Na2SO4 and concentrated under re-
duced pressure to yield the title compound 11 as a yellow oil.
trated under reduced pressure. The crude product was purified
using column chromatography (8% ethyl acetate in n-hexane) to
give the title compound 16 as a yellow solid.
6.2.7. Ethyl 5,7-dimethoxy-3-aryl-4-oxo-3,4-dihydroquinoline-
6.3. Experimental procedure for biological screening
1(2H)-carboxylate (12a–e)
A
mixture of ethyl 3-((3,5-dimethoxyphenyl)(ethoxycar-
6.3.1. Cell culture
bonyl)amino)-2-aryl propanoic acid 11 (4.4 mmol) and polyphos-
phoric acid (4.4 mmol) was heated at 70 °C for 30 min under a
nitrogen atmosphere. The resulting mixture was cooled to 0 °C,
and was taken up in a mixture of dichloromethane–water (1:1,
100 mL). The organic layer was separated and the aqueous phase
was extracted with dichloromethane (2 ꢁ 100 mL). The combined
organic extracts were washed with saturated sodium bicarbonate
(2 ꢁ 150 mL), dried over anhydrous Na2SO4 and concentrated un-
der vacuum to give a crude oil which was purified by column chro-
matography (15% ethyl acetate in n-hexane) to give the title
compound 12 as a white solid.
All cell lines were cultured at 37 °C, under 5% CO2 in a humidi-
fied atmosphere and were maintained in Dulbecco’s modified Ea-
gle’s medium (Gibco, Invitrogen) supplemented with 10% foetal
bovine serum.
6.3.2. In vitro growth inhibition assays
In vitro growth inhibition assays were performed in triplicate
using the Alamar Blue assay. Briefly, cells in logarithmic phase
growth were seeded onto 96 well plates at an optimal fixed density
using a Multidrop 384 (Thermo Scientific) and allowed to adhere.
After 24 h incubation test compounds and vehicle only controls
were added to duplicate wells using a Hamilton Nimbus robotic
platform. After 72 h drug exposure, metabolic activity was detected
by addition of Alamar blue reagentand determinedby measurement
of fluorescence intensity (excitation 555 nm, emission 585 nm)
using a SpectraMax M5 (Molecular Devices) plate reader. Percentage
6.2.8. 5,7-Dimethoxy-3-aryl-2,3-dihydroquinolin-4(1H)-one
(13a–e)
To a solution of ethyl 5,7-dimethoxy-3-aryl-4-oxo-3,4-dihydro-
quinoline-1(2H)-carboxylate 12 (2.7 mmol) in MeOH (10 mL) was
added NaOH pellets (13.5 mmol) at room temperature. The reac-
tion mixture was stirred at room temperature for about 1 h and
the reaction progress was monitored by TLC. After completion,
the solvent was evaporated under reduced pressure and the result-
ing solid was taken up in ethyl acetate (100 mL). The solution was
washed with water (2 ꢁ 50 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude solid was purified
by column chromatography (25% ethyl acetate in n-hexane) and
recrystallized from MeOH to give compound 13 as white crystals.
cell viability was determined at a fixed drug concentration of 25
A value of 0% is indicative of total cell growth inhibition.
lM.
6.4. Experimental data
6.4.1. (Z)-Ethyl 2-(4-bromophenyl)-3-((3,5-dimethoxyphenyl)
amino)acrylate (7a)
White solid (9.45 g, 63%). Mp 142–144 °C; UV (MeOH): kmax 210
(e
86178 cmꢂ1 Mꢂ1), 330 (79512) nm; IR (KBr): mmax 3297, 2969,
2843, 1664, 1588, 1455, 1371 cmꢂ1 1H NMR (300 MHz, CDCl3): d
;
6.2.9. 5,7-Dihydroxy-3-aryl-2,3-dihydroquinolin-4(1H)-one
(14a, e, d)
1.22 (t, J = 7.1 Hz, 3H, CH3CH2), 3.70 (s, 6H, OMe), 4.18 (q,
J = 7.1 Hz, 2H, CH2CH3), 6.08 (s, 3H, ArH), 7.13 (d, J = 8.7 Hz, 2H,
ArH20, ArH60), 7.25 (d, J = 12.4 Hz, 1H, @CH), 7.37 (d, J = 8.7 Hz,
2H, ArH30, ArH50), 10.24 (d, J = 12.4 Hz, 1H, NH); 13C NMR
(75.6 MHz, CDCl3): d 14.8 (Me), 55.8 (2 ꢁ OMe), 60.5 (OCH2), 94.8
(ArC2, ArC6), 95.3 (ArC4), 102.4 (@CCOO), 120.4 (ArC40), 131.4
(ArC30, ArC50), 131.5 (ArC20, ArC60), 137.2 (ArC10), 143.9 (@CH),
144.9 (ArC1), 162.3 (ArC3, ArC5), 169.3 (C@O); HRMS (ESI) m/z
Calcd for C19H21BrNO4 (M+H)+ 406.0654. Found 406.0644; Anal.
Calcd for C19H20BrNO4: C, 56.17; H, 4.96; N, 3.45. Found: C,
56.25; H, 5.04; N, 3.56.
To
a solution of 5,7-dimethoxy-3-aryl-2,3-dihydroquinolin-
4(1H)-one 13 (0.8 mmol) in dichloromethane (10 mL) was added
boron tribromide (4.1 mmol) at 0 °C. The reaction was stirred at
room temperature overnight. The resulting mixture was diluted
in dichloromethane (50 mL), washed with sat. NaHCO3 (50 mL),
water (50 mL), dried over anhydrous Na2SO4 and concentrated un-
der reduced pressure. The crude residue was purified using column
chromatography (12% ethyl acetate in n-hexane) to give the title
compound 14 as a yellow solid.
6.2.10. 5-Hydroxy-7-methoxy-3-aryl-quinolin-4(1H)-one
(15a–f)
6.4.2. (Z)-Ethyl 3-((3,5-dimethoxyphenyl)amino)-2-(4-
fluorophenyl)acrylate (7b)
A suspension of 5,7-dimethoxy-3-aryl-quinolin-4(1H)-one 8
(0.65 mmol), CeCl3.7H2O (1 mmol) and NaI (1 mmol) in acetonitrile
(5 mL) was heated at reflux overnight. The brown suspension was
cooled to room temperature, and concentrated under reduced
pressure. The solid residue was then taken up in ethyl acetate,
and washed with aqueous Na2S2O3 (1 M, 10 mL) and brine
(2 ꢁ 10 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure to give the target com-
pound 15 as a yellowish solid.
White solid (10.6 g, 61%). M.p. 106-108 °C; UV (MeOH): kmax
210 (
e
145517 cmꢂ1 Mꢂ1), 247 (80689), 333 (188276) nm; IR
(KBr): mmax 3283, 3067, 2999, 2974, 2940, 2898, 2840, 1672,
1589, 1206, 1156, 1072, 782, 696 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d 1.21 (t, J = 7.1 Hz, 3H, CH3CH2), 3.70 (s, 6H, OMe), 4.17 (q,
J = 7.1 Hz, 2H, CH2CH3), 6.07 (m, 3H, ArH), 6.94 (m, 2H, ArH30,
ArH50), 7.21 (m, 2H, ArH20, ArH60), 7.24 (d, J = 12.8 Hz, 1H, @CH),
10.20 (d, J = 12.8 Hz, 1H, NH); 13C NMR (75.6 MHz, CDCl3): d 14.8
(Me), 55.8 (2 ꢁ OMe), 60.5 (OCH2), 94.7 (ArC2, ArC6), 95.1 (ArC4),
102.5 (@CCOO), 115.1 (ArC30), 115.3 (ArC50), 131.5 (ArC20, ArC60),
131.6 (ArC10), 142.8 (@CH), 143.8 (ArC1), 162.3 (ArC3, ArC5),
163.5 (ArC40) 169.6 (C@O); HRMS (ESI) m/z Calcd for C19H21FNO4
(M + H)+ 346.1455. Found 346.1444; Anal. Calcd for C19H20FNO4:
C, 66.08; H, 5.84; N, 4.06. Found: C, 66.09; H, 5.91; N, 4.15.
6.2.11. 5-Hydroxy-7-methoxy-3-aryl-2,3-dihydroquinolin-
4(1H)-one (16a, c, d, e)
A
suspension of 5,7-dimethoxy-3-aryl-2,3-dihydroquinolin-
4(1H)-one 13 (1 mmol), CeCl3.7H2O (1.5 mmol) and NaI (1.5 mmol)
in acetonitrile (50 mL) was refluxed overnight. The brown suspen-
sion was cooled to room temperature, and concentrated under re-
duced pressure. The solid residue was then taken up in ethyl
acetate (100 mL), washed with aqueous Na2S2O3 (1 M, 50 mL),
brine solution (50 mL), dried over anhydrous Na2SO4 and concen-
6.4.3. (Z)-Ethyl 3-((3,5-dimethoxyphenyl)amino)-2-(p-tolyl)
acrylate (7c)
White solid (10 g, 60%). Mp 126–128 °C; UV (MeOH): kmax 209
(e
100775 cmꢂ1 Mꢂ1), 334 (78294) nm; IR (KBr): mmax 3296, 3085,

110
S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
3021, 2991, 2968, 2940, 1664, 1648, 1477, 1295, 1198, 1154, 1055,
780, 708, 686 cmꢂ1; 1H NMR (300 MHz, CDCl3): d 1.22 (t, J = 7.2 Hz,
3H, CH3CH2), 2.28 (s, 3H, MeAr0), 3.69 (s, 6H, OMe), 4.17 (q,
J = 7.2 Hz, 2H, CH2CH3), 6.08 (m, 3H, ArH), 7.07 (d, J = 7.9 Hz, 2H,
ArH30, ArH50), 7.15 (d, J = 8.3 Hz, 2H, ArH20, ArH60), 7.26 (d,
J = 12.8 Hz, 1H, @CH), 10.19 (d, J = 12.4 Hz, 1H, NH); 13C NMR
(75.6 MHz, CDCl3): d 14.8 (Me), 21.5 (MeAr0), 55.3 (OMe), 55.8
(OMe), 60.4 (OCH2), 94.5 (ArC2, ArC6), 95.1 (ArC4), 102.4 (@CCOO),
129.5 (ArC10), 129.6 (ArC50), 129.9 (ArC30), 135.3 (ArC20, ArC60),
136.2 (ArC40), 143.6 (@CH), 145.0 (ArC1), 162.2 (ArC3, ArC5),
6.4.8. 3-(4-Bromophenyl)-5,7-dimethoxyquinolin-4(1H)-one
(8a)
Pale yellow solid (1 g, 59%). Mp 312–314 °C; UV (1% CF3COOH/
MeOH): kmax 208 (
nm; IR (KBr): mmax 3263, 3076, 2931, 1627, 1604, 1523, 1466,
720, 692 cmꢂ1 1H NMR (300 MHz, DMSO-d6): d 3.79 (s, 3H,
e
48052 cmꢂ1 Mꢂ1), 263 (128961), 303 (10389)
;
OMe), 3.81 (s, 3H, OMe), 6.32 (d, J = 2.1 Hz, 1H, ArH6), 6.51 (d,
J = 2.4 Hz, 1H, ArH8), 7.52 (d, J = 8.4 Hz, 2H, ArH20, ArH60), 7.60
(d, J = 8.4 Hz, 2H, ArH30, ArH50), 7.88 (s, 1H, H2), 11.58 (br s, 1H,
NH); 13C NMR (75.6 MHz, DMSO-d6): d 55.7 (OMe), 56.0 (OMe),
91.6 (ArC6), 95.0 (ArC8), 111.8 (ArC), 119.4 (ArC3), 120.5 (ArC40),
130.8 (ArC20, ArC60), 130.9 (ArC30, ArC50), 136.1 (ArC2), 136.3
(Ar0C1), 143.9 (ArC), 161.8 (ArC5), 162.3 (ArC7), 173.9 (C@O);
HRMS (ESI) m/z Calcd for C17H15BrNO3 (M+H)+ 360.0235. Found
360.0229.
