Microwave-assisted solvent-free synthesis of substituted 2-quinolones

Article abstract of DOI:10.1016/j.tet.2006.11.030

A rapid and efficient method for the preparation of a variety of substituted 2-quinolones has been developed through the reactions of o-aminoarylketones with ester compounds containing a reactive α-methylene moiety in the presence of a catalytic amount of

Full text of DOI:10.1016/j.tet.2006.11.030

Tetrahedron 63 (2007) 892–897
Microwave-assisted solvent-free synthesis of substituted
2
-quinolones
a
Cheng-Sheng Jia, Ya-Wei Dong, Shu-Jiang Tu and Guan-Wu Wang
a
b
a,*
a
Hefei National Laboratory for Physical Sciences at Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei, Anhui 230026, PR China
Department of Chemistry and Key Laboratory of Biotechnology for Medicinal Plants, Xuzhou Normal University,
Xuzhou, Jiangsu 221116, PR China
b
Received 5 September 2006; revised 10 November 2006; accepted 13 November 2006
Available online 27 November 2006
Abstract—A rapid and efficient method for the preparation of a variety of substituted 2-quinolones has been developed through the reactions
of o-aminoarylketones with ester compounds containing a reactive a-methylene moiety in the presence of a catalytic amount of cerium chlo-
ride heptahydrate under solvent-free conditions in high yields. The rate and yield of the reaction are considerably improved by employing
microwave irradiation.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
conditions. Thus, development of simple, convenient, and
efficient methods for the preparation of these important
molecules still continues to be an interesting and attractive
area of research in synthetic organic chemistry.
The 2-quinolone (carbostyril) skeleton is an important struc-
tural moiety present in a large number of alkaloids and in
biologically active compounds. Some of them exhibit, for
example, antioxidative activity, nitric oxide production
inhibitory activity, and cytotoxicity against human tumor
cell lines. Some of them are angiotensin II receptor an-
tagonist, glycine NMDA receptor antagonists, endothelin
receptor antagonist, antiplatelet agents, and antitumor
1
–3
1
–8
1
In recent years, microwave-assisted reactions have attracted
much research interest because of the simplicity in opera-
tion, enhanced reaction rates, and great selectivity. Thus, mi-
crowave irradiation, which has become a powerful synthetic
tool for the rapid synthesis of a variety of biologically active
compounds, is used to enhance the rates of classical organic
2
3
4
5
6
7
8
agents. 2-Quinolones are also valuable intermediates in
organic synthesis. The classic methods for the synthesis
9
23
reactions.
of 2-quinolones involve acid-catalyzed cyclization of acyl-
acetoanilides (the Knorr synthesis), Heck reaction, and
1
0
11
Cerium chloride heptahydrate (CeCl $7H O) has emerged
3
2
1
2
cyclization/rearrangement. The Knorr synthesis stands
out as the most general method. The growing importance of
these compounds has led to the development of new methods
as a potentially useful Lewis acid, and imparts high regio-
and chemoselectivity in various chemical transformations.
It is also a cheap, non-toxic, and water-tolerant catalyst.
Due to its unique catalytic properties, CeCl $7H O has
1
3
for their synthesis, including solid-phase synthesis, micro-
wave-enhanced synthesis, acylation/cyclodehydration of
3
2
1
4
been extensively used for a plethora of organic transforma-
tions such as hydrooxacyclization of unsaturated 3-hydroxy
esters, Michael addition, dihydroxylation of unreactive
1
5
16
anilines and o-aminobenzophenones, palladium-cata-
lyzed carbonylative annulation of alkynes, palladium-cata-
1
7
24
25
1
8
26
27
lyzed amidation of o-carbonyl-substituted aryl halides,
palladium-catalyzed Ullmann cross-coupling of 1-bromo-
2-nitroarenes with a-halo-esters, electrocyclic reaction of
o-isocyanatostyrenes, cyclization of Baylis–Hillman ad-
olefins, and Julia olefination of cyclopropyl carbinols.
