Synthesis and antitumor activity of novel coumarin derivatives via a three-component reaction in water

Article abstract of DOI:10.1002/cjoc.201201130

An efficient synthesis of novel coumarin derivatives via a three-component condensation of 4-hydroxycoumarin, aldehydes and aromatic amines catalyzed by sulfonic acid functionalized ionic liquid L-2-(hydroxymethyl)-1-(4-sulfobutyl) pyrrolidinium hydrogen sulfate ([HYSBPI]·HSO₄) is reported. The condensed product was obtained with excellent yields in water under microwave irradiation condition. The antitumor activities of all the synthesized compounds were assessed on two different human cancer cell lines (A-549 and MCF-7), and the results showed that these compounds had weak-to-good antitumor activities and their IC₅₀ ranged from 0.05 to more than 100 μmol·L^-1. An efficient synthesis of novel coumarin derivatives via a three-component condensation of 4-hydroxycoumarin, aldehydes and aromatic amines catalyzed by sulfonic acid functionalized ionic liquid L-2-(hydroxymethyl)-1-(4-sulfobutyl) pyrrolidinium hydrogen sulfate [HYSBPI]·HSO₄ is reported. The condensed product was obtained with excellent yields in water under microwave irradiation condition. The antitumor activities of all the synthesized compounds were assessed on two different human cancer cell lines (A-549 and MCF-7), and the results showed that these compounds had weak-to-good antitumor activities and their IC₅₀ ranged from 0.05 to more than 100 μmol·L^-1.

Full text of DOI:10.1002/cjoc.201201130

FULL PAPER
DOI: 10.1002/cjoc.201201130
Synthesis and Antitumor Activity of Novel Coumarin Deriva-
tives via a Three-component Reaction in Water
Zhiwei Chen, Jianhao Bi, and Weike Su*
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College
of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
An efficient synthesis of novel coumarin derivatives via a three-component condensation of 4-hydroxycoumarin,
aldehydes and aromatic amines catalyzed by sulfonic acid functionalized ionic liquid L-2-(hydroxymethyl)-
1-(4-sulfobutyl)pyrrolidinium hydrogen sulfate ([HYSBPI]•HSO4) is reported. The condensed product was obtained
with excellent yields in water under microwave irradiation condition. The antitumor activities of all the synthesized
compounds were assessed on two different human cancer cell lines (A-549 and MCF-7), and the results showed that
these compounds had weak-to-good antitumor activities and their IC50 ranged from 0.05 to more than 100 μmol•L−1.
Keywords coumarins, multicomponent reactions, antitumor activity, sulfonic acid functionalized ionic liquids
Introduction
MCF-7) (Scheme 1).
Multicomponent reactions (MCRs) have proven to
be a valuable asset in medicinal chemistry, drug design,
and drug discovery because of their simplicity, effi-
ciency and high selectivity.[1] Besides typical multi-step
syntheses, an increasing number of bioactive small
molecules were synthesized by multicomponent reac-
tions (MCRs). Such processes in which three or more
reactants are combined together in a single reaction
flask to provide a product incorporating most of the at-
oms contained in the starting materials have the advan-
tages of the intrinsic atom economy, simpler procedures
and equipment, time and energy savings, as well as
wide environmental friendliness.[2]
Scheme 1
O
O
S
O
O
O
R
R
HN
HN
O
R
B
A
O
O
O
R
HN
O
O
R
The coumarin derivatives have interesting biological
properties, such as antiallergic, antitumor, anticoagulant,
antibacterial, and calcium channel blocking activity.[3]
In particular, 1-benzopyrano[3,4-b][1,4]benzothiazin-
6-ones A[4] have been synthesized and displayed inter-
esting antioxidant and estrogenic-like effects in HepG2
and MCF-7 cells. Chromeno[4,3-b]quinoline deriva-
tives B[5] were synthesized from 4-amino-coumarin,
aldehydes and 1,3-cyclohexadione, and showed moder-
ate cytotoxic capacity and very low calcium channel
antagonist activity. Also, coumarin derivatives have
been synthesized by three-component condensation of
4-hydroxycoumarin, aldehydes and β-naphthylamine[6]
or 2-aminoanthracene[7] or cyclic 1,3-dicarbonyl com-
pounds C.[8] Benzopyrano[3,2-c]-chromene-6,8-dione
derivatives C showed weak-to-moderate anticancer ac-
tivity against four cell lines (Raji, HeLa, LS180, and
C
4
To the best of our knowledge, the preparation of
7,12-dihydro-6H-chromeno[4,3-b]quinoline derivatives
4 via a three-component condensation of 4-hydroxy-
coumarin, aldehydes and aniline has not been reported
(Scheme 1). In continuing with our ongoing work on the
development of multicomponent reaction for the rapid
access to biologically active coumarin derivatives,[9]
herein we report the first construction of 7,12-dihydro-
6H-chromeno[4,3-b]quinolines via three-component
reaction catalyzed by a novel sulfonic acidic ionic liquid
(Scheme 2) in water. Most importantly, these previously
unreported novel series of coumarin derivatives dis-
played good antitumor activity.
*
E-mail: pharmlab@zjut.edu.cn; Tel.: 0086-0571-88320752; Fax: 0086-571-088320752
Received November 15, 2012; accepted March 10, 2013; published online April 3, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201130 or from the author.
Chin. J. Chem. 2013, 31, 507—514
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
507

Chen, Bi & Su
FULL PAPER
Scheme 2
of 4-hydroxycoumarin, benzaldehyde and aniline.
In our initial study, 4-hydroxycoumarin (1a), ben-
zaldehyde (2a) and aniline (3a) were chosen as model
reagents to optimize the reaction conditions, and the
results are summarized in Table1. Firstly, several cata-
lysts such as p-TSA, Yb(OTf)3, Zn(OTf)2, NH4OAc,
ZnCl2 and FeCl3 were examined to establish standard
reaction conditions. It was found that 54% of the target
compound 4a was obtained in refluxing CH3COOH for
8 h in the presence of catalyst p-TSA (Table1, Entry 3).