169.8 (C@O); HRMS (ESI) m/z Calcd for
342.1756. Found 342.1750; Anal. Calcd for C20H23NO3: C, 70.36;
H, 6.79; N, 4.10. Found: C, 70.28; H, 6.93; N, 4.19.
C
20H24NO3 (M+H)+
6.4.4. (Z)-Ethyl 3-((3,5-dimethoxyphenyl)amino)-2-(4-methoxyphenyl)
acrylate19 (7d)
White solid (11.2 g, 63.5%). M.p. 94-96 °C, lit.19 93–94 °C
(EtOH); 1H NMR (300 MHz, CDCl3): d 1.21 (t, J = 7.1 Hz, 3H, CH3-
CH2), 3.69 (s, 6H, OMe), 3.74 (s, 3H, OMe), 4.17 (q, J = 7.1 Hz, 2H,
CH2CH3), 6.04-6.07 (m, 3H, ArH), 6.81 (d, J = 8.4 Hz, 2H, ArH20 &
ArH60), 7.17–7.25 (m, 3H, ArH30, ArH50, @CH), 10.16 (d,
J = 12.4 Hz, 1H, NH).
6.4.9. 3-(4-Fluorophenyl)-5,7-dimethoxyquinolin-4(1H)-one
(8b)
Pale yellow solid (1 g, 59%). Mp 262–264 °C; UV (1% CF3COOH/
MeOH): kmax 203 (
316 (23017) nm; IR (KBr): mmax 3072, 2939, 1624, 1560, 1255,
1199, 1162, 1109, 1073, 777, 719, 708 cmꢂ1 1H NMR (300 MHz,
e
36034 cmꢂ1 Mꢂ1), 237 (52586), 266 (60344),
;
DMSO-d6): d 3.77 (s, 3H, OMe), 3.83 (s, 3H, OMe), 6.31 (d,
J = 2.1 Hz, 1H, ArH6), 6.50 (d, J = 2.4 Hz, 1H, ArH8), 7.16 (m, 2H,
ArH30, ArH50), 7.63 (m, 2H, ArH20, ArH60), 7.84 (s, 1H, H2), 11.53
(br s, 1H, NH); 13C NMR (75.6 MHz, DMSO-d6): d 55.8 (OMe),
56.1 (OMe), 91.8 (ArC6), 95.0 (ArC8), 111.6 (ArC), 114.6 (ArC30),
114.9 (ArC50), 121.0 (ArC3), 130.8 (ArC20), 130.9 (ArC60), 136.1
(ArC2, ArC10), 144.0 (ArC), 161.9 (ArC5, ArC10), 162.8 (ArC7),
174.3 (C@O); HRMS (ESI) m/z Calcd for C17H15FNO3 (M+H)+
300.1036. Found 300.1027.
6.4.5. (Z)-Ethyl 3-((3,5-dimethoxyphenyl)amino)-2-phenylacry-
late19 (7e)
White solid (12.2 g, 60%). Mp 72–74 °C, lit.19 75–76 °C; 1H NMR
(300 MHz, CDCl3): d 1.34 (t, J = 6.9 Hz, 3H, CH3CH2), 3.80 (s, 6H,
OMe), 4.30 (q, J = 6.9 Hz, 2H, CH2CH3), 6.17 (d, J = 2.1 Hz, 2H,
ArH), 6.20 (d, J = 2.1 Hz, 2H, ArH), 7.27–7.37 (m, 5H, Ph), 7.41 (d,
J = 11.7 Hz, 1H, @CH), 10.35 (d, J = 12.6 Hz, 1H, NH).
6.4.6. (Z)-Ethyl 2-(3-bromophenyl)-3-((3,5-dimethoxyphenyl)
amino)acrylate (7f)
6.4.10. 5,7-Dimethoxy-3-(p-tolyl)quinolin-4(1H)-one (8c)
Pale yellow solid (0.9 g, 51.5%). Mp 282–284 °C; UV (1%
White solid (9.2 g, 61.5%). Mp 84–86 °C; UV (MeOH): kmax 210
CF3COOH/MeOH): kmax 207 (
nm; IR (KBr): mmax 3264, 3076, 2932, 2858, 1627, 1604, 1521,
1225, 1209, 1156, 1117, 700, 671 cmꢂ1 1H NMR (300 MHz,
e
149789 cmꢂ1 Mꢂ1), 261 (192405)
(e
223837 cmꢂ1 Mꢂ1), 244 (75581), 333 (204069) nm; IR (KBr):
mmax 3384, 3062, 2984, 2936, 2898, 2837, 1655, 1607, 1251,
;
1194, 1065, 1024, 796, 718 cmꢂ1 1H NMR (300 MHz, CDCl3): d
;
DMSO-d6): d 2.31 (s, 3H, MeAr0), 3.77 (s, 3H, OMe), 3.82 (s, 3H,
OMe), 6.30 (d, J = 2.4 Hz, 1H, ArH6), 6.50 (d, J = 2.4 Hz, 1H, ArH8),
7.14 (d, J = 8.1 Hz, 2H, ArH30, ArH50), 7.48 (d, J = 8.1 Hz, 2H, ArH20,
ArH60), 7.77 (s, 1H, H2), 11.46 (br s, 1H, NH); 13C NMR (75.6 MHz,
DMSO-d6): d 21.2 (MeAr0), 56.7 (OMe), 57.7 (OMe), 92.8 (ArC6),
99.6 (ArC8), 113.6 (ArC), 117.5 (ArC30, ArC50), 119.0 (ArC3), 129.4
(ArC20), 129.7 (ArC60), 129.9 (ArC10), 130.4 (ArC2), 138.2 (ArC40),
144.1 (ArC), 165.0 (ArC5), 166.7 (ArC7), 173.2 (C@O); HRMS (ESI)
m/z Calcd for C18H18NO3 (M + H)+ 296.1286. Found 296.1275.
1.22 (t, J = 7.1 Hz, 3H, CH3CH2), 3.70 (s, 6H, OMe), 4.18 (q,
J = 7.1 Hz, 2H, CH2CH3), 6.08 (m, 3H, ArH), 7.12 (d, J = 7.5 Hz,
1H, ArH60), 7.18 (m, 1H, ArH50), 7.28 (m, 1H, ArH40), 7.26 (d,
J = 12.8 Hz, 1H, @CH), 7.41 (t, J = 1.5 Hz, 1H, Ar0H2), 10.25 (d,
J = 12.5 Hz, 1H, NH); 13C NMR (75.6 MHz, CDCl3): d 14.7 (Me),
55.8 (2 ꢁ OMe), 60.5 (OCH2), 94.9 (ArC2, ArC6), 95.4 (ArC4),
102.2 (@CCOO), 122.3 (ArC30), 128.5 (ArC60), 129.4 (ArC20),
129.8 (ArC50), 132.7 (ArC40), 140.4 (ArC10), 142.6 (@CH), 144.2
(ArC1), 162.3 (ArC3, ArC5), 169.2 (C@O); HRMS (ESI) m/z Calcd
for C19H21BrNO4 (M+H)+ 406.0654. Found 406.0644; Anal. Calcd
for C19H20BrNO4: C, 56.17; H, 4.96; N, 3.45. Found: C, 56.25; H,
5.08; N, 3.54.
6.4.11. 5,7-Dimethoxy-3-(4-methoxyphenyl)quinolin-4(1H)-
one19 (8d)
Pale yellow solid (1 g, 58%). Mp 264–266 °C, lit.19 262-263 °C;
1H NMR (300 MHz, DMSO-d6): d 3.87 (s, 3H, OMe), 3.88 (s, 3H,
OMe), 3.93 (s, 3H, OMe), 6.40 (d, J = 3.0 Hz, 1H, ArH6), 6.60 (d,
J = 3.0 Hz, 1H, ArH8), 7.01 (d, J = 9.0 Hz, 2H, ArH20, ArH60), 7.63
(d, J = 9.0 Hz, 2H, ArH30, ArH50), 7.84 (d, J = 3.0 Hz, 1H, H2), 11.55
(br s, 1H, NH).
6.4.7. (Z)-Ethyl 2-(2,5-dimethoxyphenyl)-3-((3,5-dimethoxyphenyl)
amino)acrylate (7g)
White solid (7.1 g, 46.5%). Mp 114–116 °C; UV (MeOH): kmax
209 (e
52907 cmꢂ1 Mꢂ1), 322 (33333) nm; IR (KBr): mmax 3315,
2981, 2937, 2837, 1693, 1589, 1494, 1154, 1036, 772, 734,
677 cmꢂ1; 1H NMR (300 MHz, CDCl3): d 1.18 (t, J = 7.2 Hz, 3H, CH3-
CH2), 3.67 (s, 6H, MeO), 4.13 (q, J = 7.2 Hz, 2H, CH2CH3), 5.97–6.05
(m, 3H, ArH), 6.70–6.88 (m, 3H, ArH20, ArH40, ArH60), 7.21 (d,
J = 12.8 Hz, 1H, @CH), 10.09 (d, J = 12.4 Hz, 1H, NH); 13C NMR
(75.6 MHz, CDCl3): d 14.6 (Me), 55.6 (2 ꢁ OMe), 55.7 (2 ꢁ OMe),
59.94 (OCH2), 94.6 (2 ꢁ ArC), 99.2 (ArC), 111.5 (@CCOO), 112.3
(ArC60), 113.1 (ArC30), 114.1 (ArC40), 117.8 (ArC10), 142.6 (@CH),
143.1 (ArC), 151.7 (ArC30), 152.3 (ArC50), 161.8 (ArC3, ArC5),
6.4.12. 5,7-Dimethoxy-3-phenylquinolin-4(1H)-one19 (8e)
Pale yellow solid (1.2 g, 70.5%). Mp 176–178 °C, lit.19 179–180 °C;
1H NMR (300 MHz, DMSO-d6): d 3.81 (s, 3H, OMe), 3.93 (s, 3H, OMe),
6.44 (d, J = 2.0 Hz, 1H, ArH6), 6.57 (d, J = 2.0 Hz, 1H, ArH8), 7.26–
7.36 (m, 3H, ArH0), 7.62 (m, 2H, ArH0), 7.99 (s, 1H, H2).
