Rapid and efficient synthesis of poly-substituted quinolines assisted by p-toluene sulphonic acid under solvent-free conditions: Comparative study of microwave irradiation versus conventional heating

Article abstract of DOI:10.1039/b513721g

A rapid and efficient method for the preparation of various poly-substituted quinolines has been developed through the Friedlaender condensation of 2-aminoarylketone or 2-aminoarylaldehyde with carbonyl compounds in the presence of p-toluene sulphonic aci

Full text of DOI:10.1039/b513721g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Rapid and efficient synthesis of poly-substituted quinolines assisted by
p-toluene sulphonic acid under solvent-free conditions: comparative
study of microwave irradiation versus conventional heating
Cheng-Sheng Jia,a Ze Zhang,a Shu-Jiang Tub and Guan-Wu Wang*a
Received 27th September 2005, Accepted 28th October 2005
First published as an Advance Article on the web 18th November 2005
DOI: 10.1039/b513721g
A rapid and efficient method for the preparation of various poly-substituted quinolines has been
developed through the Friedla¨nder condensation of 2-aminoarylketone or 2-aminoarylaldehyde with
carbonyl compounds in the presence of p-toluene sulphonic acid, which was achieved by both
microwave irradiation and conventional heating under solvent-free conditions.
solvent-free conditions, including using microwave irradiation and
Introduction
conventional heating techniques.9
It is well known that the quinoline ring system is an important
structural unit widely existing in alkaloids, therapeutics and
synthetic analogues with interesting biological activities.1 A large
To the best of our knowledge, p-toluene sulphonic acid
(p-TsOH) is a convenient, easily available and cheap reagent, which
has been used as a catalyst under microwave irradiation leading to
a variety of heterocyclic compounds.10 Although p-TsOH has been
variety of quinoline derivatives have been used as antimalarial,
anti-inflammatory agents, antiasthmatic, antibacterial, antihyper-
employed in the Friedla¨nder reaction, it is limited to a substantial
tensive and tyrokinase PDGF-RTK inhibiting agents.2,3 Further-
more, poly-substituted quinolines have been found to undergo
extent due to the use of an organic solvent such as toluene and a
very low yield.11a Recently, p-TsOH has been used to catalyze the
hierarchical self-assembly into a variety of nano- and mesostruc-
solvent-free Friedla¨nder condensation of 2-aminonicotinaldehyde
tures with enhanced electronic and photonic functions.4 In view
with acetoacetanilide or benzoylacetanilide by hand grinding,
but the utilized carbonyl substrates were just amides.11b As a
continuation of our interest in solvent-free organic reactions,12
herein we report a solvent-free methodology for the p-TsOH-
assisted synthesis of a large variety of poly-substituted quino-
lines by microwave irradiation and conventional heating with
improved efficiencies and cost effectiveness. Concretely speaking,
treatment of 2-aminoarylketone or 2-aminoarylaldehyde with
various carbonyl compounds in the presence of p-TsOH promoted
by microwave irradiation or conventional heating results in the
formation of the corresponding quinoline derivatives with good
to excellent yields.
of these points, a great deal of effort has been drawn to develop
new and efficient synthetic routes to quinoline derivatives in both
synthetic organic and medicinal chemistry. Up to now, versatile
methods have been developed for the preparation of these kinds
of derivatives, such as Skraup, Doebner-von Miller, Friedla¨nder,
Combes methods and so on.5–7 Among these methods, Friedla¨nder
annulation,7c,d an acid- or base-catalyzed condensation followed
by a cyclodehydration between an aromatic 2-aminoaldehyde
or ketone and a carbonyl compound containing a reactive a-
methylene group, is one of the most simple and straightforward
approaches for the synthesis of poly-substituted quinolines. But
even with this classical method, it is still not fully satisfactory with
regard to relatively low yield, drastic reaction conditions, gener-
ality and operational complexity due to the occurrence of several
side reactions. Furthermore, under base-catalyzed conditions, o-
aminobenzophenone fails to react with simple ketones such as
cyclohexanone and b-ketoesters.8 Therefore, a simple, general and
efficient procedure is still in demand for the synthesis of these
important heterocyclic compounds.