When ionic liquid [DMDBSI]•2HSO4 was used, we
were delighted to find that 83% yield of 4a was got in
CH3COOH reflux condition, compared to 15% in re-
fluxing EtOH and 56% of 4a in water reflux condition
(Table 1, Entries 7－9). Finally, the best result was
achieved when [HYSBPI]•HSO4 was used as the cata-
lyst in H2O (Table1, Entry 10). It is possible that the
novel SO3H-functionalized ionic liquid [HYSBPI]•
HSO4 has a structure of hydroxyl group in the cation,
which enhanced the solubility of reactant in water.
n
+
OH
OH
CH3CN, reflux
O
+
N
S
H
N
H
O
O
n
-
SO3
+
N
-
H2SO4
HSO
OH
4
H
C2H5OH
n
SO3H
.
.
[HYSBPl] HSO4: n = 2
[HYSPPl] HSO4: n = 1
Results and Discussion
Previously, manolov[10] has reported a two-step reac-
tion for the preparation of 3-benzylidene-4-phenyl-
iminocoumarin used 4-hydroxycoumarin, aniline and
benzaldehyde as starting materials. During our work,
the unexpected condensation product 4a was obtained in
good yields via one-pot three-component condensation
Table 1 Optimization of reaction conditions for the synthesis of 4aa
O
O
O
OO
O
O
O
CHO
NH2
+
+
+
HN
OH
OH
OH
1a
2a
3a
4a
5a
Yieldc/%
Entry
Catalyst (Loading/mol%)
Reaction condition
4a
5a
56
1
2
None
EtOH, reflux, 8 h
EtOH, reflux, 8 h
Trace
15
54
13
25
20
15
83
56
84
93
94
93
86
90
92
87
92
L-Proline (10)
62
3
p-TSA (10)
CH3COOH, reflux, 8 h
EtOH, reflux, 8 h
23
4
Yb(OTf)3 (10)
65
5
NH4OAc (10)
CH3COOH, reflux, 8 h
EtOH, reflux, 8 h
49
6
ZnCl2 (10)
46
7
[DMDBSI]•2HSO4 (10)
[DMDBSI]•2HSO4 (10)
[DMDBSI]•2HSO4 (10)
[HYSBPI]•HSO4 (10)
[HYSBPI]•HSO4 (10)
[HYSBPI]•HSO4 (20)
[HYSBPI]•HSO4 (15)
[HYSBPI]•HSO4 (10)
[HYSBPI]•CF3SO3 (10)
[HYSBPI]•CF3CO3 (10)
[HYSBPI]•CH3COO (10)
[HYSPPI]•HSO4 (10)
EtOH, reflux, 8 h
43
8
CH3COOH, reflux, 6 h
H2O, reflux, 8 h
Trace
16
9
10
11b
12b
13b
14b
15b
16b
17b
18b
H2O, reflux, 8 h
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
H2O, 150 ℃, 15 min
H2O, 150 ℃, 13 min
H2O, 150 ℃, 13 min
H2O, 140 ℃, 20 min
H2O, 150 ℃, 15 min
H2O, 150 ℃, 15 min
H2O, 150 ℃, 15 min
H2O, 150 ℃, 15 min
a 1 mmol 4-hydroxycoumarin, 1 mmol benzaldehyde, 1 mmol aniline. b Experiments were carried out in a Discover-CEM monomode
microwave apparatus. c Isolated yields based on 1a.
508
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 507—514

Synthesis and Antitumor Activity of Novel Coumarin Derivatives
Recently, organic reactions accelerated by micro-
wave irradiation have drawn attention and exhibited
several advantages over conventional heating.[11] In or-
der to improve yield and shorten the reaction time, the
microwave irradiation was exploited. The desired prod-
uct 4a was obtained with 93% isolated yield at 150 ℃
for 15 min as shown in Table 1 (Entry 11). To further
optimize the reaction conditions, the amount of [HYS-
BPI]•HSO4 required for this reaction was tested, and the
results from Table 1 (Entries 11－13) showed that 10
mol% of [HYSBPI]•HSO4 was enough to promote the
reaction efficiently. Some other TSILs with different
Table 2 Synthesis of 7,12-dihydro-6H-chromeno[4,3-b]quino-
line derivativesa
O
O
NH2
R1
O
O
R1CHO
+
+
HN
R2
R2
OH
2
3
4
1
Entry
1
R1
Ph
Ph
R2
H
Product Yieldb/%
93
94
91
90
91
90
89
92
90
90
91
92
81
83
84
80
81
93
94
92
4a
4b
4c
4d
4e
4f
2
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Cl
anions such as CF SO3− , CH3COO−, CF3COO− were
3
3
4-Cl-C6H4
undertaken and proved to be very active, leading to 87%
－92% yields of 4a (Table 1, Entries 15－17). In ad-
dition, the change of the length of alkyl sulfonic acid
(n＝1) of the TSILs also resulted in excellent yields
(Table 1, Entry 18).
The experimental procedure was remarkably simple
in view of the fact that the insoluble crude products
were isolated by simple filtration after the completion of
the reaction and recrystallized to obtain pure products,
while the catalyst [HYPPSI]•HSO4 dissolved in water
could directly be recovered and recycled. When the re-
covered catalyst was applied for six cycles of reactions,
there was almost no effect in the yields (yield: 93%,
92%, 92%, 91%, 90%, 91%).
The subsequent study was performed under the op-
timized conditions: with 10 mol% [HYSBPI]•HSO4 in
water under microwave irradiation for 15 min at 150 ℃.
As shown in Table 2, this protocol could be applied not
only to the aromatic aldehydes with either electron-
withdrawing groups (such as halide groups) or electron-
donating groups (such as alkoxyl and hydroxyl groups)
but also to the aliphatic aldehydes under the same con-
ditions. When aliphatic aldehyde such as isobutyralde-
hyde was used, the yield was slightly decreased due to
the incomplete consume of raw materials. Furthermore,
a wide range of aromatic amines including p-toluidine,
m-toluidine, p-ethoxyaniline, p-methoxyaniline, p-chlo-
roaniline and p-bromoaniline were employed success-
fully in this reaction with excellent results, and the ani-
lines with electron-donating groups generally showed
slightly higher yields than those with electron-with-
drawing groups. However, the reaction failed with
p-nitroaniline due to the strong electron withdrawing
effect.