Recently, Bose and Kumar developed the CeCl $7H O-
3
2
1
9
catalyzed Friedl €a nder condensation of o-aminoarylketones
with a-methylene ketones at ambient temperature in aceto-
nitrile solutions to afford quinoline derivatives. To the
2
0
2
1
28
ducts, and cyclization of o-amino-functionalized benzoyl
acetates. However, most of these synthetic methods for
-quinolones have their own drawbacks such as difficulties
2
2
best of our knowledge, there has been no report on its use
for the 2-quinolone synthesis. Although the synthesis of
2-quinolones from o-aminoarylketone and b-ketoester or
2
2
9
in obtaining the starting materials, expensive catalysts, low
yields, prolonged reaction time, and/or drastic reaction
3
0
9a
ethyl cyanoacetate or ethyl malonyl chloride /diethyl
malonate /malonic acid has been reported, it is limited
to a substantial extent due to operational difficulties,
9
b
13b
*
Corresponding author. E-mail: gwang@ustc.edu.cn
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.030

C.-S. Jia et al. / Tetrahedron 63 (2007) 892–897
893
prolonged reaction time, and drastic reaction conditions. In
continuation of our interest in solvent-free organic reac-
Table 1. The reaction conditions and yields for the synthesis of 2-quinolone
a with different catalysts
4
3
1
tions, herein we report a simple and facile approach to
the preparation of substituted 2-quinolones using catalytic
amount of CeCl $7H O under solvent-free conditions by
Entry
Catalyst
Equivalent
Power
(W)
Yield
(%)
3
2
1
2
3
4
5
6
7
8
9
None
CuSO $5H O
—
450
450
450
450
450
450
450
450
450
450
450
450
300
600
700
51
68
42
46
25
72
58
79
85
90
90
91
62
88
85
microwave-promoted reactions of o-aminoarylketones with
various ester compounds containing a reactive a-methylene
moiety.
0.20
0.20
0.20
0.20
0.20
0.20
0.10
0.15
0.20
0.25
0.50
0.20
0.20
0.20
4
2
CuCl
CuCl
Cu(OAc)
2
$2H
2
O
2
$H O
2
NH
NH
4
Cl
OAc
4
2
. Results and discussion
CeCl
CeCl
CeCl
CeCl
CeCl
3
3
3
3
3
$7H
$7H
$7H
$7H
$7H
2
2
2
2
2
O
O
O
O
O
1
1
1
0
1
2
Recently, we reported the synthesis of substituted quinolines
through Friedl €a nder condensation by both microwave
irradiation and conventional heating under solvent-free
13
14
15
CeCl $7H O
3
2
3
1e
conditions.
Various catalysts were screened for the
CeCl
3
$7H
2
O
CeCl $7H O
0
3
2
Friedl €a nder condensation of 2-amino-4 -fluorobenzophe-
none (1a) with ethyl acetoacetate (2a) under microwave con-
ditions (300 W, 30 s, SANYO EM-350S microwave oven) in
order to find the best catalyst. The use of equivalent TsOH,
BiCl , SnCl $5H O, and FeCl $6H O afforded only quino-
F
F
3
4
2
3
2
line derivative 3a in over 80% yield after irradiation at
00 W for 30 s (Scheme 1).
CO Et
3
1e
2
3
catalyst
MW, 4 min
O
+
O
O
F
F
NH2
1a
Scheme 2.
N
H
O
TsOH
or BiCl
3
4
3
2a
4a
CO Et
2
or SnCl
or FeCl
+
CO Et
2
O
O
3
00 W, 30 s
NH2
N
appeared to be the best catalyst among the examined cata-
lysts. When the amount of CeCl $7H O was increased to
3
2
1a
2a
3a
0.2 equiv, the yield was increased up to 90% at 450 W (entry
10 vs entries 8 and 9). More than 0.2 equiv of CeCl $7H O
Scheme 1.
3
2
did not improve the yields significantly (entries 11 and 12).
The power level of 450 W was found to be the most appro-
priate one (entry 10) as lower power level gave lower yield
(entry 13) and higher power likewise resulted in a slightly
lower yield (entries 14 and 15). These optimization results
prompted us to employ 0.2 equiv of CeCl $7H O and
450 W of irradiation power for the further library synthesis
of 2-quinolones 4 from 1a or 2-aminoacetophenone (1b)
and various ester compounds containing a reactive a-meth-
ylene moiety (2a–m).
However, when equivalent CuSO $5H O, CuCl, and
4
2
CuCl $2H O were used as the catalysts, the reaction didn’t
2
2
proceed efficiently at 300 W for 30 s, and just furnished
quinoline 3a in lower yields, i.e., 35%, 50%, and 48%,
3
1e
respectively. In addition, when 0.2 equiv of the catalyst,
higher irradiation power (450 W), and longer reaction time
3
2
(
4 min) were employed for the reaction, another major prod-
uct was formed besides quinoline 3a, which was obtained in
4%, 36%, and 35% yields, respectively. This compound
2
turned out to be another type of product, i.e., 2-quinolone de-
rivative (4a) and was obtained in 68%, 42%, and 46% yields
with CuSO $5H O, CuCl, and CuCl $2H O as the catalysts,
respectively (entries 2–4 in Table 1). To achieve the highest
yield of 2-quinolone 4a from the reaction of 1a with 2a
The reaction times, yields, and melting points for the reac-
tions of o-aminoarylketones 1a and b with ester compounds
2a–m are summarized in Table 2.