Results and discussion
2-Amino-4ꢀ-fluorobenzophenone (1a) has been used as the starting
material to synthesize quinoline derivatives, which can functional-
ize as HMG-CoA reductase inhibitors.11a,13 We therefore first chose
1a and searched for the optimized conditions for its reaction with
ethyl acetoacetate (2a) affording quinoline 3a under microwave
(SANYO EM-350S microwave oven) conditions (Scheme 1).
On the other hand, for the stringent and growing environ-
mental regulations, organic chemists are requested to develop
environmentally benign synthetic methodologies. One of the most
promising approaches is to perform organic reactions under
aHefei National Laboratory for Physical Sciences at Microscale and
Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui, 230026, P. R. China. E-mail: gwang@ustc.edu.cn;
Fax: +86-551-360-7864
bDepartment of Chemistry and Key Laboratory of Biotechnology for
Medicinal Plants, Xuzhou Normal University, Xuzhou, Jiangsu, 221116,
P. R. China
Scheme 1
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Table 1 Optimization of the catalyst in the synthesis of quinoline 3a
under microwave irradiation conditions
3,5-dibromobenzaldehyde (1c) and various carbonyl compounds
(2) under microwave irradiation conditions (Scheme 2).
Entry
Catalyst
Yield (%)
1
2
3
—
Trace
35
50
CuSO4·5H2O
CuCl
4
5
CuCl2·2H2O
ZnCl2
48
68
6
7
8
9
NiCl2·6H2O
FeSO4·7H2O
FeCl3·6H2O
BiCl3
10
Trace
82
86
10
11
12
13
14
15
AlCl3
35
86
71
18
58
92
SnCl4·5H2O
H3PO4
Scheme 2
CH3CO2H
CF3CO2H
p-TsOH
In a typical case, a molar equivalent of substrates 1, 2 and
p-TsOH was mixed and then irradiated in a SANYO EM-350S mi-
crowave oven at 300 W or 150 W for a designated time as required
to complete the reaction (determined by TLC). The resulting
reaction mixture was treated with aqueous NaOH (10%) and the
desired product was collected simply by filtration. Under these
conditions, the reactions proceed smoothly and efficiently with
almost quantitative yield in very short time (not exceeding 60 s).
The detailed results for these reactions are collected in Table 3.
From the above results, it can be seen that the generality of
this facile condensation was established in the presence of p-TsOH
under solvent-free conditions to furnish the corresponding poly-
substituted quinolines. By comparison, substrate 1c demonstrates
a superior reaction activity to 1a and 1b, in which the employed
microwave output is only 150 W.
First, we employed various catalysts to determine which one
has the most effective catalytic activity. The results of these
comparative experiments are summarized in Table 1.
From the above results it can be seen that all the catalysts
except FeSO4·7H2O can promote the reaction to a certain
extent. Although FeCl3·6H2O (entry 8), BiCl3 (entry 9) and
SnCl4·5H2O (entry 11) exhibited good catalytic activity, the water-
insoluble solids formed from these catalysts when treated with an
aqueous solution of NaOH make the work-up procedure more
complicated. It is obvious that p-TsOH (entry 15) demonstrated
superior catalytic activity and was the best catalyst among those
examined. In order to further evaluate the influence of p-TsOH,
this reaction was carried out using different amount of p-TsOH
under microwave irradiation and conventional heating conditions.
The results are listed in Table 2.
From Table 2 it can be seen that the reaction hardly proceeded
in the absence of p-TsOH. The increase in the amount of p-TsOH
afforded higher yield. When 1.0 equivalent of p-TsOH was used,
the yield was significantly increased up to 92% under microwave
irradiation and 95% under conventional heating, respectively
(entry 7). However, an excess of p-TsOH did not help to increase
the yield. On the contrary, more than one equivalent of p-TsOH
resulted in a slightly lower yield (entry 8).