4
4-Me-C6H4
4-F-C6H4
5
6
4-MeO-C6H4
2,4-(Cl)2-C6H3
3-MeO-C6H4
2-MeO-C6H4
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
3-MeO-4-OH-C6H3
4j
2-Cl-C6H4
1-Naphthyl
t-Bu
4k
4l
4m
4n
4o
4p
4q
4r
4s
Ph
4-Me-C6H4
4-Cl-C6H4
Ph
4-Cl
4-Cl
4-Br
Ph
4-MeO
4-EtO
3-Me
Ph
Ph
4t
a All reactions were carried out with 1 mmol 4-hydroxycoumarin,
1 mmol aldehydes, and 1 mmol aniline compounds in the pres-
b
ence of 0.1 mmol [HYSBPI]•HSO4 in H2O (2 mL). Isolated
yields based on 1a.
condition. The target compound 4a was obtained in
similar yield.
Considering that pyridine is also a core skeleton in
bioactive molecules, the aromatization of the products
4b or 4d was attempted by using 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) as the oxidant
(Scheme 4). It was fortunately found that products 6a
and 6b could be attained in high yields (96%, 95%) un-
der the reflux condition.
All the synthesized compounds were subjected to in
vitro anticancer evaluation using the MTT assay in two
human cancer cell lines representative of major cancer
sub-types-MCF-7 (breast) and A-549 (non-small cell
lung) and IC50 (μmol•L−1) are presented in Table 3.
Among the tested compounds, the products 4b, 4d, 4e,
4h, 4m, 4j, 4n, 4q, 4r had stronger inhibitory effects
than Cisplatin both in MCF-7 cells and in A-549 cells.
Based on the literature,[12] the proposed mechanism
for the synthesis of 4a is described in Scheme 3. First,
the condensation of aldehyde 2 and aromatic amine 3
gave Schiff base 7. 4-Hydroxycoumarin I with the addi-
tion of Schiff base 7 furnished the intermediate product
IV, which then formed 4 via the intermolecular cycliza-
tion and the subsequent dehydration. To test the mecha-
nism described above, the reaction of intermediate
product N-benzylideneaniline and 4-hydroxycoumarin
was carried out in water at 150 ℃ in the presence of
catalyst [HYSBPI]•HSO4 under microwave irradiation
Chin. J. Chem. 2013, 31, 507—514
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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509

Chen, Bi & Su
FULL PAPER
Scheme 3
6210 TOF LC/MS using ESI or EI (electrospray ioniza-
tion) techniques.
OH
O
R1
N
Table 3 Cytotoxic activity of synthetic compounds assessed by
the MTT reduction assay
NH2
+
O
R1CHO
2
IC50/(μmol•L−1)
R2
Entry
Compound
R2
3
7
MCF-7
30.10
0.52
A-549
9.21
OH R1
OH R1
1
2
4a
4b
4c
NH
0.14
NH
3
68.86
4.41
1.02
O
O
O
O
R2
R2
4
4d
4e
0.42
II
I
5
0.63
0.16
H2N
R2
O
O
6
4f
30.80
51.96
0.65
3.95
O
O
R1
7
4g
＞100
0.05
O
8
4h
4i
O
R1
H2N
R2
9
29.82
1.53
14.00
1.19
III
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4j
IV
4k
4l
48.13
＞100
1.11
77.01
＞100
1.04
O
O
O
O
R1
R1
-H2O
4m
4n
4o
HO
HN
HN
0.82
0.74
R2
R2
10.01
7.86
2.15
V
4
4p
4q
4r
7.46
1.69
0.91
Scheme 4
0.82
0.41
O
N
O
O
O
4s
41.41
12.53
＞100
＞100
6.38
25.66
0.32
DDQ ( 1.0 equiv.)
EtOH, reflux, 2 h
4t
HN
6a
＞100
＞100
10.32
6b
Cisplatin
4b
6a
But the compounds 4l, 6a and 6b were found to be
fairly inactive for IC50 values of higher than 100
μmol•L−1 in all cell lines. Compounds 4b, 4e, 4h, 4n, 4r
could be used as the most potent anticancer drugs for
IC50 values of lower than 1 μmol•L−1. Furthermore, IC50
(＞100 μmol•L−1) values of the oxidation products 6a
and 6b were higher than those of 4b and 4d, and the
results show that the cytotoxic activity of 7,12-dihydro-
6H-chromeno[4,3-b]quinolines was higher than that of
the oxidation products 6H-chromeno[4,3-b]quinolines.
General procedure for the synthesis of [HYSBPI]•
HSO4
To a solution of L-prolinol (20 mmol) in CH3CN (10
mL) was added 1,4-butanesultone (20 mmol) in portion
within 30 min, and then the mixture was stirred at reflux
for 5 h and then filtered, and washed with ether. Then
H2SO4 (20 mmol) was added dropwise in ethanol (3 mL)
in 30 min. The final solution was stirred at 50 ℃ for
another 1 h and evaporated under reduced pressure to
give [HYSBPI]•HSO4 as a viscous light liquid.
[HYSBPI]•HSO4: n＝2, viscous light brown liquid.
1H NMR (400 MHz, D2O) δ: 4.25－4.21 (m, 1H),
4.09－4.04 (m, 1H), 3.76－3.70 (m, 1H), 3.61－3.46
(m, 2H), 3.34－3.22 (m, 1H), 3.09－2.93 (m, 2H),
2.81－2.77 (m, 2H), 2.18－1.63 (m, 7H); 13C NMR
(100 MHz, D2O) δ: 69.5, 67.4, 65.9, 59.93, 50.6, 26.3,
24.3, 22.5, 21.9; MS (ESI) m/z: 238.1 [M−HSO4]＋.
[HYSPPI]•HSO4: n＝1, viscous light brown liquid.