4
2
2
2
(
Scheme 2), other catalysts were examined under the micro-
As shown in Table 2, the scope and generality of this proto-
col is illustrated with respect to o-aminoarylketones (1a,b)
and a wide variety of ester compounds containing a reactive
a-methylene group such as b-ketoesters (2a–e), ethyl cya-
noacetate (2f), and diethyl malonate (2g). Good to excellent
isolated yields were obtained for all of the employed sub-
strates. The reaction process was solvent-free and thus envi-
ronmentally benign, only catalytic amount of CeCl $7H O
was required, and the experimental procedure was very sim-
ple. All of the products were isolated in practically pure form
by simple filtration and washing, and, in most cases, no fur-
ther purification was needed. The current method is fairly
general, clean, rapid, and efficient, thus providing an expedi-
tious access to the preparation of various 2-quinolones 4a–m.
wave conditions to sort out which one had the most effective
catalytic activity.
Typically, a mixture of 1a (1.0 mmol) and 2a (1.0 mmol),
and the desired amount of catalysts was subjected to irradia-
tion in a SANYO EM-350S microwave oven at a given power
for 4 min. Subsequent work-up afforded 4a. The yields,
microwave irradiation powers, and amounts of the catalyst
used for the reaction of 1a with 2a are listed in Table 1.
3
2
From Table 1, it is obvious that the reaction could proceed to
a certain extent in all cases, even in the absence of catalyst.
CeCl $7H O demonstrated superior catalytic activity and
3
2

894
C.-S. Jia et al. / Tetrahedron 63 (2007) 892–897
Table 2. Reaction times, yields, and melting points of 2-quinolones 4a–m by the CeCl
3
-catalyzed reaction under microwave irradiation conditions
R1
R1
R2
O
CeCl3 7H2O (20%)
3
2
+
R CH2CO2R
450 W
NH2
N
H
O
1
2
4
F
O
1a:
1b:
NH2
O
NH2
a
Substrate 1
Substrate 2
2-Quinolone 4
Time
(min)
Yield
(%)
Mp (lit.)
ꢀ
b
c
2
3
1
2
( C)
R
R
R
R
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
CH
3
CO
Et
Et
Me
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
2a
2b
2c
2d
2e
2f
2g
2a
2b
2c
2d
2e
2f
p-FC
p-FC
6
6
6
6
6
6
6
H
4
H
4
H
4
H
4
H
4
H
4
H
4
CH
3
CO
4a
4b
4c
4d
4e
4f
4g
4h
4i
4
5
5
6
6
5
6
5
6
6
5
5
6
90
91
86
89
95
82
89
88
85
89
85
91
86
250–251
216–218
232–234
264–265 (263.0–264.5)
222–224
308–310
204–205 (204–206)
278–280
208–209
226–228
188–189
n-PrCO
i-PrCO
c-PrCO
PhCO
CN
n-PrCO
i-PrCO
c-PrCO
PhCO
CN
p-FC
p-FC
p-FC
p-FC
p-FC
3
2
9a
CO
CH
2
Et
CO
CO
CH
2
Et
3
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
CO
n-PrCO
i-PrCO
c-PrCO
PhCO
CN
n-PrCO
i-PrCO
c-PrCO
PhCO
CN
4j
4k
4l
262–264
>300 (320)
3
0
4m
a
b
c
1
13
All products were fully characterized by HRMS, H NMR, C NMR, and IR spectra.
Reaction time for each product was optimized from several comparative runs.
Isolated yield.
2
8
In order to draw a direct comparison between microwave ir-
radiation and conventional heating, a few selected reactions
were carried out at an identical temperature in a monomodal
EmrysÔ Creator microwave synthesizer as well as in a ther-
mostated oil bath. The results are collected in Table 3.
affording quinoline derivatives in high yields. However,
our solvent-free reactions of o-aminoarylketones with a-
ketoesters gave selectively quinolone derivatives under
microwave irradiation conditions or preferentially quinolone
derivatives under thermal heating conditions, reflecting
different reaction mechanism under solvent-free conditions.
ꢀ
3 2
Table 3. Synthesis of 2-quinolones 4 catalyzed by CeCl $7H O at 160 C
a
For the microwave-assisted reactions in a SANYO E-350S
microwave oven (Table 2), the required reaction time could
be even shorter than that in a monomodal EmrysÔ Creator.