6.4.13. 3-(3-Bromophenyl)-5,7-dimethoxyquinolin-4(1H)-one
(8f)
169.5 (C@O); HRMS (ESI) m/z Calcd for
388.1760. Found 388.1750.
C
21H26NO6 (M+H)+
Pale yellow solid (0.95 g, 55%). Mp 268–270 °C; UV (1% CF3-
COOH/MeOH): kmax 211 (e
114049 cmꢂ1 Mꢂ1), 262 (252479), 317

S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
111
(20247) nm; IR (KBr): mmax 3075, 2931, 2837, 1629, 1591, 1560,
1222, 1199, 1158, 1110, 781, 723, 707, 687 cmꢂ1 1H NMR
(300 MHz, CDCl3): d 1.11 (t, J = 6.0 Hz, 3H, CH3CH2), 2.26 (s, 3H,
MeAr), 3.32 (dd, J = 6.0, 12.0 Hz, 1H, CHAr0), 3.65 (s, 6H, OMe),
3.79–3.89 (m, 2H, CH2N), 4.08 (q, J = 6.0 Hz, 2H, CH2CH3), 5.70 (d,
J = 3.0 Hz, 2H, ArH2, ArH6), 5.81 (t, J = 3.0 Hz, 1H, ArH4), 7.15–
7.12 (m, 4H, ArH20, ArH30, ArH50, ArH60); 13C NMR (75.6 MHz,
CDCl3): d 14.5 (Me), 21.5 (MeAr0), 47.2 (CHAr0), 50.8 (CH2N), 55.6
(2 ꢁ OMe), 61.4 (OCH2), 90.5 (ArC), 92.3 (2 ꢁ ArC), 128.3 (ArC30,
ArC50), 130.0 (ArC20, ArC60), 134.2 (ArC10), 137.8 (ArC40), 149.8
(ArC), 162.2 (ArC3, ArC5), 173.4 (C@O); HRMS (ESI) m/z Calcd for
;
(300 MHz, DMSO-d6): d 3.78 (s, 3H, OMe), 3.83 (s, 3H, OMe), 6.36
(d, J = 1.5 Hz, 1H, ArH6), 6.54 (d, J = 1.5 Hz, 1H, ArH8), 7.32 (t,
J = 7.9 Hz, 1H, ArH60), 7.44 (d, J = 7.9 Hz, 1H, ArH50), 7.61 (d,
J = 7.5 Hz, 1H, ArH40), 7.92 (s, 2H, ArH20, @CH), 11.62 (br s, 1H,
NH); 13C NMR (75.6 MHz, DMSO-d6): d 55.8 (OMe), 56.1 (OMe),
91.8 (ArC6), 95.2 (ArC8), 111.8 (ArC), 120.2 (ArC3), 121.4 (ArC30),
127.6 (ArC60), 129.2 (ArC20, ArC50), 130.2 (ArC40),131.5 (ArC10),
139.4 (ArC2), 144.0 (ArC), 161.9 (ArC5), 162.4 (ArC7), 173.8
(C@O); HRMS (ESI) m/z Calcd for C17H15BrNO3 (M+H)+ 360.0235.
Found 360.0227.
C
20H26NO4 (M+H)+ 344.1862. Found 344.1847.
6.4.18. Ethyl 3-(3,5-dimethoxyphenylamino)-2-(4-methoxyphen-
yl)propanoate (9d)
6.4.14. 3-(2,5-Dimethoxyphenyl)-5,7-dimethoxyquinolin-4(1H)-
one (8g)
Yellow oil (11.9 g, 67%); UV (MeOH): kmax 201 (
217 (60800) nm; IR (KBr): mmax 3405, 2935, 2838, 1723, 1595,
1510, 1247, 1202, 1173, 1058, 1030, 808, 683 cmꢂ1 1H NMR
e
84800 cmꢂ1 Mꢂ1),
Pale yellow solid (0.85 g, 47.7%). Mp 230–232 °C; UV (1%
;
CF3COOH/MeOH): kmax 206 (
300 (28140) nm; IR (KBr): mmax 3081, 2935, 2831, 1626, 1557,
1219, 1108, 1068, 722, 678 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
e
146733 cmꢂ1 Mꢂ1), 255 (254773),
(300 MHz, CDCl3): d 1.12 (t, J = 6.0 Hz, 3H, CH3CH2), 3.32 (dd,
J = 6.0, 12.0 Hz, 1H, CHAr0), 3.67 (s, 6H, OMe), 3.73 (s, 3H, OMe),
3.78–3.84 (m, 2H, CH2N), 4.06 (q, J = 6.0 Hz, 2H, CH2CH3), 5.71 (d,
J = 3.0 Hz, 2H, ArH2, ArH6), 5.82 (t, J = 3.0 Hz, 1H, ArH4), 6.80 (d,
J = 9.0 Hz, 2H,ArH20, ArH60), 7.14 (d, J = 9.0 Hz, 2H, ArH30, ArH50);
13C NMR (75.6 MHz, CDCl3): d 14.5 (Me), 47.2 (CHAr0), 50.4
(CH2N), 55.6 (2 ꢁ OMe), 55.7 (OMe), 61.4 (OCH2), 90.5 (2 ꢁ ArC),
92.3 (ArC), 114.7 (ArC20, ArC60), 129.2 (ArC10), 129.5 (ArC30, ArC50),
149.7 (ArC), 159.5 (ArC40), 162.2 (ArC3, ArC5), 173.5 (C@O); HRMS
(ESI) m/z Calcd for C20H26NO5 (M+H)+ 360.1811. Found 360.1800.
;
d 3.62 (s, 3H, OMe), 3.70 (s, 3H, OMe), 3.75 (s, 3H, OMe), 3.82 (s,
3H, OMe), 6.31 (d, J = 2.2 Hz, 1H, ArH6), 6.49 (d, J = 2.2 Hz, 1H,
ArH8), 6.80 (m, 2H, ArH20, ArH40), 6.92 (m, 1H, ArH60), 7.60 (s,
1H, H2), 11.40 (br s, 1H, NH); 13C NMR (75.6 MHz, DMSO-d6): d
55.7 (OMe), 55.8 (OMe), 56.1 (OMe), 56.4 (OMe), 91.7 (ArC6),
94.8 (ArC8), 111.5 (ArC60), 112.6 (ArC), 112.9 (ArC40), 118.3 (ArC30),
119.7 (ArC3), 126.9 (ArC10), 137.0 (ArC2), 151.8 (ArC20), 153.1
(ArC50, ArC),161.7 (ArC5), 162.2 (ArC7), 173.7 (C@O); HRMS (ESI)
m/z Calcd for C19H20NO5 (M+H)+ 342.1341. Found 342.1330.
6.4.19. Ethyl 3-(3,5-dimethoxyphenylamino)-2-phenylpropanoa-
te (9e)
6.4.15. Ethyl 2-(4-bromophenyl)-3-(3,5-
dimethoxyphenylamino)propanoate (9a)
Yellow oil (10.6 g, 70%); UV (MeOH): kmax 216 (
Mꢂ1); IR (KBr): mmax 3404, 2917, 2848, 1724, 1592, 1515, 1485,
1459, 1409, 1370, 1193, 1172, 1070, 1010, 808, 681 cmꢂ1 1H
Yellow oil (11.2 g, 65%). UV (MeOH): kmax 215 (
Mꢂ1); IR (KBr): mmax 3406, 2936, 2840, 1723, 1594, 1454, 1202,
1172, 1057, 926, 808, 734, 698 cmꢂ1 1H NMR (300 MHz, CDCl3):
e -
79487 cmꢂ1
e
53906 cmꢂ1
-
;
d 1.25 (t, J = 6.0 Hz, 3H, CH3CH2), 3.49 (dd, J = 6.0, 12.0 Hz, 1H,
CHAr0), 3.79 (s, 6H, OMe), 3.86–4.03 (m, 2H, CH2NH), 4.21 (q,
J = 6.0 Hz, 2H, CH2CH3), 5.85 (d, J = 3.0 Hz, 2H, ArH2, ArH6), 5.96
(t, J = 3.0 Hz, 1H, ArH4), 7.33–7.40 (m, 5H, Ph); 13C NMR
(75.6 MHz, CDCl3): d 14.5 (Me), 47.2 (CHAr0), 51.3 (CH2NH), 55.6
(2 ꢁ OMe), 61.5 (OCH2), 90.4 (ArC), 92.3 (2 ꢁ ArC), 128.1 (ArC40),
128.3 (ArC30, ArC50), 129.4 (ArC20, ArC60), 137.3 (ArC10), 149.7
(ArC), 162.2 (ArC3, ArC5), 173.3 (C@O); HRMS (ESI) m/z Calcd for
;
NMR (300 MHz, CDCl3): d 1.20 (t, J = 6.0 Hz, 3H, CH3CH2), 3.39
(dd, J = 6.0, 15.0 Hz, 1H, CHAr0), 3.74 (s, 6H, OMe), 3.88-3.95 (m,
2H, CH2N), 4.14 (q, J = 6.0 Hz, 2H, CH2CH3), 5.77 (d, J = 3.0 Hz, 2H,
ArH2, ArH6), 5.89 (t, J = 3.0 Hz, 1H, ArH4), 7.17 (d, J = 9.0 Hz, 2H,
ArH30, ArH50), 7.47 (d, J = 9.0 Hz, 2H, ArH20, ArH60); 13C NMR
(75.6 MHz, CDCl3): d 14.0 (Me), 46.5 (CHAr0), 50.1 (CH2N), 55.1
(2 ꢁ OMe), 61.1 (OCH2), 90.0 (ArC), 91.8 (2 ꢁ ArC), 121.6 (ArC40),
129.7 (ArC20, ArC60), 131.9 (ArC30, ArC50), 135.7 (ArC10), 148.9
(ArC), 161.7 (ArC3, ArC5), 172.3 (C@O); HRMS (ESI) m/z Calcd for
C
19H24NO4 (M+H)+ 330.1705. Found 330.1693.
6.4.20. 2-(4-Bromophenyl)-3-((3,5-dimethoxyphenyl)(ethoxycar-
bonyl)amino)propanoic acid (11a)
C
19H23BrNO4 (M+H)+ 407.0810. Found 408.0800.