1H NMR (400 MHz, D2O) δ: 4.14－4.10 (m, 1H),
3.98－3.93 (m, 1H), 3.66－3.62 (m, 1H), 3.50－3.24
(m, 3H), 3.08－2.90 (m, 2H), 2.79－2.67 (m, 2H),
Experimental
All microwave irradiation experiments were carried
out in a Discover-CEM monomode microwave appara-
tus. Melting points were determined on a Büchi B-540
capillary melting point apparatus and uncorrected. IR
spectra were recorded on an AVATAR-370, samples
1
were prepared as KBr plates. H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a Varian
400-MHz spectrometer. Mass spectra were measured
with a Thermo Finnigan LCQ-Advantage. High resolu-
tion mass spectra (HRMS) were measured on an Agilent
510
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Chin. J. Chem. 2013, 31, 507—514

Synthesis and Antitumor Activity of Novel Coumarin Derivatives
2.07－1.55 (m, 5H); 13C NMR (100 MHz, D2O) δ: 69.7,
67.5, 65.8, 55.2, 55.0, 26.2, 22.4, 21.3; MS (ESI) m/z:
224.1 [M−HSO4]＋.
J＝7.6 Hz, 1H), 7.34 (d, J＝8.0 Hz, 1H), 7.22 (d, J＝
8.0 Hz, 1H), 7.08 (d, J＝7.2 Hz, 2H), 6.98 (d, J＝7.6 Hz,
4H), 5.12 (s, 1H), 2.17 (s, 6H); 13C NMR (100 MHz,
DMSO) δ: 160.2, 152.0, 144.5, 143.3, 135.0, 132.8,
132.5, 131.5, 129.4, 128.7, 127.8, 126.8, 124.2, 123.5,
122.57, 116.7, 116.0, 113.3, 96.0, 40.7, 20.6, 20.5; IR
(KBr) ν: 3326, 1664, 1612, 1529, 1503, 1480, 1413,
1197, 1050 cm−1; MS (ESI) m/z: 353.9 [M＋H]＋.
General procedure for the synthesis of 7,12-dihydro-
6H-chromeno[4,3-b]quinoline derivatives 4a－4t
In a 10 mL pressurized vial snap-on cap, 4-hydro-
xycoumarin 1 (1 mmol), aldehyde 2 (1 mmol), aniline 3
(1 mmol) and [HYSBPI]•HSO4 (0.1 mmol) in water (2
mL) were added. The reaction mixture was irradiated
for 15 min at 150 ℃. After the completion of the reac-
tion, the reaction mixture was cooled to room tempera-
ture, filtered, and washed with water, and recrystallized
from acetic acid/ethylenedichloride chloride (12 mL,
V∶V＝1∶3) to give the corresponding compounds 4a
－4t.
7-(4-Fluorophenyl)-9-methyl-7,12-dihydro-6H-
chromeno[4,3-b]quinolin-6-one (4e): White solid, m.p.
1
293.4－294.5 ℃; H NMR (400 MHz, DMSO) δ: 9.85
(s, 1H, NH), 8.13 (dd, J1＝1.2 Hz, J2＝8.0 Hz, 1H),
7.63－7.59 (m, 1H), 7.45－7.41 (m, 1H), 7.36－7.33
(m, 1H), 7.25－7.22 (m, 3H), 7.03－6.99 (m, 3H), 5.20
(s, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO) δ:
161.3, 159.7, 158.9, 151.7, 143.0, 132.6, 132.3, 130.9,
128.9, 128.3, 128.3, 127.5, 123.4, 122.9, 122.1, 116.2,
115.7, 114.5, 114.4, 114.21, 113.0, 95.6, 19.9; IR (KBr)
ν: 3311, 1660, 1613, 1526, 1506, 1480, 1384, 1229,
1199, 1052 cm−1; MS (ESI) m/z: 358.1 [M＋H]＋.
7-Phenyl-7,12-dihydro-6H-chromeno[4,3-b]quino-
1
lin-6-one (4a): White solid, m.p.＞300 ℃; H NMR
(400 MHz, DMSO) δ: 9.88 (s, 1H, NH), 8.33 (d, J1＝
0.8 Hz, J2＝8.0 Hz, 1H), 7.61－7.65 (m, 1H), 7.44 (t,
J＝8.0 Hz, 1H), 7.35 (t, J＝8.0 Hz, 2H), 7.17－7.24 (m,
6H), 7.07－7.11 (m, 1H), 6.97 (t, J＝8.0 Hz, 1H), 5.24
(s, 1H); 13C NMR (100 MHz, DMSO) δ: 151.9, 147.1,
143.5, 135.2, 131.5, 129.2, 128.1, 127.2, 126.8, 126.0,
124.1, 123.6, 123.5, 122.5, 116.7, 116.1, 113.2, 96.1,
40.9; IR (KBr) ν: 3312, 1659, 1618, 1528, 1482, 1445,
1254, 1089 cm−1; MS (ESI) m/z: 326.2 [M＋H]＋;
HRMS (ESI) calcd for C22H16NO2 [M＋H]＋ 326.1181,
found 326.1186.
7-(4-Methoxyphenyl)-9-methyl-7,12-dihydro-6H-
chromeno[4,3-b]quinolin-6-one (4f): White solid, m.p.
1
＞300 ℃; H NMR (400 MHz, DMSO) δ: 9.80 (s, 1H,
NH), 8.30 (dd, J1＝1.2 Hz, J2＝8.0 Hz, 1H), 7.63－7.58
(m, 1H), 7.44－7.40 (m, 1H), 7.35－7.33 (m, 1H), 7.23
－7.21 (d, J＝8.8 Hz, 1H), 7.12－7.10 (m, 2H), 6.99－
6.95 (m, 2H), 6.76－6.72 (m, 2H), 5.11 (s, 1H), 3.64 (s,
3H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO) δ:
159.7, 157.1, 151.7, 142.7, 139.3, 137.1, 132.7, 132.1,
130.8, 128.9, 127.5, 127.2, 123.9, 122.9, 122.0, 116.1,
115.6, 113.3, 113.1, 96.0, 54.6, 20.0; IR (KBr) ν: 3317,
1663, 1609, 1527, 1504, 1215, 1049, 1024 cm−1; MS
(ESI) m/z: 369.9 [M＋H]＋.