One possible reason is that the microwave output power
under microwave irradiation using a monomodal EmrysÔ Creator and con-
ventional heating in a thermostated oil bath
1
2
4
Microwave irradiation
Conventional heating
b
b
Time (min)
Yield (%) Time (min)
Yield (%)
(450 W) in a SANYO E-350S microwave oven was higher
than the power (300 W) in an EmrysÔ Creator. It can be
seen from the results in Tables 2 and 3 that good yields in
a commercially available and cheap SANYO E-350S do-
mestic microwave oven could be reproduced in a monomodal
EmrysÔ Creator and thus could be transferred to a more
modern microwave synthesizer.
1
1
1
1
a
a
b
b
2a 4a
2e 4e
2a 4h
2e 4l
5
8
6
9
89
93
87
90
35
61
65
52
58
50
50
60
a
Reaction temperature was optimized based on the results in an oil bath.
Time at which the maximum yield was obtained.
b
By comparison of the data in Table 3, it is obvious that the
microwave irradiation protocol resulted in much faster reac-
tions and significantly higher yields than the thermal heating
process at the same temperature, reflecting the specific non-
thermal effects under microwave irradiation conditions.
Furthermore, under thermal heating conditions the reactions
produced quinoline derivatives as the side products besides
3. Conclusion
We have developed a novel and efficient approach for the
rapid synthesis of various substituted 2-quinolones using
CeCl $7H O as an inexpensive catalyst. The notable fea-
tures of this procedure are mild and solvent-free reaction
conditions, operational simplicity, improved yields, and en-
hanced reaction rates, which make it an attractive protocol
to synthesize polysubstituted 2-quinolones of biological
importance.
3
2
2-quinolones, thus resulting in lower yields. It should be
noted that while our work was in process Bose and Kumar
reported the CeCl $7H O-catalyzed Friedl €a nder condensa-
3
2
tion of o-aminobenzophenone with a-ketoesters in solutions

C.-S. Jia et al. / Tetrahedron 63 (2007) 892–897
895
4. Experimental
(KBr) 3406, 2968, 2875, 1713, 1646, 1606, 1553, 1501,
482, 1435, 1381, 1281, 1226, 1159, 1099, 996, 916, 846,
806, 768, 641, 585 cm ; HRMS (+EI) calcd for
1
ꢁ
1
4
.1. General
+
C H FNO (M ): 309.1165, found: 309.1159.
2
1
9
16
Melting points were determined on an XT-4 apparatus and
were uncorrected. IR spectra were taken on a Bruker Vec-
4.2.3. 4-(4-Fluorophenyl)-3-isobutyryl-2(1H)-quinoli-
ꢀ
ꢁ1
1
tor-22 spectrometer in KBr pellets and reported in cm
H NMR spectra were recorded at 300 MHz on a Bruker
.
none (4c). Mp 232–234 C; H NMR (300 MHz, DMSO-
d ) d 0.83 (d, J¼7.0 Hz, 6H), 2.67 (heptet, J¼7.0 Hz, 1H),
1
6
Avance-300 spectrometer in CDCl and DMSO-d with
3
7.04–7.23 (m, 2H), 7.33–7.43 (m, 4H), 7.56 (t, J¼7.7 Hz,
6
1
3
chemical shifts (d) given in parts per million relative to TMS
1H), 7.64–7.73 (m, 1H), 12.20 (s, 1H); C NMR
(75.5 MHz, DMSO-d ) d 17.90 (2C), 41.21, 115.97 (d,
1
3
as an internal standard. C NMR spectra were recorded on
a Bruker Avance-300 (75.5 MHz) spectrometer with com-
plete proton decoupling; chemical shifts are reported in parts
per million relative to the solvent resonance as the internal
standard (CDCl , d 77.16 ppm; DMSO-d , d 39.52 ppm).
6
2
JC–F¼21.8 Hz, 2C), 116.36, 119.50, 123.33, 127.50,
4
3
130.65 (d,
8.2 Hz, 2C), 133.46, 138.82, 147.26, 160.10, 163.09 (d,
J
¼3.2 Hz), 132.08, 132.12 (d,
J
¼
C–F
C–F
1
JC–F¼247.2 Hz), 208.59; FTIR (KBr) 3382, 2972, 2838,
3
6
1
3
All intensities in the C NMR spectral data are 1C except
where indicated. High-resolution mass spectra (HRMS)
were obtained on a Micromass GCT mass spectrometer
with positive EI mode.