Yellow oil (9 g, 95.5%); UV (MeOH): kmax 203 (
Mꢂ1), 282 (1851) nm; IR (KBr): mmax 2938, 1702, 1593, 1456,
1408, 1381, 1303, 1203, 1062, 1010, 928, 829, 767, 697 cmꢂ1 1H
e -
73662 cmꢂ1
6.4.16. Ethyl 3-(3,5-dimethoxyphenylamino)-2-(4-fluorophenyl)
propanoate (9b)
;
Yellow oil (12.6 g, 70%); UV (MeOH): kmax 215 (
Mꢂ1); IR (KBr): mmax 3406, 2936, 2841, 1724, 1594, 1508, 1460,
1202, 1058, 927, 808, 682 cmꢂ1 1H NMR (300 MHz, CDCl3): d
e
63043 cmꢂ1
-
NMR (300 MHz, CDCl3): d 1.10 (t, J = 6.0 Hz, 3H, CH3CH2), 3.62 (s,
6H, OMe), 3.94–4.08 (m, 4H, CH2CH3 & CH2N), 4.18 (dd, J = 6.0,
12.0 Hz, 1H, CHAr0), 5.98 (d, J = 3.0 Hz, 2H, ArH2, ArH6), 6.23 (t,
J = 3.0 Hz, 1H, ArH4), 7.08 (d, J = 9.0 Hz, 2H, ArH30, ArH50), 7.34
(d, J = 9.0 Hz, 2H, ArH20, ArH60); 13C NMR (75.6 MHz, CDCl3): d
14.9 (Me), 49.8 (CHAr0), 52.8 (CH2N), 55.7 (2 ꢁ OMe), 62.4
(OCH2), 99.7 (ArC), 106.0 (2 ꢁ ArC), 122.4 (ArC40), 130.8 (ArC20,
ArC60), 132.2 (ArC30, ArC50), 135.2 (ArC10), 143.5 (ArC), 155.9
(C@O), 161.1 (2 ꢁ ArC), 177.1 (COOH); HRMS (ESI) m/z Calcd for
;
1.12 (t, J = 6.0 Hz, 3H, CH3CH2), 3.32 (dd, J = 6.0, 12.0 Hz, 1H, CHAr0),
3.66 (s, 6H, OMe), 3.82–3.87 (m, 2H, CH2N), 4.05 (q, J = 6.0 Hz, 2H,
CH2CH3), 5.70 (d, J = 3.0 Hz, 2H, ArH2, ArH6), 5.82 (t, J = 3.0 Hz, 1H,
ArH4), 6.93–6.99 (m, 2H, ArH30, ArH50), 7.17–7.21 (m, 2H, ArH20,
13
ArH60); C NMR (75.6 MHz, CDCl3): d 14.5 (Me), 47.2 (CHAr0),
50.4 (CH2N), 55.6 (2 ꢁ OMe), 61.6 (OCH2), 90.4 (ArC), 92.3
(2 ꢁ ArC), 116.1 (ArC30), 116.3 (ArC50), 130.0 (ArC20), 130.1 (ArC60),
133.0 (ArC10), 149.5 (ArC), 162.1 (ArC3), 162.2 (ArC5), 164.3
(ArC40), 173.1 (C@O); HRMS (ESI) m/z Calcd for C19H23FNO4
(M+H)+ 348.1611. Found 348.1599.
C
20H23BrNO6 (M+H)+ 452.0709. Found 452.0703.
6.4.21. 3-((3,5-Dimethoxyphenyl)(ethoxycarbonyl)amino)-2-(4-
fluorophenyl)propanoic acid (11b)
Yellow oil (11 g, 94%); UV (MeOH): kmax 203 (e -
62426 cmꢂ1
6.4.17. Ethyl 3-(3,5-dimethoxyphenylamino)-2-p-tolylpropanoa-
Mꢂ1), 282 (587) nm; IR (KBr): mmax 2940, 2842, 1703, 1593, 1509,
1459, 1409, 1306, 1222, 1203, 1062, 1035, 928, 833, 768,
688 cmꢂ1; 1H NMR (300 MHz, CDCl3): d 1.09 (t, J = 6.0 Hz, 3H, CH3-
CH2), 3.61 (s, 6H, OMe), 3.93–4.08 (m, 4H, CH2CH3, CH2N), 4.16 (dd,
J = 6.0, 15.0 Hz, 1H, CHAr0), 6.00 (d, J = 3.0 Hz, 2H, ArH2, ArH6), 6.23
te (9c)
Yellow oil (13 g, 69.5%); UV (MeOH): kmax 216 (
Mꢂ1); IR (KBr): mmax 3361, 2824, 1714, 1597, 1514, 1452, 1418,
1369, 1337, 1193, 1062, 1018, 813, 782, 681 cmꢂ1 1H NMR
e -
53906 cmꢂ1
;

112
S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
(t, J = 3.0 Hz, 1H, ArH4), 6.88–6.93 (m, 2H, ArH30, ArH50), 7.15–7.20
(m, 2H, ArH20, ArH60); 13C NMR (75.6 MHz, CDCl3): d 14.9 (Me),
49.7 (CHAr0), 52.9 (CH2N), 55.7 (2 ꢁ OMe), 62.4 (OCH2), 99.7
(ArC), 106.0 (2 ꢁ ArC), 115.8 (ArC30), 116.1 (ArC50), 130.6 (ArC20),
130.7 (ArC60), 131.8 (ArC10), 131.9 (ArC40), 143.5 (ArC), 155.9
(C@O), 161.1 (ArC), 161.2 (ArC), 178.0 (COOH); HRMS (ESI) m/z
Calcd for C20H23FNO6 (M + H)+ 392.1509. Found 392.1502.
7.05 (d, J = 9.0 Hz, 2H, ArH20, ArH60), 7.42 (d, J = 9.0 Hz, 2H, ArH30,
13
ArH50); C NMR (75.6 MHz, CDCl3): d 14.2 (Me), 50.1 (CHAr0),
54.2 (CH2N), 55.5 (OMe), 56.0 (OMe), 62.4 (OCH2), 95.8 (ArC8),
100.3 (ArC6), 109.9 (ArC), 121.2 (ArC40), 130.1 (ArC20, ArC60),
131.6 (ArC30, ArC50), 136.5 (ArC10), 147.0 (ArC), 153.8 (COO),
164.4 (ArC5, ArC7), 191.7 (C@O); HRMS (ESI) m/z Calcd for
C
C
20H21BrNO3 (M+H)+ 434.0705. Found 434.0698; Anal. Calcd for
20H20BrNO5: C, 55.31; H, 4.64; N, 3.23. Found: C, 55.49; H, 4.61;
6.4.22. 3-((3,5-Dimethoxyphenyl)(ethoxycarbonyl)amino)-2-p-
N, 3.19.
tolylpropanoic acid (11c)
Yellow oil (10.5 g, 94%); UV (MeOH): kmax 204 (
e
46050 cmꢂ1
-
6.4.26. Ethyl 3-(4-fluorophenyl)-5,7-dimethoxy-4-oxo-3,4-
dihydroquinoline-1(2H)-carboxylate (12b)
Mꢂ1); IR (KBr): mmax 3352, 2971, 1693, 1594, 1513, 1473, 1446,
1427, 1328, 1295, 1269, 1200, 1155, 1064, 1043, 926, 820, 770,
730 cmꢂ1; 1H NMR (300 MHz, CDCl3): d 1.10 (t, J = 6.0 Hz, 3H, CH3-
CH2), 2.23 (s, 3H, MeAr0), 3.60 (s, 6H, OMe), 3.92–4.08 (m, 4H, CH2-
CH3, CH2N), 4.19 (dd, J = 12.0, 18.0 Hz, 1H, CHAr0), 6.01 (d,
J = 3.0 Hz, 2H, ArH2, ArH6), 6.23 (t, J = 3.0 Hz, 1H, ArH4), 7.02 (d,
J = 6.0 Hz, 2H, ArH30, ArH50), 7.08 (d, J = 6.0 Hz, 2H, ArH20, ArH60);
13C NMR (75.6 MHz, CDCl3): d 14.9 (Me), 21.4 (MeAr0), 50.0 (CHAr0),
53.0 (CH2N), 55.7 (2 ꢁ OMe), 62.3 (OCH2), 99.8 (ArC), 106.0
(2 ꢁ ArC), 128.9 (ArC30, ArC50), 129.7 (ArC20, ArC60), 133.2 (ArC10),
138.0 (ArC40), 143.7 (ArC), 156.0 (C@O), 161.0 (2 ꢁ ArC), 178.2
(COOH); HRMS (ESI) m/z Calcd for C21H26NO6 (M+H)+ 388.1760.
Found 388.1752.
White solid (1.2 g, 64%). Mp 70–72 °C; UV (MeOH): kmax 294 (
e
22400 cmꢂ1 Mꢂ1) nm; IR (KBr):
m
max 2938, 1707, 1669, 1597, 1568,
1509, 1455, 1371, 1297, 1245, 1158, 1044, 955, 830, 761 cmꢂ1 1H
;
NMR (300 MHz, CDCl3): d 1.11 (t, J = 6.0 Hz, 3H, CH3CH2), 3.75 (dd,
J = 6.0, 9.0 Hz, 1H, H3), 3.80 (s, 3H, OMe), 3.82 (s, 3H, OMe), 4.04-
4.12 (m, 3H, CH2CH3, H2a), 4.26 (dd, J = 6.0, 12.0 Hz, 1H, H2b),
6.23 (d, J = 3.0 Hz, 1H, ArH6), 6.88 (d, J = 3.0 Hz, 1H, ArH8), 6.92
(d, J = 9.0 Hz, 2H, ArH20, ArH60), 7.06 (d, J = 9.0 Hz, 2H, ArH30,
13
ArH50); C NMR (75.6 MHz, CDCl3): d 14.7 (Me), 50.8 (CHAr0),
54.5 (CH2N), 56.0 (OMe), 56.5 (OMe), 62.9 (OCH2), 96.3 (ArC8),
100.8 (ArC6), 110.4 (ArC), 115.7 (ArC30), 116.0 (ArC50), 130.4
(ArC10), 133.8 (ArC20), 133.9 (ArC60), 147.6 (ArC), 153.4 (COO),
164.0 (ArC40), 164.8 (ArC5, ArC7), 192.6 (C@O); HRMS (ESI) m/z
Calcd for C20H21FNO5 (M+H)+ 374.1404. Found 374.1393.