9-Methyl-7-phenyl-7,12-dihydro-6H-chromeno[4,3-
1
b]quinolin-6-one (4b): White solid, m.p.＞300 ℃; H
NMR (400 MHz, DMSO) δ: 9.83 (s, 1H, NH), 8.31 (dd,
J1＝1.2 Hz, J2＝8.0 Hz, 1H), 7.59－7.63 (m, 1H), 7.40
－7.44 (m, 1H), 7.34 (d, J＝8.0 Hz, 1H), 7.16－7.24 (m,
5H), 7.06－7.10 (m, 1H), 6.98－7.00 (m, 2H), 5.17 (s,
1H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO) δ:
160.1, 151.9, 147.3, 143.4, 132.8, 132.6, 131.5, 129.4,
128.1, 127.8, 126.9, 126.0, 124.0, 123.5, 122.5, 116.7,
116.0, 113.3, 95.8, 41.1, 20.5; IR (KBr) ν: 3323, 1658,
1612, 1527, 1504, 1481, 1384, 1203, 1054 cm−1; MS
(ESI) m/z: 340.0 [M＋H]＋.
7-(2,4-Dichlorophenyl)-9-methyl-7,12-dihydro-6H-
chromeno[4,3-b]quinolin-6-one (4g): White solid, m.p.
1
＞300 ℃; H NMR (400 MHz, DMSO) δ: 9.87 (s, 1H,
NH), 8.32 (dd, J1＝1.2 Hz, J2＝8.0 Hz, 1H), 7.65－7.61
(m, 1H), 7.52 (dd, J1＝0.4 Hz, J2＝2.0 Hz, 1H), 7.46－
7.42 (m, 1H), 7.36－7.34 (m, 1H), 7.27－7.20 (m, 3H),
6.99 (dd, J1＝1.6 Hz, J2＝8.0 Hz, 1H), 6.91 (s, 1H),
5.69 (s, 1H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO)
δ: 159.8, 152.0, 144.2, 144.0, 132.7, 132.5, 131.7, 131.6,
131.2, 128.5, 128.3, 127.7, 123.5, 122.8, 122.7, 116.7,
116.4, 113.0, 94.8, 37.6, 20.5; IR (KBr) ν: 3271, 1669,
1611, 1533, 1503, 1385, 1254, 1049, 1022 cm−1; MS
(ESI) m/z: 407.9 [M＋H]＋.
7-(4-Chlorophenyl)-9-methyl-7,12-dihydro-6H-
chromeno[4,3-b]quinolin-6-one (4c): White solid, m.p.
1
297.4－298.6 ℃; H NMR (400 MHz, DMSO) δ: 9.87
(s, 1H, NH), 8.31 (d, J＝7.6 Hz, 1H), 7.61 (t, J＝7.6 Hz,
1H), 7.43 (d, J＝8.0 Hz, 1H), 7.35 (d, J＝8.4 Hz, 1H),
7.25 (s, 5H), 6.99－7.02 (m, 2H), 5.21 (s, 1H), 2.18 (s,
3H); 13C NMR (100 MHz, DMSO) δ: 160.1, 151.9,
146.2, 143.4, 132.7, 132.7, 131.5, 130.6, 129.3, 128.8,
128.0, 128.0, 123.5, 123.4, 122.6, 116.6, 116.1, 113.2,
95.4, 40.5, 20.4; IR (KBr) ν: 3322, 1658, 1611, 1529,
7-(3-Methoxyphenyl)-9-methyl-7,12-dihydro-6H-
chromeno[4,3-b]quinolin-6-one (4h): White solid, m.p.
1
280.1－281.4 ℃; H NMR (400 MHz, DMSO) δ: 9.83
(s, 1H, NH), 8.31－8.29 (m, 1H), 7.63－7.59 (m, 1H),
7.45－7.40 (m, 1H), 7.36－7.33 (m, 1H), 7.23 (d, J＝
8.0 Hz, 1H), 7.10 (t, J＝8.0 Hz, 1H), 7.02－6.98 (m,
2H), 6.79－6.74 (m, 2H), 6.69－6.66 (m, 1H), 5.14 (s,
1H), 3.65 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz,
DMSO) δ: 160.2, 158.9, 152.0, 148.8, 143.5, 132.9,
132.6, 131.5, 129.4, 129.3, 127.9, 123.9, 123.5, 122.6,
119.3, 116.7, 116.1, 113.5, 113.4, 110.7, 95.8, 54.9,
41.1, 20.5; IR (KBr) ν: 3320, 1670, 1612, 1505, 1481,
1503, 1480, 1386, 1257, 1052, 1013 cm−1; MS (ESI)
＋
m/z: 374.1 [M ＋ H] ; HRMS (ESI) calcd for
C23H17ClNO2 [M＋H]＋ 374.0948, found 374.0945.
9-Methyl-7-p-tolyl-7,12-dihydro-6H-chromeno[4,3-
b]quinolin-6-one (4d): White solid, m.p. 291.3－292.6
1
℃; H NMR (400 MHz, DMSO) δ: 9.80 (s, 1H , NH),
8.30 (d, J＝8.0 Hz, 1H), 7.61 (t, J＝8.0 Hz, 1H), 7.42 (t,
Chin. J. Chem. 2013, 31, 507—514
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
511

Chen, Bi & Su
FULL PAPER
1263, 1193, 1047 cm−1; MS (ESI) m/z: 370.0 [M＋H]＋.
7-(2-Methoxyphenyl)-9-methyl-7,12-dihydro-6H-
chromeno[4,3-b]quinolin-6-one (4i): White solid, m.p.
19.7, 17.6; IR (KBr) ν: 3340, 1660, 1612, 1529, 1503,
1481, 1196, 1041 cm−1; MS (ESI) m/z: 306.1 [M＋H]＋;
HRMS (ESI) calcd for C20H20NO2 [M＋H]＋ 306.1494,
found 306.1481.