1699, 1639, 1604, 1548, 1509, 1497, 1479, 1433, 1378,
1275, 1224, 1156, 1095, 1038, 1003, 822, 800, 762, 654,
560 cm ; HRMS (+EI) calcd for C H FNO (M ):
ꢁ1
+
1
9
16
2
309.1165, found: 309.1162.
4
.2. General procedure for the synthesis of compounds 4
4.2.4. 3-Cyclopropanecarbonyl-4-(4-fluorophenyl)-
2(1H)-quinolinone (4d). Mp 264–265 C; H NMR
ꢀ
(300 MHz, CDCl ) d 1.02–1.08 (m, 2H), 1.27–1.32 (m,
1
with microwave irradiation in a SANYO EM-350S
microwave oven
3
2H), 2.16–2.24 (m, 1H), 7.12–7.22 (m, 2H), 7.28–7.41 (m,
o-Aminoarylketone (1a/1b) (1 mmol) and an ester com-
pound (2a–g) (1 mmol) were mixed with a given amount
of CeCl $7H O or other catalyst, and introduced into a test
tube (10 mL). The mixture was subjected to microwave irra-
diation at an output of 450 W or other designated output
power for a given time (monitored by TLC). After it was
cooled to room temperature, water (5 mL) was added to the
reaction mixture. Then the mixture was stirred for 5 min
and the solid was collected by B €u chner filtration, washed
4H), 7.41 (d, J¼7.8 Hz, 1H), 7.55 (ddd, J¼8.2, 7.1,
1
3
1.2 Hz, 1H), 12.15 (s, 1H); C NMR (75.5 MHz, DMSO-
d ) d 11.18 (2C), 22.72, 115.08 (d, J ¼21.5 Hz, 2C),
2
3
2
6
C–F
4
115.52, 118.83, 122.15, 126.78, 130.46 (d, J ¼3.4 Hz),
C–F
3
131.10, 131.25 (d, JC–F¼8.2 Hz, 2C), 133.95, 138.51,
1
146.09, 159.08, 162.06 (d, J ¼245.8 Hz), 203.28; FTIR
C–F
(KBr) 3004, 2850, 1688, 1644, 1605, 1499, 1385, 1225,
1162, 1043, 993, 773, 575 cm ; HRMS (+EI) calcd for
ꢁ
1
+
C H FNO (M ) 307.1009, found: 307.1006.
1
9
14
2
with H O (5 mLꢂ3) and ethyl acetate–petroleum ether
2
(
1:4, 3 mLꢂ3), and air-dried to give the product as white
4.2.5. 3-Benzoyl-4-(4-fluorophenyl)-2(1H)-quinolinone
ꢀ
1
powder. The product was further purified by recrystallization
from ethanol when necessary. For the reactions affording low
to moderate product yields in Table 1, column separation on
a silica gel column was employed to get pure 4a.
(4e). Mp 222–224 C; H NMR (300 MHz, CDCl ) d 7.01
3
(t, J¼8.2 Hz, 2H), 7.15 (t, J¼8.2 Hz, 1H), 7.21–7.32 (m,
4H), 7.38 (t, J¼7.8 Hz, 2H), 7.46–7.55 (m, 2H), 7.82 (d,
1
3
J¼8.3 Hz, 2H), 12.37 (s, 1H); C NMR (75.5 MHz,
2
DMSO-d ) d 115.27 (d,
J
119.04, 122.38, 126.80, 128.70 (2C), 128.84 (2C), 130.10
¼21.7 Hz, 2C), 115.76,
6
C–F
4
.2.1. 3-Acetyl-4-(4-fluorophenyl)-2(1H)-quinolinone
ꢀ
s, 3H), 7.13–7.26 (m, 4H), 7.29–7.35 (m, 2H), 7.45 (d,
1
4
3
(
4a). Mp 250–251 C; H NMR (300 MHz, CDCl ) d 2.35
3
(d, J ¼3.4 Hz), 131.20 (d, J ¼9.2 Hz, 2C), 131.26,
C–F
C–F
(
131.42, 133.61, 136.41, 138.79, 147.46, 159.53, 162.56 (d,
JC–F¼246.4 Hz), 194.19; FTIR (KBr) 3434, 2850, 1678,
1
J¼7.8 Hz, 1H), 7.56 (ddd, J¼8.3, 6.8, 1.5 Hz, 1H), 12.44
1
3
(
(
s, 1H); C NMR (75.5 MHz, DMSO-d ) d 31.40, 115.46
6
1651, 1607, 1556, 1508, 1498, 1479, 1377, 1240, 1159,
826, 757, 687 cm ; HRMS (+EI) calcd for C H FNO
(M ): 343.1009, found: 343.1001.