6.4.23. 3-((3,5-Dimethoxyphenyl)(ethoxycarbonyl)amino)-2-(4-
methoxyphenyl) propanoic acid (11d)
Yellow oil (8.9 g, 95%); UV (MeOH): kmax 204 (
Mꢂ1), 282 (1411) nm; IR (KBr): mmax 2938, 2839, 1703, 1593,
1511, 1203, 1178, 1062, 1031, 769, 733, 688 cmꢂ1 1H NMR
e
52217 cmꢂ1
-
6.4.27. Ethyl 5,7-dimethoxy-4-oxo-3-p-tolyl-3,4-dihydroquinoline-
1(2H)-carboxylate (12c)
;
White solid (1.1 g, 55%). Mp 104–106 °C; UV (MeOH): kmax 201
(300 MHz, CDCl3): d 1.11 (t, J = 6.0 Hz, 3H, CH3CH2), 3.62 (s, 6H,
OMe), 3.70 (s, 3H, OMe), 3.90–4.07 (m, 4H, CH2CH3, CH2N), 4.18
(dd, J = 6.0, 12 Hz, 1H, CHAr0), 6.02 (d, J = 3.0 Hz, 2H, ArH2, ArH6),
6.24 (t, J = 3.0 Hz, 1H, ArH4), 6.75 (d, J = 9.0 Hz, 2H, ArH30, ArH50),
7.12 (d, J = 9.0 Hz, 2H, ArH20, ArH60); 13C NMR (75.6 MHz, CDCl3):
d 14.9 (Me), 49.6 (CHAr0), 53.0 (CH2N), 55.6 (OMe), 55.7 (2 ꢁ OMe),
62.3 (OCH2), 99.8 (ArC), 106.0 (2 ꢁ ArC), 114.5 (ArC30, ArC50), 128.2
(ArC10), 130.1 (ArC20, ArC60), 143.7 (ArC), 155.9 (C@O), 159.7
(ArC40), 161.0 (ArC3, ArC5), 178.6 (COOH); HRMS (ESI) m/z Calcd
for C21H26NO7 (M + H)+ 404.1709. Found 404.1700.
(e
28899 cmꢂ1 Mꢂ1), 239 (29474), 294 (20484) nm; IR (KBr): mmax
2987, 2912, 2850, 1700, 1661, 1598, 1573, 1454, 1400, 1302,
1263, 1214, 1154, 1048, 1021, 952, 811, 763, 721 cmꢂ1 1H
;
NMR (300 MHz, CDCl3): d 1.10 (t, J = 6.0 Hz, 3H, CH3CH2), 2.23
(s, 3H, MeAr0), 3.72 (dd, J = 6.0, 9.0 Hz, 1H, H3), 3.80 (s, 3H,
OMe), 3.81 (s, 3H, OMe), 4.03–4.10 (m, 3H, CH2CH3, H2a), 4.27
(dd, J = 6.0 Hz, 15 Hz, 1H, H2b), 6.22 (d, J = 3.0 Hz, 1H, ArH6),
6.88 (d, J = 3.0 Hz, 1H, ArH8), 6.97–7.05 (m, 5H, ArH20, ArH30,
ArH50, ArH60); 13C NMR (75.6 MHz, CDCl3): d 14.7 (Me), 21.4
(MeAr0), 50.9 (CHAr0), 55.0 (CH2N), 56.0 (OMe), 56.5 (OMe), 62.8
(OCH2), 96.3 (ArC8), 100.7 (ArC6), 110.7 (ArC), 128.7 (ArC30,
ArC50), 129.7 (ArC20, ArC60), 135.0 (ArC10), 137.2 (ArC40), 147.7
(ArC), 154.4 (COO), 163.0 (ArC5), 164.6 (ArC7), 193.2 (C@O);
HRMS (ESI) m/z Calcd for C21H24NO5 (M+H)+ 370.1654. Found
370.1642; Anal. Calcd for C21H23NO5: C, 66.28; H, 6.28; N, 3.79.
Found: C, 67.99; H, 6.26; N, 3.74.
6.4.24. 3-((3,5-Dimethoxyphenyl)(ethoxycarbonyl)amino)-2-
phenylpropanoic acid (11e)
Yellow oil (8.9 g, 96%); UV (MeOH): kmax 204 (
Mꢂ1), 282 (1149) nm; IR (KBr): mmax 2939, 2841, 1703, 1593,
1455, 1248, 1203, 1062, 1033, 834, 765, 698 cmꢂ1 1H NMR
e -
63793 cmꢂ1
;
(300 MHz, CDCl3): d 1.10 (t, J = 6.0 Hz, 3H, CH3CH2), 3.60 (s, 6H,
OMe), 3.96–4.08 (m, 4H, CH2CH3, CH2N), 4.21 (dd, J = 9.0, 15.0 Hz,
1H, CHAr0), 6.01 (d, J = 3.0 Hz, 2H, ArH2, ArH6), 6.23 (t, J = 3.0 Hz,
1H, ArH4), 7.19–7.23 (m, Ph); 13C NMR (75.6 MHz, CDCl3): d 14.9
(Me), 50.5 (CHAr0), 53.0 (CH2N), 55.7 (2 ꢁ OMe), 62.3 (OCH2),
99.8 (ArC), 106.0 (2 ꢁ ArC), 128.3 (ArC10), 129.0 (ArC30, ArC50),
129.1 (ArC20, ArC60), 136.2 (ArC40), 143.7 (ArC), 156.0 (C@O),
161.0 (ArC3, ArC5), 178.0 (COOH); HRMS (ESI) m/z Calcd for
6.4.28. Ethyl 5,7-dimethoxy-3-(4-methoxyphenyl)-4-oxo-3,4-
dihydroquinoline-1(2H)-carboxylate (12d)
White solid (1.2 g, 62%). Mp 108–110 °C; UV (MeOH): kmax 201
(e
29678 cmꢂ1 Mꢂ1), 229 (33704), 293 (19828) nm; IR (KBr): mmax
2973, 2832, 1699, 1661, 1595, 1570, 1512, 1455, 1247, 1153,
1049, 1022, 855, 829, 808 cmꢂ1 1H NMR (300 MHz, CDCl3): d
;
1.17 (t, J = 6.0 Hz, 3H, CH3CH2), 3.75 (s, 3H, OMe), 3.79 (dd,
J = 6.0, 9.0 Hz, 1H, H3), 3.86 (s, 3H, OMe), 3.87 (s, 3H, OMe),
4.09-4.17 (m, 3H, CH2CH3, H2a), 4.32 (dd, J = 3.0, 12.0 Hz, 1H,
H2b), 6.28 (d, J = 3.0 Hz, 1H, ArH6), 6.82 (d, J = 9.0 Hz, ArH20, ArH60),
6.94 (d, J = 3.0 Hz, 1H, ArH8), 7.08 (d, J = 9 Hz, 2H, ArH30, ArH50), 13C
NMR (75.6 MHz, CDCl3): d 14.2 (Me), 50.4 (CHAr0), 54.0 (CH2N),
55.1 (OMe), 55.5 (OMe), 56.0 (OMe), 62.3 (OCH2), 95.8 (ArC6),
100.2 (ArC8), 110.1 (ArC), 114.0 (ArC30, ArC50), 129.4 (ArC20,
ArC60), 129.6 (ArC10), 147.1 (ArC), 153.9 (COO), 158.6 (ArC40),
162.5 (ArC5), 164.1 (ArC7), 192.6 (C@O); HRMS (ESI) m/z Calcd
for C21H24NO6 (M+H)+ 386.1604. Found 386.1592; Anal. Calcd for
C
20H24NO6 (M + H)+ 374.1604. Found 374.1591.
6.4.25. Ethyl 3-(4-bromophenyl)-5,7-dimethoxy-4-oxo-3,4-
dihydroquinoline-1(2H)-carboxylate (12a)
White solid (1.2 g, 63.5%). Mp 136–138 °C; UV (MeOH): kmax
202 (
mmax 3358, 2934, 1699, 1662, 1597, 1568, 1453, 1373, 1298,
1261, 1212, 1046, 1010, 951, 821, 766, 718, 669 cmꢂ1 1H NMR
e
39036 cmꢂ1 Mꢂ1), 230 (42813), 294 (25792) nm; IR (KBr):
;
(300 MHz, CDCl3): d 1.18 (t, J = 6.0 Hz, 3H, CH3CH2), 3.79 (dd,
J = 6.0, 9.0 Hz, 1H, H3), 3.87 (s, 3H, OMe), 3.89 (s, 3H, OMe),
4.11–4.18 (m, 3H, CH2CH3, H2a), 4.34 (dd, J = 6.0, 15.0 Hz, 1H,
H2b), 6.29 (d, J = 3.0 Hz, 1H, ArH6), 6.94 (d, J = 3.0 Hz, 1H, ArH8),
C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.41; H, 6.02;
N, 3.68.

S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
113
6.4.29. Ethyl 5,7-dimethoxy-4-oxo-3-phenyl-3,4-dihydroquinoli-
ne-1(2H)-carboxylate (12e)
(ArC10, ArC40), 155.2 (ArC), 165.7 (ArC5, ArC7), 191.4 (C@O); HRMS
(ESI) m/z Calcd for C18H20NO3 (M+H)+ 298.1443. Found 298.1434;
Anal. Calcd for C18H19NO3. 0.25MeOH: C, 71.78; H, 6.60; N, 4.59.
Found: C, 71.88; H, 6.45; N, 4.60.
Colourless oil (1.2 g, 63%); UV (MeOH): kmax 203
(e
25587 cmꢂ1 Mꢂ1), 238 (25694), 294 (17936) nm; IR (KBr): mmax
2935, 1707, 1669, 1597, 1568, 1453, 1245, 1156, 1094, 1044,
829, 757, 699 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
1.08 (t,
6.4.33. 5,7-Dimethoxy-3-(4-methoxyphenyl)-2,3-
dihydroquinolin-4(1H)-one (13d)
J = 6.0 Hz, 3H, CH3CH2), 3.77 (dd, J = 6.0, 9.0 Hz, 1H, H3), 3.80 (s,
3H, OMe), 3.82 (s, 3H, OMe), 4.00–4.15 (m, 3H, CH2CH3, H2a),
4.27 (dd, J = 6.0, 15.0 Hz, 1H, H2b), 6.23 (d, J = 3.0 Hz, 1H, ArH6),
6.88 (d, J = 3.0 Hz, 1H, ArH8), 7.08–7.22 (m, 5H, Ph); 13C NMR
(75.6 MHz, CDCl3): d 14.7 (Me), 50.9 (CHAr0), 55.3 (CH2N), 56.0
(OMe), 56.5 (OMe), 62.8 (OCH2), 96.3 (ArC6), 100.8 (ArC8), 110.7
(ArC), 127.6 (ArC30, ArC50), 128.9 (ArC20, ArC60), 129.0 (ArC10,
ArC40), 147.7 (ArC), 154.4 (COO), 163.0 (ArC5), 164.7 (ArC7),
White crystals (0.6 g, 76.5%). Mp 150–152 °C; UV (MeOH): kmax
203 (e
26296 cmꢂ1 Mꢂ1), 221 (28718), 245 (26837), 290 (14900),
358 (4102) nm; IR (KBr): mmax 3269, 2971, 2941, 1600, 1578,
1507, 1437, 1382, 1348, 1206, 1103, 1031, 983, 818, 724,
687 cmꢂ1 1H NMR (300 MHz, CDCl3): d 3.59–3.71 (m, 3H, H2,
;
H3), 3.75 (s, 6H, OMe), 3.80 (s, 3H, OMe), 4.75 (br s, 1H, NH),
5.69 (d, J = 3.0 Hz, 1H, ArH6), 5.79 (d, J = 3.0 Hz, 1H, ArH8), 6.81
(d, J = 9.0 Hz, 2H, ArH20, ArH60), 7.17 (d, J = 9.0 Hz, 2H, ArH30,
193.0 (C@O); HRMS (ESI) m/z Calcd for
356.1498. Found 356.1485.
C
20H22NO5 (M+H)+
13
ArH50); C NMR (75.6 MHz, CDCl3): d 47.5 (CH2N), 52.1 (CHAr0),
55.1 (2 ꢁ OMe), 55.7 (OMe), 89.5 (ArC8), 90.2 (ArC6), 104.1 (ArC),
113.5 (ArC30), 113.7 (ArC50), 129.3 (ArC20, ArC60), 130.0 (ArC10),
154.8 (ArC), 163.4 (ArC40), 165.2 (ArC5, ArC7), 191.0 (C@O); HRMS
(ESI) m/z Calcd for C18H20NO4 (M + H)+ 314.1392. Found 314.1381;
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.82; H, 6.16; N, 4.50.