1
292.1－293.9 ℃; H NMR (400 MHz, DMSO) δ: 9.75
(s, 1H, NH), 8.32 (dd, J1＝1.2 Hz, J2＝8.0 Hz, 1H),
7.63－7.59 (m, 1H), 7.45－7.41 (m, 1H), 7.36－7.33
(m, 1H), 7.16 (d, J＝8.0 Hz, 1H), 7.10－7.00 (m, 3H),
6.94－6.92 (m, 2H), 6.76－6.73 (m, 1H), 5.59 (m, 1H),
3.83 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO)
δ: 159.5, 155.3, 151.8, 143.7, 135.8, 132.6, 131.7, 130.8,
128.4, 127.8, 127.0, 126.7, 124.2, 122.8, 122.0, 120.1,
116.1, 115.5, 113.1, 111.6, 95.2, 55.5, 34.6, 20.1; IR
(KBr) ν: 3334, 1664, 1610, 1529, 1458, 1385, 1251,
1191, 1025 cm−1; MS (ESI) m/z: 369.9 [M＋H]＋.
9-Chloro-7-phenyl-7,12-dihydro-6H-chromeno[4,3-
b]quinolin-6-one (4n): White solid, m.p.＞300 ℃; H
1
NMR (400 MHz, DMSO) δ: 9.99 (s, 1H, NH), 8.29 (d,
J＝8.0 Hz, 1H), 7.65－7.61 (m, 1H), 7.46－7.10 (m,
10H), 5.25 (s, 1H); 13C NMR (100 MHz, DMSO) δ:
160.02, 152.02, 146.80, 143.44, 134.29, 131.75, 128.71,
128.37, 127.24, 126.95, 126.36, 126.24, 123.68, 122.61,
117.88, 116.78, 113.13, 96.12, 40.75; IR (KBr) ν: 3316,
1658, 1607, 1525, 1479, 1276, 1185, 1053 cm−1; MS
(ESI) m/z: 360.0 [M＋H]＋.
7-(4-Hydroxy-3-methoxyphenyl)-9-methyl-7,12-
dihydro-6H-chromeno[4,3-b]quinolin-6-one (4j): White
solid, m.p.＞300 ℃; H NMR (400 MHz, DMSO) δ:
9-Chloro-7-p-tolyl-7,12-dihydro-6H-chromeno[4,3-
b]quinolin-6-one (4o): White solid, m.p.＞300 ℃; H
1
1
NMR (400 MHz, DMSO) δ: 9.96 (s, 1H, NH), 8.29 (d,
J＝8.0 Hz, 1H), 765－7.61 (m, 1H), 7.44 (t, J＝7.6 Hz,
1H), 7.37－7.32 (m, 2H), 7.27 (s, 1H), 7.24－7.21 (m,
1H), 7.12 (d, J＝8.0 Hz, 2H), 7.01 (d, J＝8.0 Hz, 2H),
5.20 (s, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO)
δ: 159.5, 151.7, 143.4, 142.8, 134.9, 134.0, 131.1, 128.4,
128.2, 126.6, 126.5, 126.4, 126.0, 123.1, 122.1, 117.4,
116.2, 112.8, 96.1, 20.1; IR (KBr) ν: 3313, 1660, 1627,
1524, 1488, 1478, 1376, 1054 cm−1; MS (ESI) m/z:
374.0 [M＋H]＋; HRMS (ESI) calcd for C23H17ClNO2
[M＋H]＋ 374.0948, found 374.0939.
9.78 (s, 1H, NH), 8.73 (s, 1H), 8.29 (d, J＝8.0 Hz, 1H),
7.62－7.58 (m, 1H), 7.43－7.33 (m, 2H), 7.21 (d, J＝
8.0 Hz, 1H), 7.02－6.97 (m, 2H), 6.87 (d, J＝1.6 Hz,
1H), 6.56 (d, J＝8.0 Hz, 1H), 6.48－6.45 (m, 1H), 5.06
(s, 1H), 3.68 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz,
DMSO) δ: 159.7, 151.7, 146.7, 144.6, 142.7, 138.3,
132.7, 132.0, 130.8, 128.9, 127.2, 124.0, 122.9, 122.0,
119.1, 116.1, 115.5, 115.0, 113.1, 112.0, 96.2, 55.6,
20.0; IR (KBr) ν: 3552, 3317, 1665, 1614, 1527, 1509,
1272, 1199, 1050, 1029 cm−1; MS (ESI) m/z: 385.7 [M
＋H]＋.
9-Chloro-7-(4-chlorophenyl)-7,12-dihydro-6H-chro-
meno[4,3-b]quinolin-6-one (4p): White solid, m.p.＞
7-(2-Chlorophenyl)-9-methyl-7,12-dihydro-6H-chro-
meno[4,3-b]quinolin-6-one (4k): White solid, m.p.
1
300 ℃; H NMR (400 MHz, DMSO) δ: 10. 01 (s, 1H,
1
270.1－271.9 ℃; H NMR (400 MHz, DMSO) δ: 9.85
NH), 8.29 (s, 1H), 7.63－7.27 (m, 10H), 5.29 (s, 1H);
13C NMR (100 MHz, DMSO) δ: 159.3, 151.6, 144.9,
142.9, 133.9, 131.1, 130.5, 128.3, 128.1, 127.6, 126.8,
126.6, 125.1, 122.9, 122.0, 117.4, 116.1, 112.6, 95.4; IR
(KBr) ν: 3311, 1661, 1615, 1523, 1488, 1407, 1257,
1090, 1052 cm−1; MS (ESI) m/z: 394.0 [M＋H]＋.