2
ꢁ1
d, J ¼22.0 Hz, 2C), 115.64, 118.93, 122.34, 126.95,
C–F
22 14
2
4
3
+
1
1
2
1
1
30.46 (d, J ¼3.3 Hz), 131.02 (d, J ¼8.3 Hz, 2C),
C–F
C–F
1
31.21, 133.58, 138.44, 146.16, 159.23, 162.12 (d, J
¼
C–F
45.9 Hz), 201.63; FTIR (KBr) 3449, 2995, 2846, 1701,
648, 1602, 1551, 1509, 1497, 1478, 1431, 1377, 1280,
225, 1158, 1075, 826, 761, 653, 644 cm ; HRMS (+EI)
4.2.6. 4-(4-Fluorophenyl)-2(1H)-quinolinone-3-carbo-
ꢀ
1
nitrile (4f). Mp 308–310 C; H NMR (300 MHz, CDCl )
3
ꢁ
1
d 7.23–7.34 (m, 3H), 7.40 (d, J¼7.9 Hz, 1H), 7.47–7.51
+
calcd for C H FNO (M ): 281.0852, found: 281.0854.
1
(m, 2H), 7.62 (d, J¼8.0 Hz, 1H), 7.70 (t, J¼7.4 Hz, 1H),
7
12
2
1
3
1
2.73 (s, 1H); C NMR (75.5 MHz, DMSO-d ) d 106.42,
6
2
4
.2.2. 3-Butyryl-4-(4-fluorophenyl)-2(1H)-quinolinone
ꢀ
115.26, 115.89 (d, J ¼21.9 Hz, 2C), 116.17, 117.97,
C–F
1
4
3
C–F C–F
(
4b). Mp 216–218 C; H NMR (300 MHz, CDCl ) d 0.78
3
123.02, 127.86, 130.05 (d, J ¼3.2 Hz), 131.11 (d, J
¼
(
t, J¼7.4 Hz, 3H), 1.52 (sextet, J¼7.3 Hz, 2H), 2.55 (t,
8.7 Hz, 2C), 133.80, 139.78, 158.39, 159.38, 162.83 (d,
JC–F¼247.5 Hz); FTIR (KBr) 3482, 2991, 2851, 2231,
1
J¼7.2 Hz, 2H), 7.13–7.26 (m, 4H), 7.29–7.36 (m, 2H),
7
1
.42 (d, J¼7.8 Hz, 1H), 7.55 (ddd, J¼8.3, 7.0, 1.5 Hz,
1673, 1602, 1500, 1481, 1378, 1281, 1233, 1159, 842,
1
3
ꢁ1
766 cm ; HRMS (+EI) calcd for C H FN O (M ):
16 9 2
+
H), 12.25 (s, 1H); C NMR (75.5 MHz, DMSO-d )
6
2
d 13.15, 15.90, 45.04, 115.38 (d, JC–F¼21.7 Hz, 2C),
264.0699, found: 264.0690.
4
1
1
1
15.63, 118.94, 122.36, 126.84, 130.23 (d, J ¼3.0 Hz),
C–F
3
31.17, 131.28 (d, JC–F¼8.4 Hz, 2C), 133.62, 138.42,
4.2.7. Ethyl 4-(4-fluorophenyl)-2(1H)-quinolinone-3-car-
ꢀ
1
1
46.00, 159.25, 162.13 (d, J ¼245.6 Hz), 203.69; FTIR
C–F
boxylate (4g). Mp 204–205 C; H NMR (300 MHz,

896
C.-S. Jia et al. / Tetrahedron 63 (2007) 892–897
CDCl ) d 1.04 (t, J¼7.1 Hz, 3H), 4.15 (q, J¼7.1 Hz, 2H),
6.8, 1.2 Hz, 1H), 7.74 (d, J¼8.1 Hz, 1H), 7.98 (d, J¼6.9 Hz,
3
1
3
7
.14–7.28 (m, 4H), 7.36–7.41 (m, 2H), 7.45 (d, J¼8.0 Hz,
2H), 11.81 (s, 1H); C NMR (75.5 MHz, DMSO-d )
6
1
3
1
NMR (75.5 MHz, CDCl ) d 13.93, 61.55, 115.66 (d,
H), 7.56 (ddd, J¼8.3, 6.9, 1.3 Hz, 1H), 12.14 (s, 1H);
C
d 15.61, 115.73, 119.15, 122.30, 125.36, 128.88 (2C),
129.05 (2C), 130.85, 131.10, 133.96, 136.50, 138.32, 144.63,
159.72, 195.74; FTIR (KBr) 3442, 2944, 2848, 1688, 1641,
1561, 1502, 1483, 1433, 1386, 1370, 1312, 1282, 1245,
3
2
JC–F¼21.7 Hz, 2C), 117.10, 119.56, 123.14, 126.66,
4
3
1
27.39, 130.66 (d,
J
¼3.5 Hz), 130.90 (d,
J
.2 Hz, 2C), 131.77, 138.60, 149.61, 161.22, 163.15 (d,
¼
C–F
C–F
ꢁ
1
8
1153, 925, 899, 820, 750, 689, 580 cm ; HRMS (+EI) calcd
for C H NO (M ): 263.0946, found: 263.0945.