6.4.30. 3-(4-Bromophenyl)-5,7-dimethoxy-2,3-dihydroquinolin-
4(1H)-one (13a)
White crystals (0.65 g, 79.5%). Mp 212–214 °C; UV (MeOH):
kmax 203 (
e
32729 cmꢂ1 Mꢂ1), 220 (34958), 244 (31058), 291
(18105), 348 (3899) nm; IR (KBr): mmax 3282, 2937, 2819, 1607,
1575, 1524, 1484, 1435, 1382, 1346, 1264, 1207, 1147, 1106,
1071, 1008, 983, 939, 765, 687 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
6.4.34. 5,7-Dimethoxy-3-phenyl-2,3-dihydroquinolin-4(1H)-one
(13e)
d 3.61–3.71 (m, 3H, H2, H3), 3.78 (s, 3H, OMe), 3.82 (s, 3H, OMe),
4.66 (br s, 1H, NH), 5.70 (d, J = 3.0 Hz, 1H, ArH6), 5.81 (d,
J = 3.0 Hz, 1H, ArH8), 7.13 (d, J = 9.0 Hz, 2H, ArH20, ArH60), 7.40
(d, J = 9.0 Hz, 2H, ArH30, ArH50); 13C NMR (75.6 MHz, CDCl3): d
47.2 (CH2N), 52.3 (CHAr0), 55.2 (OMe), 55.7 (OMe), 89.7 (ArC6),
90.3 (ArC8), 104.0 (ArC), 120.9 (ArC40), 130.1 (ArC20, ArC60), 131.4
(ArC30, ArC50), 136.9 (ArC10), 154.6 (ArC), 163.5 (ArC5), 165.4
(ArC7), 190.0 (C@O); HRMS (ESI) m/z Calcd for C17H17BrNO3 (M +
H)+ 362.0392. Found 362.0382; Anal. Calcd for C17H16BrNO3: C,
56.37; H, 4.45; N, 3.87. Found: C, 56.27; H, 4.34; N, 3.82.
White crystals (0.8 g, 85%). Mp 160–162 °C; UV (MeOH): kmax
203
(e
37345 cmꢂ1 Mꢂ1), 244 (31681), 291 (19115), 348
(4070) nm; IR (KBr): mmax 3277, 3056, 2970, 1629, 1607, 1579,
1525, 1436, 1262, 1242, 1152, 1107, 985, 936, 852, 817, 782,
696 cmꢂ1 1H NMR (300 MHz, CDCl3): d 3.60–3.70 (m, 3H, H2,
;
H3), 3.72 (s, 3H, OMe), 3.76 (s, 3H, OMe), 4.55 (br s, 1H, NH),
5.64 (d, J = 3.0 Hz, 1H, ArH6), 5.75 (d, J = 3.0 Hz, 1H, ArH8),
7.14–7.22 (m, 5H, Ph); 13C NMR (75.6 MHz, CDCl3):
d 46.2
(CH2N), 52.3 (CHAr0), 55.4 (OMe), 55.6 (OMe), 88.7 (ArC8), 90.3
(ArC6), 103.2 (ArC), 126.4 (ArC30), 126.9 (ArC50), 128.2 (ArC20),
128.5 (ArC60), 128.6 (ArC40), 139.3 (ArC10), 155.7 (ArC), 163.1 (ArC),
164.9 (ArC), 189.5 (C@O); HRMS (ESI) m/z Calcd for C17H18NO3
(M+H)+ 284.1287. Found 284.1277; Anal. Calcd for C17H17NO3: C,
72.07; H, 6.05; N, 4.94. Found: C, 71.95; H, 6.12; N, 5.00.
6.4.31. 3-(4-Fluorophenyl)-5,7-dimethoxy-2,3-dihydroquinolin-
4(1H)-one (13b)
White crystals (1.3 g, 80%). Mp 196–198 °C; UV (MeOH): kmax
204
(e
27980 cmꢂ1 Mꢂ1), 244 (28732), 291 (17440), 348
(4140) nm; IR (KBr): mmax 3293, 2965, 2841, 1595, 1523, 1505,
1438, 1380, 1348, 1265, 1206, 1149, 1108, 1063, 985, 833, 790,
6.4.35. 3-(4-Bromophenyl)-5,7-dihydroxy-2,3-dihydroquinolin-
4(1H)-one (14a)
681 cmꢂ1 1H NMR (300 MHz, CDCl3): d 3.58–3.75 (m, 3H, H2,
;
H3), 3.78 (s, 3H, OMe), 3.82 (s, 3H, OMe), 4.68 (br s, 1H, NH),
5.71 (d, J = 3.0 Hz, 1H, ArH6), 5.81 (d, J = 3.0 Hz, 1H, ArH8),
6.94–7.00 (m, 2H, ArH20, ArH60), 7.20-7.26 (m, 2H, ArH30, ArH50);
13C NMR (75.6 MHz, CDCl3): d 47.5 (NCH2), 52.2 (CHAr0), 55.2
(OMe), 55.7 (OMe), 89.7 (ArC6), 90.2 (ArC8), 104.1 (ArC), 115.0
(ArC30), 115.2 (ArC50), 129.9 (ArC20), 130.0 (ArC60), 133.6 (ArC10),
154.7 (ArC), 160.2 (ArC40), 163.5 (ArC5), 165.3 (ArC7), 190.4
(C@O); HRMS (ESI) m/z Calcd for C17H17FNO3 (M+H)+ 302.1192.
Found 302.1181; Anal. Calcd for C17H16FNO3: C, 67.76; H, 5.35;
N, 4.65. Found: C, 67.71; H, 5.54; N, 4.62.
Yellow solid (0.1 g, 48%). Mp 164–166 °C; UV (MeOH): kmax 203
(e
34785 cmꢂ1 Mꢂ1), 244 (25000), 299 (13365) nm; IR (KBr): mmax
3401, 3316, 2920, 2855, 1635, 1590, 1515, 1440, 1379, 1263,
1239, 1157, 1126, 1093, 1040, 858, 817, 807, 757, 720, 656 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 3.62–3.86 (m, 3H, H2, H3), 5.33 (s,
1H, OH), 5.64 (d, J = 2.1 Hz, 1H, ArH6), 5.76 (d, J = 2.1 Hz, 1H,
ArH8), 7.18 (d, J = 8.1 Hz, 2H, ArH20, ArH60), 7.50 (d, J = 8.4 Hz,
2H, ArH30, ArH50), 12.56 (s, 1H, OH); 13C NMR (75.6 MHz, CDCl3):
d 46.8 (CH2N), 50.5 (CHAr0), 91.1 (ArC8), 92.2 (ArC6), 101.0 (ArC),
120.5 (ArC40), 130.4 (ArC30), 130.7 (ArC50), 130.9 (ArC20), 131.3
(ArC60), 137.6 (ArC10), 154.7 (ArC), 165.7 (ArC5), 166.0 (ArC7),
196.4 (C@O); HRMS (ESI) m/z Calcd for C15H13BrNO3 (M+H)+
334.0079. Found 334.0069.
6.4.32. 5,7-Dimethoxy-3-p-tolyl-2,3-dihydroquinolin-4(1H)-one
(13c)
White crystals (0.7 g, 85%). Mp 150–152 °C; UV (MeOH): kmax
218
(
e
30778 cmꢂ1 Mꢂ1), 244 (27803), 292 (16933), 368
6.4.36. 5,7-dihydroxy-3-(p-tolyl)-2,3-dihydroquinolin-4(1H)-
one (14c)
(4118) nm; IR (KBr): mmax 3286, 3000, 2929, 2821, 1629, 1607,
1530, 1439, 1383, 1348, 1261, 1206, 1154, 1106, 1096, 984, 813,
Yellow solid (0.1 g, 45.5%). Mp 184–186 °C; UV (MeOH): kmax
782, 676 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 2.23 (s, 3H, MeAr0),
299 (
2919, 1638, 1588, 1514, 1445, 1379, 1348, 1264, 1158, 1127,
1040, 814 cmꢂ1 1H NMR (300 MHz, CDCl3): d 2.32 (s, 3H, MeAr0),
e
24899 cmꢂ1 Mꢂ1), 374 (2288) nm; IR (KBr): mmax 3323,
3.62–3.68 (m, 3H, H2, H3), 3.71 (s, 3H, OMe), 3.76 (s, 3H, OMe),
4.53 (br s, 1H, NH), 5.63 (d, J = 3.0 Hz, 1H, ArH6), 5.74 (d,
J = 3.0 Hz, 1H, ArH8), 7.01–7.10 (m, 4H, ArH20, ArH30, ArH40, ArH60);
13C NMR (75.6 MHz, CDCl3): d 21.5 (MeAr0), 48.0 (CH2N), 53.0
(CHAr0), 55.6 (OMe), 56.2 (OMe), 90.1 (ArC8), 90.7 (ArC6), 104.2
(ArC), 126.2 (ArC30), 128.7 (ArC50), 129.4 (ArC20, ArC60), 129.5
;
3.63–3.81 (m, 3H, H2, H3), 4.61 (br s, 1H, NH), 5.58 (d, J = 3.0 Hz,
1H, ArH6), 5.72 (d, J = 3.0 Hz, 1H, ArH8), 7.15–7.23 (m, 5H, ArH20,
ArH30, ArH50, ArH60, OH), 12.68 (s, 1H, OH); 13C NMR (75.6 MHz,
CDCl3): d 21.1 (Me), 47.9 (CH2N), 51.2 (CHAr0), 91.6 (ArC8), 93.5

114
S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
(ArC6), 102.0 (ArC), 128.4 (ArC20), 128.7 (ArC60), 129.1 (ArC30),
129.4 (ArC50), 133.9 (ArC10), 137.3 (ArC40), 153.9 (ArC), 164.7
(ArC5), 165.5 (ArC7), 197.4 (C@O); HRMS (ESI) m/z Calcd for
6.4.41. 5-Hydroxy-7-methoxy-3-(4-methoxyphenyl)quinolin-
4(1H)-one (15d)
Yellow solid (0.75 g, 81.5%). Mp 232–234 °C19, 236–237 °C; 1H
NMR (300 MHz, DMSO-d6): d 3.78 (s, 3H, OMe), 3.81 (s, 3H,
OMe), 6.18 (d, J = 2.2 Hz, 1H, ArH6), 6.42 (d, J = 2.2 Hz, 1H, ArH8),
6.96 (d, J = 8.7 Hz, 2H, ArH20, ArH60), 7.61 (d, J = 9.0 Hz, 2H, ArH30,
ArH50), 8.07 (s, 1H, H2), 12.23 (s, 1H, NH), 14.98 (s, 1H, OH).