(s, 1H, NH), 8.32 (dd, J1＝1.2 Hz, J2＝8.0 Hz, 1H),
7.65－7.61 (m, 1H), 7.46－7.42 (m, 1H), 7.37－7.34
(m, 2H), 7.25－7.20 (m, 2H), 7.17－7.10 (m, 2H), 6.99
－6.97 (m, 2H), 5.72 (s, 1H), 2.15 (s, 3H); 13C NMR
(100 MHz, DMSO) δ: 159.8, 152.0, 145.1, 143.9, 132.5,
131.5, 130.5, 130.0, 129.0, 128.4, 128.1, 127.6, 127.4,
123.4, 123.3, 122.6, 116.6, 116.3, 113.1, 95.2, 20.5; IR
(KBr) ν: 3316, 1706, 1667, 1610, 1529, 1501, 1419,
1254, 1049 cm−1; MS (ESI) m/z: 374.0 [M＋H]＋.
9-Bromo-7-phenyl-7,12-dihydro-6H-chromeno[4,3-
b]quinolin-6-one (4q): White solid, m.p. 281.3－283.0
1
℃; H NMR (400 MHz, DMSO) δ: 10.00 (s, 1H, NH),
8.30 (d, J＝8.0 Hz, 1H), 7.66－7.62 (m, 1H), 7.47－
7.10 (m, 9H), 6.80 (d, J＝8.4 Hz, 1H), 5.26 (s, 1H); 13C
NMR (100 MHz, DMSO) δ: 159.9, 152.0, 146.8, 143.4,
134.7, 131.7, 131.5, 130.0, 128.3, 126.9, 126.6, 126.3,
123.6, 122.6, 120.09, 118.2, 116.7, 114.8, 113.1, 96.2;
IR (KBr) ν: 3324, 1659, 1624, 1524, 1478, 1404, 1053
cm−1; MS (ESI) m/z: 404.0 [M＋H]＋.
9-Methyl-7-(naphthalen-1-yl)-7,12-dihydro-6H-chro-
meno[4,3-b]quinolin-6-one (4l): White solid, m.p.＞300
1
℃; H NMR (400 MHz, DMSO) δ: 9.89 (s, 1H, NH),
8.67 (s, 1H), 8.37 (s, 1H), 7.87－7.26 (m, 10), 6.93－
6.84 (m, 2H), 6.06 (s, 1H), 2.03 (s, 3H); IR (KBr) ν:
3276, 1653, 1609, 1527, 1501, 1392, 1199, 1055 cm−1;
MS (ESI) m/z: 389.9 [M＋H]＋; HRMS (ESI) calcd for
C27H20NO2 [M＋H]＋ 390.1494, found 390.1482.
9-Methoxy-7-phenyl-7,12-dihydro-6H-chromeno-
[4,3-b]quinolin-6-one (4r): Yellow solid, m.p. 289.2－
1
7-Isopropyl-9-methyl-7,12-dihydro-6H-chromeno-
[4,3-b]quinolin-6-one (4m): White solid, m.p. 276.4－
290.8 ℃; H NMR (400 MHz, DMSO) δ: 9.83 (s, 1H,
NH), 8.29 (d, J＝8.0 Hz, 1H), 7.61 (t, J＝7.6 Hz, 1H),
7.42 (t, J＝7.6 Hz, 1H), 7.35－7.17 (m, 6H), 7.11－
7.07 (m, 1H), 6.82－6.80 (m, 2H), 5.22 (s, 1H), 3.66 (s,
3H); 13C NMR (100 MHz, DMSO) δ: 160.2, 155.6,
151.9, 147.0, 143.3, 131.4, 128.8, 128.1, 126.8, 126.0,
125.3, 123.4, 122.5, 117.2, 116.7, 113.9, 113.3, 113.0,
94.2, 55.1, 41.2; IR (KBr) ν: 3325, 1655, 1612, 1533,
1503, 1391, 1250, 1208, 1053 cm−1; MS (ESI) m/z:
356.0 [M＋H]＋.
1
278.0 ℃; H NMR (400 MHz, DMSO) δ: 9.66 (s, 1H,
NH), 8.23 (dd, J1＝1.2 Hz, J2＝8.0 Hz, 1H), 7.63－7.58
(m, 1H), 7.42－7.35 (m, 2H), 7.17 (d, J＝8.0 Hz, 1H),
7.05－7.02 (m, 1H), 6.96 (s, 1H), 3.89 (d, J＝3.6 Hz,
1H), 2.28 (s, 3H), 0.84 (d, J＝6.8 Hz, 3H), 0.60 (d, J＝
6.8 Hz, 3H); 13C NMR (100 MHz, DMSO) δ: 160.6,
151.8, 144.5, 134.8, 131.7, 131.2, 129.5, 127.5, 123.3,
122.1, 121.0, 116.6, 115.2, 113.3, 94.6, 40.8, 35.2, 20.5,
512
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 507—514

Synthesis and Antitumor Activity of Novel Coumarin Derivatives
9-Ethoxy-7-phenyl-7,12-dihydro-6H-chromeno[4,3-
b]quinolin-6-one (4s): Yellow solid, m.p. 249.1－252.0
℃; H NMR (400 MHz, DMSO) δ: 9.81 (s, 1H, NH),
(m, 1H), 7.71－7.67 (m, 1H), 7.57－7.52 (m, 1H), 7.42
－7.36 (m, 3H), 7.33－7.30 (m, 2H), 7.18－7.16 (m,
2H), 2.53 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 159.3, 154.7, 152.3, 148.9, 148.7, 137.6,
137.0, 135.0, 134.0, 131.8, 130.8, 129.0, 128.9, 127.8,
126.6, 125.4, 124.3, 119.8, 116.7, 113.15, 22.0, 21.7; IR
(KBr) ν: 1750, 1735, 1594, 1549, 1460, 1264, 1182,
1100 cm−1; MS (ESI) m/z: 352.2 [M＋H]＋.