1
+
JC–F¼249.0 Hz), 165.60; FTIR (KBr) 3436, 2984, 2852,
17
13
2
1
732, 1651, 1608, 1557, 1500, 1434, 1391, 1381, 1291,
245, 1159, 1133, 1087, 766, 592 cm ; HRMS (+EI) calcd
ꢁ
1
4
Mp>300 C; H NMR (300 MHz, CDCl ) d 2.84 (s, 3H),
.2.13. 4-Methyl-2(1H)-quinolinone-3-carbonitrile (4m).
ꢀ
1
for C H FNO (M ): 311.0958, found: 311.0960.
1
+
3
1
8
14
3
7
.33–7.39 (m, 2H), 7.68 (ddd, J¼8.4, 7.1, 1.3 Hz, 1H),
1
3
4
2
2
1
.2.8. 3-Acetyl-4-methyl-2(1H)-quinolinone (4h). Mp
ꢀ
7.80 (d, J¼8.7 Hz, 1H), 10.98 (s, 1H); C NMR
(75.5 MHz, DMSO-d ) d 18.22, 105.99, 115.61, 116.12,
1
78–280 C; H NMR (300 MHz, CDCl ) d 2.49 (s, 3H),
3
6
.66 (s, 3H), 7.28–7.34 (m, 2H), 7.56 (ddd, J¼8.3, 7.1,
118.08, 122.99, 126.53, 133.78, 138.97, 158.47, 158.80;
FTIR (KBr) 3447, 3147, 3013, 2894, 2854, 2222, 1660,
1602, 1504, 1475, 1430, 1389, 1368, 1275, 1246, 1162,
.2 Hz, 1H), 7.78 (dd, J¼7.8, 1.0 Hz, 1H), 11.54 (s, 1H);
1
3
C NMR (75.5 MHz, DMSO-d ) d 15.11, 31.29, 115.60,
6
ꢁ
1
1
1
1
1
19.14, 122.28, 125.62, 131.09, 132.88, 138.02, 143.65,
59.52, 203.50; FTIR (KBr) 3435, 2930, 2849, 1693, 1661,
604, 1547, 1505, 1484, 1432, 1390, 1345, 1283, 1220,
1123, 863, 842, 756, 673, 663 cm ; HRMS (+EI) calcd
for C H N O (M ): 184.0637, found: 184.0636.
+
1
1 8 2
ꢁ
1
139, 1107, 1031, 906, 872, 750, 663 cm ; HRMS (+EI)
4.3. General procedure for the synthesis of compounds 4
with microwave irradiation in a monomodal EmrysÔ
Creator microwave synthesizer
+
calcd for C H NO (M ): 201.0790, found: 201.0788.
1
2
11
2
4
2
.2.9. 3-Butyryl-4-methyl-2(1H)-quinolinone (4i). Mp
ꢀ
08–209 C; H NMR (300 MHz, CDCl ) d 1.05 (t,
3
1
The experiments were carried out in a monomodal EmrysÔ
Creator from Personal Chemistry (Uppsala, Sweden). The
reactions were performed in sealed microwave process vials
utilizing the standard level (300 W maximum power). Reac-
tion times under microwave irradiation conditions reflected
the time that the reaction mixture was kept at the designated
temperature (fixed hold time). Typically, a mixture of o-ami-
noarylketone (1a/1b) (1 mmol), ethyl acetoacetate (2a)/ethyl
benzoylacetate (2e) (1 mmol), and CeCl $7H O (0.2 mmol)
J¼7.4 Hz, 3H), 1.81 (sextet, J¼7.3 Hz, 2H), 2.45 (s, 3H),
2
7
1
.95 (t, J¼7.3 Hz, 2H), 7.27 (ddd, J¼8.2, 7.1, 1.1 Hz, 1H),
.39 (dd, J¼8.2, 0.8 Hz, 1H), 7.55 (ddd, J¼8.3, 7.2, 1.2 Hz,
1
3
H), 7.76 (dd, J¼8.2, 0.9 Hz, 1H), 12.72 (s, 1H); C NMR
(
75.5 MHz, DMSO-d ) d 13.59, 15.15, 16.52, 45.04,
6
1
1
1
1
15.60, 119.16, 122.27, 125.53, 131.02, 132.82, 138.02,
43.54, 159.58, 205.82; FTIR (KBr) 3442, 2923, 2846,
684, 1656, 1606, 1555, 1503, 1485, 1434, 1389, 1273,
3
2
ꢁ
1
198, 1084, 1033, 986, 904, 875, 743 cm ; HRMS (+EI)
in a sealed 10-mL EmrysÔ reaction vial was irradiated at
160 C for a given time, then the sample was cooled using
+
calcd for C H NO (M ): 229.1103, found: 229.1112.