C
16H15NO3Na (M+Na)+ 292.0950. Found 292.0942.
6.4.37. 5,7-Dihydroxy-3-phenyl-2,3-dihydroquinolin-4(1H)-
one(14e)
Yellow solid (0.1 g, 44.5%). Mp 198–200 °C; UV (MeOH): kmax
205 (
368 (6002) nm; IR (KBr): mmax 3415, 3393, 3298, 1633, 1592,
1513, 1263, 1175, 855, 802, 695 cmꢂ1 1H NMR (300 MHz,
e
43422 cmꢂ1 Mꢂ1), 225 (35632), 242 (36398), 298 (26947),
6.4.42. 5-Hydroxy-7-methoxy-3-phenylquinolin-4(1H)-one
(15e)
;
Yellow solid (0.8 g, 84%). Mp 240–242 °C; UV (1% CF3COOH/
DMSO-d6): d 3.50–3.55 (m, 2H, H2), 3.80 (dd, J = 6.0, 9.0 Hz, 1H,
H3), 5.45 (d, J = 3.0 Hz, 1H, ArH6), 5.61 (d, J = 3.0 Hz, 1H, ArH8),
7.07 (br s, 1H, NH), 7.21–7.33 (m, 5H, Ph), 10.23 (s, 1H, OH),
12.64 (s, 1H, OH); 13C NMR (75.6 MHz, DMSO-d6): d 46.6 (CH2N),
50.5 (CHAr0), 91.1 (ArC), 92.0 (ArC), 100.7 (ArC), 127.3 (ArC40),
128.7 (ArC30, ArC50), 128.9 (ArC20, ArC60), 138.4 (ArC10), 155.0
(ArC), 165.0 (ArC5), 166.4 (ArC7), 197.0 (C@O); HRMS (ESI) m/z
Calcd for C15H14NO3 (M+H)+ 256.0974. Found 256.0964.
MeOH): kmax 203 (e
44866 cmꢂ1 Mꢂ1), 230 (38877), 265 (54973),
316 (13743) nm; IR (KBr): mmax 3261, 3163, 3113, 2948, 2919,
2849, 1655, 1558, 1443, 1271, 1202, 1160, 1072, 1032, 795,
702 cmꢂ1 1H NMR (300 MHz, DMSO-d6): d 3.88 (s, 3H, OMe),
;
6.26 (d, J = 2.1 Hz, 1H, ArH6), 6.50 (d, J = 2.4 Hz, 1H, ArH8),
7.36–7.49 (m, 3H, Ph), 7.72–7.75 (m, 2H, Ph), 8.20 (s, 1H, H2),
12.33 (br s, 1H, NH), 14.88 (s, 1H, OH); 13C NMR (75.6 MHz,
DMSO-d6): d 55.9 (OMe), 90.2 (ArC6), 96.9 (ArC8), 111.9 (ArC),
118.6 (ArC3), 127.1 (ArC40), 128.4 (ArC20, ArC60), 129.0 (ArC30,
ArC50), 135.2 (ArC2), 139.8 (ArC10), 142.0 (ArC), 163.5 (ArC5),
164.0 (ArC7), 179.4 (C@O); HRMS (ESI) m/z Calcd for C16H14NO3
(M+H)+ 268.0974. Found 268.0965.
6.4.38. 3-(4-Bromophenyl)-5-hydroxy-7-methoxyquinolin-
4(1H)-one (15a)
Yellow solid (0.15 g, 89.5%). Mp > 300 °C; UV (1% CF3COOH/
MeOH): kmax 202 (
319 (14376) nm; IR (KBr): mmax 3479, 3211, 3111, 2924, 1643,
1587, 1562, 1200, 1157, 1075, 1062, 718, 704, 692 cmꢂ1 1H
NMR (300 MHz, DMSO-d6): 3.82 (s, 3H, OMe), 6.21 (d,
e
37593 cmꢂ1 Mꢂ1), 233 (38445), 269 (52183),
6.4.43. 3-(3-Bromophenyl)-5-hydroxy-7-methoxyquinolin-
4(1H)-one (15f)
;
d
Yellow solid (0.2 g, 79.5%). Mp 254–256 °C; UV (1% CF3COOH/
J = 1.9 Hz, 1H, ArH6), 6.45 (d, J = 1.9 Hz, 1H, ArH8), 7.58 (d,
J = 8.7 Hz, 2H, ArH20, ArH60), 7.80 (d, J = 8.3 Hz, 2H, ArH30, ArH50),
8.19 (s, 1H, H2), 14.78 (s, 1H, OH); 13C NMR (75.6 MHz, DMSO-
d6): d 55.8 (OMe), 90.2 (ArC6), 97.0 (ArC8), 108.6 (ArC), 117.1
(ArC), 120.1 (Ar0C4), 130.8 (ArC20, ArC60), 131.2 (ArC30, ArC50),
134.2 (ArC2), 139.7 (ArC10), 141.8 (ArC), 163.3 (ArC5), 164.0
(ArC7), 179.1 (C@O); HRMS (ESI) m/z Calcd for C16H13BrNO3
(M+H)+ 346.0079. Found 346.0067.
MeOH): kmax 202 (
320 (20581) nm; IR (KBr): mmax 3457, 3211, 3092, 2963, 1656,
1555, 1439, 1281, 1200, 1162, 1062, 1027, 774, 713, 686 cmꢂ1
e
59302 cmꢂ1 Mꢂ1), 234 (54534), 269 (65697),
;
1H NMR (300 MHz, DMSO-d6): d 3.87 (s, 3H, OMe), 6.28 (d,
J = 2.3 Hz, 1H, ArH6), 6.51 (d, J = 2.3 Hz, 1H, ArH8), 7.42 (t,
J = 7.5 Hz, 1H, ArH60), 7.53 (m, 1H, ArH50), 7.74 (m, 1H, ArH40),
8.00 (t, J = 1.9 Hz, 1H, ArH20), 8.28 (s, 1H, H2), 14.80 (s, 1H, OH);
13C NMR (75.6 MHz, DMSO-d6): d 55.8 (OMe), 90.4 (ArC6), 97.1
(ArC8), 108.6 (ArC), 116.7 (ArC), 121.6 (ArC30) 127.6 (ArC60),
129.7 (ArC50), 130.5 (ArC20), 131.2 (ArC40), 137.5 (ArC10), 140.2
(ArC2), 141.9 (ArC), 163.3 (ArC5), 164.0 (ArC7), 179.1 (C@O); HRMS
(ESI) m/z Calcd for C16H13BrNO3 (M+H)+ 346.0079. Found 346.0073.
6.4.39. 3-(4-Fluorophenyl)-5-hydroxy-7-methoxyquinolin-
4(1H)-one (15b)
Yellow solid (0.15 g, 86%). Mp 240–242 °C; UV (MeOH): kmax
201 (
mmax 3209, 3092, 2960, 1661, 1554, 1512, 1447, 1271, 1202,
1165, 1087, 1068, 795, 780, 718, 657 cmꢂ1 1H NMR (300 MHz,
e
27213 cmꢂ1 Mꢂ1), 264 (53891), 316 (13012) nm; IR (KBr):
6.4.44. 3-(4-Bromophenyl)-5-hydroxy-7-methoxy-2,3-
dihydroquinolin-4(1H)-one (16a)
;
DMSO-d6): d 3.88 (s, 3H, OMe), 6.25 (d, J = 2.3 Hz, 1H, ArH6), 6.50
(d, J = 2.3 Hz, ArH8), 7.28 (m, 2H, ArH30, ArH50), 7.77 (m, 2H, ArH20,
ArH60), 8.21 (s, 1H, H2), 12.37 (br s, 1H, NH), 14.90 (s, 1H, OH); 13C
NMR (75.6 MHz, DMSO-d6): d 55.8 (OMe), 90.1 (ArC6), 96.9 (ArC8),
108.7 (ArC), 115.0 (ArC30), 115.2 (ArC50), 117.5 (ArC), 130.7 (ArC20,
ArC60), 130.8 (ArC), 139.6 (ArC2), 141.9 (ArC10), 163.3 (ArC5, ArC40),
163.9 (ArC7), 179.3 (C@O); HRMS (ESI) m/z Calcd for C16H13FNO3
(M+H)+ 286.0879. Found 286.0870.