1
8.29 (d, J＝7.6 Hz, 1H), 7.61 (t, J＝7.6 Hz, 1H), 7.44－
7.40 (m, 1H), 7.34 (d, J＝8.0 Hz, 1H), 7.27－7.17 (m,
5H), 7.10－7.07 (m, 1H), 6.80－6.77 (m, 2H), 5.20 (s,
1H), 3.91 (q, J＝6.8 Hz, 2H), 1.25 (t, J＝6.8 Hz, 3H);
13C NMR (100 MHz, DMSO) δ: 159.7, 154.6, 151.7,
146.6, 142.9, 130.9, 128.6, 127.6, 126.4, 125.5, 125.0,
122.9, 122.0, 116.8, 116.2, 114.5, 113.5, 113.1, 94.6,
63.0, 41.0, 14.2; IR (KBr) ν: 3315, 1657, 1611, 1529,
1502, 1481, 1388, 1237, 1204, 1184, 1049 cm−1; MS
(ESI) m/z: 370.1 [M＋H]＋.
Biology cell viability assay
The cytotoxicity of compounds was assessed with a
MTT viability assay against MCF-7 cells and A-549
cells. Cells were seeded in 96-well plates at 10000 cells
per well in 100 μL of complete DMEM medium sup-
plemented with 10% FBS. After incubated at 37 ℃ in
a 5% CO2 atmosphere for 24 h, cells were treated with
the compounds at different concentration and further
incubated for 72 h. MTT stock solution was then added
to each well to achieve a final concentration of 0.5
mg/mL. Following 4 h incubation at 37 ℃, the
MTT-containing medium was carefully aspirated to
avoid disturbing any formazan crystals formed and 150
μL DMSO was added to each well. Plates were incu-
bated at room temperature for 30 min and optical densi-
ties were recorded at 570 nm using a Microplate reader
(Sunrise, Tecan Trading, Switzerland). Cell viability
was expressed as a percentage of the untreated control
cells. IC50 values were calculated with the software
Curve Expert version 1.34 for windows.
10-Methyl-7-phenyl-7,12-dihydro-6H-chromeno-
[4,3-b]quinolin-6-one (4t): White solid, m.p. 284.6－
1
286.2 ℃; H NMR (400 MHz, DMSO) δ: 9.80 (s, 1H,
NH), 8.32 (d, J＝8.0 Hz, 1H), 7.64－7.60 (m, 1H),
7.46－7.42 (m, 1H), 7.35 (d, J＝8.4 Hz, 1H), 7.21－
7.15 (m, 5H), 7.09－7.06 (m, 2H), 6.79 (d, J＝7.6 Hz,
1H), 5.18 (s, 1H), 2.26 (s, 3H); 13C NMR (100 MHz,
DMSO) δ: 160.1, 151.9, 147.3, 143.4, 136.3, 135.0,
131.5, 129.0, 128.1, 126.8, 125.9, 124.4, 123.5, 122.5,
121.3, 116.6, 116.3, 113.2, 96.2, 40.6, 20.8; IR (KBr) ν:
3322, 1667, 1617, 1533, 1502, 1413, 1211, 1049 cm−1;
MS (ESI) m/z: 340.0 [M＋H]＋; HRMS (ESI) calcd for
C23H18NO2 [M＋H]＋ 340.1338, found 340.1330.
General procedure for the synthesis of 9-methyl-
7-phenyl-6H-chromeno[4,3-b]quinolin-6-ones 6a, 6b
The mixture of 9-methyl-7-phenyl-7,12-dihydro-6H-
chromeno[4,3-b]quinolin (4b) (1 mmol) and 2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1 mmol)
in EtOH (2 mL) was stirred under reflux for 3 h. After
the completion of the oxidation reaction (monitored by
TLC), the reaction mixture was cooled to room tem-
perature and then water (50 mL) was added. The aque-
ous phase was extracted with dichloromethane (10 mL
×3), and the combined organic extracts were washed
with brine (10 mL), then dried over Na2SO4 and filtered
off. The residue was then purified by column chroma-
tography on silica to give the corresponding compound
6a. Product 6b was prepared according to the same
method of 6a.
Conclusions
In summary, we have developed an efficient, clean,
and environmentally friendly procedure to generate
7,12-dihydro-6H-chromeno[4,3-b]quinoline derivatives
via the microwave-assisted three-component condensa-
tion of 4-hydroxycoumarin, aldehydes and aromatic
amines. Moreover, the cytotoxic activities of these
compounds were evaluated in vitro on two different
cancer cell lines, and the results show that some com-
pounds exhibited excellent antitumor activities against
MCF-7 and A-549.
9-Methyl-7-phenyl-6H-chromeno[4,3-b]quinolin-6-
one (6a): White solid, m.p. 270.8－272.6 ℃; H NMR
1
Acknowledgement
(400 MHz, CDCl3) δ: 8.85 (dd, J1＝1.6 Hz, J2＝7.6 Hz,
1H), 8.16 (d, J＝8.8 Hz, 1H), 7.71－7.69 (m, 1H), 7.60
－7.52 (m, 5H), 7.43－7.39 (m, 1H), 7.33－7.27 (m,
3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 159.3,
154.6, 152.7, 149.3, 149.1, 137.2, 135.1, 131.9, 129.3,
128.2, 128.1, 128.0, 126.7, 125.6, 124.4, 120.1, 116.9,
113.3, 22.0; IR (KBr) ν: 1743, 1719, 1597, 1551, 1492,
1461, 1171, 1095 cm−1; MS (ESI) m/z: 338.2 [M＋H]＋;
HRMS (ESI) calcd for C23H16NO2 [M＋H]＋ 338.1181,
found 338.1173.
We thank the National Basic Research Program of
China (973 Program) (No. 2003CB114400) and the Na-
tional Natural Science Foundation of China (Nos.
20476098 and 20676123) for financial support.
References
[1] (a) Altug, C.; Burnett, A.; Caner, E.; DÜrÜst, Y.; Elliott, M.; Glan-
ville, R. P. J.; Guy, C.; Westwell, A. D. Tetrahedron 2011, 67, 9522;
(b) Shi, C. L.; Wang, J. X.; Chen, H.; Shi, D. Q. J. Comb. Chem.
2010, 12, 430; (c) Dandia, A.; Singh, R.; Sarawgi, P.; Khaturia, S.
Chin. J. Chem. 2006, 24, 950.
9-Methyl-7-p-tolyl-6H-chromeno[4,3-b]quinolin-6-
1
one (6b): White solid, m.p. 211.9－214.0 ℃; H NMR
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