1
ꢀ
4
15
2
compressed air. The work-up procedure followed was the
same as that in a SANYO EM-350S microwave oven.
4
2
.2.10. 3-Isobutyryl-4-methyl-2(1H)-quinolinone (4j). Mp
ꢀ
26–228 C; H NMR (300 MHz, CDCl ) d 1.25 (d,
3
1
J¼7.0 Hz, 6H), 2.44 (s, 3H), 3.38 (heptet, J¼7.0 Hz, 1H),
4.4. General procedure for the synthesis of compounds 4
with conventional heating
7
.25–7.34 (m, 2H), 7.55 (ddd, J¼8.2, 7.1, 1.1 Hz, 1H), 7.76
1
3
(
DMSO-d ) d 15.56, 17.53 (2C), 40.28, 115.60, 119.15,
d, J¼7.9 Hz, 1H), 11.96 (s, 1H); C NMR (75.5 MHz,
6
A mixture of o-aminoarylketone (1a/1b) (1 mmol), ethyl
acetoacetate (2a)/ethyl benzoylacetate (2e) (1 mmol), and
CeCl $7H O (0.2 mmol) was introduced into a test tube
1
2
1
22.25, 125.55, 131.01, 132.25, 138.05, 144.22, 159.72,
09.35; FTIR (KBr) 3430, 2971, 2852, 1703, 1645, 1609,
ꢁ
1
3
2
559, 1506, 1485, 1433, 1393, 971, 749, 667, 600 cm
;
ꢀ
(
10 mL) and stirred at 160 C (oil bath temperature) for
the designated time. After the reaction was completed
monitored by TLC), the reaction mixture was separated
+
HRMS (+EI) calcd for C H NO (M ): 229.1103, found:
1
4
15
2
2
29.1106.
(
by column chromatography to give the pure product.
4.2.11. 3-Cyclopropanecarbonyl-4-methyl-2(1H)-quino-
linone (4k). Mp 188–189 C; H NMR (300 MHz, CDCl )
ꢀ
d 1.08–1.17 (m, 2H), 1.33–1.38 (m, 2H), 2.42–2.51 (m,
1
3
Acknowledgements
1
H), 2.48 (s, 3H), 7.27 (ddd, J¼8.1, 7.1, 0.9 Hz, 1H), 7.38
(
(
d, J¼7.8 Hz, 1H), 7.55 (ddd, J¼8.2, 7.1, 1.1 Hz, 1H), 7.77
We are grateful for the financial support from the National
Natural Science Foundation of China (Nos. 20125205 and
20321101) and Anhui Provincial Bureau of Human Re-
sources (2001Z019).
1
3
d, J¼8.1 Hz, 1H), 12.07 (s, 1H); C NMR (75.5 MHz,
DMSO-d ) d 11.29 (2C), 15.47, 22.75, 115.55, 119.10,
6
1
2
1
6
2
22.20, 125.57, 131.01, 132.84, 138.12, 143.64, 159.52,
05.05; FTIR (KBr) 3442, 2954, 2873, 1697, 1659, 1602,
502, 1429, 1385, 1370, 1268, 1080, 991, 909, 885, 751,
ꢁ
1
+
References and notes
38 cm ; HRMS (+EI) calcd for C H NO (M ):
2
1
4
13
27.0946, found: 227.0938.
1
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2
7
.2.12. 3-Benzoyl-4-methyl-2(1H)-quinolinone (4l). Mp
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3
.18–7.29 (m, 2H), 7.48 (t, J¼8.1 Hz, 3H), 7.61 (ddd, J¼8.0,

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