Yellow solid (0.2 g, 73.5%). Mp 142–144 °C; UV (MeOH): kmax
203 (e
29213 cmꢂ1 Mꢂ1), 225 (27959), 242 (27437), 297 (17131),
368 (3690) nm; IR (KBr): mmax 3360, 2838, 1633, 1568, 1511,
1487, 1370, 1347, 1291, 1208, 1190, 1096, 1011, 821, 795, 755,
663 cmꢂ1 1H NMR (300 MHz, CDCl3): d 3.62–3.73 (m, 2H, CH2N),
;
3.78 (s, 3H, OMe), 3.80 (dd, J = 3.0 Hz, 9.0 Hz, 1H, CHAr0), 4.59 (br
s, 1H, NH), 5.65 (d, J = 3.0 Hz, 1H, ArH6), 5.84 (d, J = 3.0 Hz, 1H,
ArH8), 7.14 (d, J = 9.0 Hz, 2H, ArH20, ArH60), 7.46 (d, J = 9.0 Hz,
2H, ArH30, ArH50), 12.51 (s, 1H, OH); 13C NMR (75.6 MHz, CDCl3):
d 47.6 (CH2N), 51.0 (CHAr0), 55.3 (OMe), 90.4 (ArC8), 91.8 (ArC6),
102.0 (ArC), 121.5 (ArC40), 130.2 (ArC20, ArC60), 131.8 (ArC30,
ArC50), 135.9 (ArC40), 153.2 (ArC), 165.5 (ArC5), 167.7 (ArC7),
196.3 (C@O); HRMS (ESI) m/z Calcd for C16H14BrNO3Na (M+Na)+
370.0055. Found 370.0043.
6.4.40. 5-Hydroxy-7-methoxy-3-(p-tolyl)quinolin-4(1H)-one
(15c)
Yellow solid (0.8 g, 86%). Mp > 300 °C; UV (1% CF3COOH/
MeOH): kmax 266 (
mmax 3444, 2919, 1660, 1552, 1446, 1291, 1197, 1158, 1071,
1028, 774, 701, 658 cmꢂ1 1H NMR (300 MHz, DMSO-d6): d 2.35
e
86250 cmꢂ1 Mꢂ1), 316 (13125) nm; IR (KBr):
;
(s, 3H, MeAr0), 3.84 (s, 3H, OMe), 6.21 (d, J = 3.0 Hz, 1H, ArH6),
6.46 (d, J = 3.0 Hz, 1H, ArH8), 7.22 (d, J = 9.0 Hz, 2H, ArH30, ArH50),
7.59 (d, J = 9.0 Hz, 2H, Ar0H2, ArH60), 8.12 (s, 1H, H2), 12.27 (br s,
1H, NH), 14.99 (s, 1H, OH); 13C NMR (75.6 MHz, DMSO-d6): d
21.1 (MeAr0), 55.7 (OMe), 90.0 (ArC6), 96.8 (ArC8), 108.7 (ArC),
118.5 (ArC), 128.7 (ArC30, ArC50), 128.9 (ArC20, ArC60), 132.0
(ArC10), 136.2 (ArC2), 139.2 (ArC40), 141.8 (ArC), 163.4 (ArC5),
163.8 (ArC7), 179.4 (C@O); HRMS (ESI) m/z Calcd for C17H16NO3
(M+H)+ 282.1130. Found 282.1122.
6.4.45. 5-Hydroxy-7-methoxy-3-(p-tolyl)-2,3-dihydroquinolin-
4(1H)-one (16c)
Yellow solid (0.2 g, 68%). Mp 134–136 °C; UV (MeOH): kmax 297
(e
14979 cmꢂ1 Mꢂ1) nm; IR (KBr): mmax 3348, 2975, 2925, 2838,
1638, 1567, 1514, 1377, 1348, 1290, 1156, 1094, 1030, 852, 817,
759 cmꢂ1 1H NMR (300 MHz, CDCl3): d 2.26 (s, 3H, MeAr0),
;
3.59–3.64 (m, 2H, H2), 3.72 (s, 3H, OMe), 3.74 (dd, J = 6.0, 9.0 Hz,
1H, H3), 4.47 (br s, 1H, NH), 5.57 (d, J = 3.0 Hz, 1H, ArH6), 5.76
(d, J = 3.0 Hz, 1H, ArH8), 7.08 (s, 4H, ArH20, ArH30, ArH50, ArH60)

S. Rajput et al. / Bioorg. Med. Chem. 22 (2014) 105–115
115
12.56 (s, 1H, OH); 13C NMR (75.6 MHz, CDCl3): d 21.1 (Me), 48.0
Acknowledgments
(CH2N), 51.3 (CHAr0), 55.4 (OMe), 90.4 (ArC8), 91.7 (ArC6), 102.3
(ArC), 128.4 (ArC20, ArC60), 129.4 (ArC30), 129.5 (ArC50), 133.9
(ArC10), 137.3 (ArC40), 153.3 (ArC), 165.6 (ArC), 167.5 (ArC), 197.4
We thank the Australian Research Council for financial support.
We also thank Dr. Mohan Bhadbhade for single crystal X-ray study,
NMR and BMSF facility, University of New South Wales.
(C@O); HRMS (ESI) m/z Calcd for
C
17H17NO3Na (M+Na)+
306.1106. Found 306.1098.
References and notes
6.4.46. 5-Hydroxy-7-methoxy-3-(4-methoxyphenyl)-2,3-dihydr-
oquinolin-4(1H)-one (16d)
1. Patel, R. P.; Boersma, B. J.; Crawford, J. H.; Hogg, N.; Kirk, M.; Kalyanaraman, B.;
Parks, D. A.; Barnes, S.; Darley-Usmar, V. Free Radical Biol. Med. 2001, 31, 1570.
2. Wang, X.; Chen, S.; Ma, G.; Ye, M.; Lu, G. NeuroReport 2005, 16, 267.
3. Park, J. S.; Woo, M. S.; Kim, D. H.; Hyun, J. W.; Kim, W. K.; Lee, J. C.; Kim, H. S. J.
Pharmacol. Exp. Ther. 2007, 320, 1237.
4. Chen, H. Q.; Jin, Z. Y.; Li, G. H. Neurosci. Lett. 2007, 417, 112.
5. Li, L.; Modolo, L. V.; Escamilla-Trevino, L. L.; Achnine, L.; Dixon, R. A.; Wang, X.-
Q. J. Mol. Biol. 2007, 370, 951.
Yellow solid (0.2 g, 78%). Mp 144–146 °C; UV (MeOH): kmax 201
(e
30988 cmꢂ1 Mꢂ1), 225 (31736), 296 (18113), 368 (2994) nm; IR
(KBr): mmax 3370, 2978, 2938, 2842, 1640, 1597, 1511, 1380, 1236,
1157, 1017, 816, 796, 755, 655 cmꢂ1; 1H NMR (300 MHz, CDCl3): d
3.64–3.70 (m, 2H, H2), 3.78 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.80
(dd, J = 6.0, 9.0 Hz, 1H, H3), 4.56 (br s, 1H, NH), 5.64 (d, J = 3.0 Hz,
1H, ArH6), 5.83 (d, J = 3.0 Hz, 1H, ArH8), 6.89 (d, J = 9.0 Hz, 2H,
ArH20, ArH60), 7.19 (d, J = 9.0 Hz, 2H, ArH30, ArH50), 12.63 (s, 1H,
6. Tsai, W.-J.; Hsin, C.-C. J. Nat. Prod. 1996, 59, 671.
7. Lo, F. H.; Mak, N. K.; Leung, K. N. Biomed. Pharmacother. 2007, 61, 591.
8. Birt, D. F.; Hendrich, S.; Wang, W. Pharmacol. Ther. 2001, 90, 157.
9. Siddaiah, V.; Maheswara, M.; Venkata Rao, C.; Venkateswarlu, S.; Subbaraju, G.
V. Bioorg. Med. Chem. Lett. 2007, 17, 1288.
10. Barve, V.; Ahmed, F.; Adsule, S.; Banerjee, S.; Kulkarni, S.; Katiyar, P.; Anson, C.
E.; Powell, A. K.; Padhye, S.; Sarkar, F. H. J. Med. Chem. 2006, 49, 3800.
11. Ruetten, H.; Thiemermann, C. Br. J. Pharmacol. 1997, 122, 59.
12. Yellayi, S.; Naaz, A.; Szewczykowski, M. A.; Sato, T.; Woods, J. A.; Chang, J.;
Segre, M.; Allred, C. D.; Helferich, W. G.; Cooke, P. S. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 7616.
13
OH); C NMR (75.6 MHz, CDCl3): d 47.9 (CH2N), 50.8 (CHAr0),
55.2 (OMe), 55.3 (OMe), 90.3 (ArC8), 91.6 (ArC6), 102.1 (ArC),
114.1 (ArC30, ArC50), 128.9 (ArC20, ArC60), 129.4 (ArC10), 153.2
(ArC), 158.9 (ArC40), 165.5 (ArC5), 167.5 (ArC7), 197.4 (C@O);
HRMS (ESI) m/z Calcd for C17H17NO4Na (M+Na)+ 300.1055. Found
300.1043.
13. Potter, S. M.; Baum, J. A.; Teng, H.; Stillman, R. J.; Shay, N. F.; Erdman, J. W., Jr.
Am. J. Clin. Nutr. 1998, 68, 1375S.
14. Huang, L.-J.; Hsieh, M.-C.; Teng, C.-M.; Lee, K.-H.; Kuo, S.-C. Bioorg. Med. Chem.
1998, 6, 1657.
15. Traxler, P.; Green, J.; Mett, H.; Furet, P. J. Med. Chem. 1999, 1018, 42.
16. Pike, A. C.; Brzozowsi, A. M.; Hubbard, R.; Bonn, T.; Engstrom, O. EMBO J. 1999,
18, 4618.
6.4.47. 5-Hydroxy-7-methoxy-3-phenyl-2,3-dihydroquinolin-4
(1H)-one (16e)
Yellow solid (0.2 g, 80.5%). Mp 146–148 °C; UV (MeOH): kmax
205
(3668) nm; IR (KBr): mmax 3312, 2977, 2870, 1638, 1568, 1531,
1386, 1267, 1193, 1231, 1136, 806, 756, 698 cmꢂ1 1H NMR
(e
28744 cmꢂ1 Mꢂ1), 243 (28879), 297 (18074), 368
17. Dodge, J. A. Pure Appl. Chem. 1998, 70, 1725.
18. Miksicek, R. J. Proc. Soc. Exp. Biol. Med. 1995, 208, 44.
19. Benoit, J.; Darro, F.; Guillaumet, G.; Kiss, R.; Frydman, A. 2001, WO2001012607.
20. Xiao, Z.-P.; Li, H.-Q.; Shi, L.; Lv, P.-C.; Song, Z.-C.; Zhu, H.-L. Chem. Med. Chem.
2008, 1077, 3.
21. Crystallographic data for the structure 14b reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as Supplementary
Publication No. CCDC 957122. X-ray crystal structures were obtained by
Mohan Bhadbhade, Crystallography Laboratory, UNSW Analytical Centre,
Sydney, Australia.
;
(300 MHz, CDCl3): d 3.67–3.73 (m, 2H, H2), 3.79 (s, 3H, OMe),
3.85 (dd, J = 3.0, 9.0 Hz, 1H, H3), 4.57 (br s, 1H, NH), 5.65 (d,
J = 3.0 Hz, 1H, ArH6), 5.84 (d, J = 3.0 Hz, 1H, ArH8), 7.25–7.35 (m,
5H, Ph), 12.61 (s, 1H, OH); 13C NMR (75.6 MHz, CDCl3): d 47.8
(CH2N), 51.6 (CHAr0), 55.3 (OMe), 90.3 (ArC8), 91.7 (ArC6), 102.2
(ArC), 127.5 (ArC30, ArC50), 128.4 (ArC20, ArC60), 128.6 (ArC10,
ArC40), 153.2 (ArC), 165.4 (ArC5), 167.5 (ArC7), 197.5 (C@O); HRMS
22. Yadav, J. S.; Reddy, B. V. S.; Madan, C. H.; Hashim, S. R. Chem. Lett. 2000, 738.
(ESI) m/z Calcd for
C
16H15NO3Na (M+Na)+ 292.0950. Found
292.0942.