Because the foregoing optimization work has demonstrated
that this kind of reaction can also be efficiently promoted by
conventional heating under neat conditions, we tried to obtain
all the above products under solvent-free conditions (Scheme 3).
As expected, the desired poly-substituted quinolines 3 were also
obtained with almost quantitative yields, as shown in Table 4.
These optimization results prompted us to select 1.0 equivalent
of p-TsOH as a catalyst for further study; that is, we used
1.0 equivalent of p-TsOH to catalyze the library synthesis of
quinoline 3 from 1a or 2-aminoacetophenone (1b) or 2-amino-
Scheme 3
It should be noted that p-TsOH has recently been
used to catalyze solvent-free Friedla¨nder condensation of 2-
aminonicotinaldehyde with acetoacetanilide or benzoylacetanilide
by hand grinding.11b We have examined the solvent-free reactions
of substrates 1a–c with 2a–h under similar conditions, and found
that these reactions could hardly proceed by hand grinding. For
example, the reaction of 1a with 2a, 2d, 2f or 2h in the presence of
p-TsOH in the solid state at room temperature by hand grinding for
30 min gave none of, or only trace amounts of products. Therefore,
heating is required for the success of the neat reactions.
In order to draw a direct comparison between microwave
irradiation and conductive heating (100 ◦C), a few selected
reactions were carried out at an identical temperature in a
monomodal EmrysTM Creator microwave synthesizer. The results
are summarized in Table 5.
Table 2 Optimization of the amount of p-TsOH in the synthesis of
quinoline 3a under microwave irradiation and conventional heating in
a thermostated oil bath
Microwave irradiation Conventional heating
Entry p-TsOH/equiv. Time/s
Yield (%) Time/min Yield (%)
1
2
3
4
5
6
7
8
0
75
75
75
60
45
45
30
30
Trace
15
50
80
84
88
92
86
5
5
5
5
3
3
3
3
Trace
50
55
67
82
90
95
94
0.1
0.2
0.3
0.4
0.5
1.0
2.0
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Table 3 Synthesis of poly-substituted quinolines 3 assisted by p-TsOH under microwave irradiation conditionsa
Substrate 1
Substrate 2
Quinoline 3
Time/s
30
Yieldb (%)
92
Mp (lit.)/◦C
118–120 (120–12113a
)
1a
2a
3a
1a
1a
2b
3b
45
30
91
94
74–76 (73.5–75.513c
)
2c
3c
114–116c
1a
1a
1a
2d
2e
2f
3d
3e
3f
30
30
30
93
93
92
140–142
139–141
172–174
1a
1a
1a
2g
2h
2i
3g
3h
3i
60
60
60
93
94
88
170–172
211–213
82–84
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Table 3 (Contd.)
Substrate 1 Substrate 2
Quinoline 3
Time/s
60
Yieldb (%)
89
Mp (lit.)/◦C
98–100
1a
2j
3j
1b
1b
1b
1b
1b
2a
2d
2e
2f
3k
3l
15
15
91
92
87
85
95
Oil (oil14)
Oil (oil14)
3m 15
58–60 (6014)
75–77 (7814)
65–66 (6815)
3n
3o
15
15
2g
1b
2h
3p
15
95
105–106
1c
1c
1c
2a
2d
2e
3q
3r
3s
60
60
60
92
96
91
116–118
162–164
110–112
1c
1c
2f
3t
60
60
93
92
106–108 (105–10616)
176–178
2g
3u
1c
2h
3v
60
96
164–166
a Products 3a–3p were obtained at 300 W and products 3q–3v were obtained at 150 W (the employed microwave output and reaction time for each
product are the optimized conditions from several comparative entries). b Yields refers to those of pure isolated products, which were fully characterized
by spectral data. c Product 3c has been characterized11a by spectral data but no melting point.
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Table 4 Synthesis of poly-substituted quinolines 3 assisted by p-TsOH
using conventional heating in a thermostated oil bath under solvent-free
conditions
microwave irradiation or a conventional heating technique. In
both methods, the process is environmentally benign and the
experimental procedure is very simple. Our protocol can be
applied to a wide range of substrates, tolerating the presence
of halogen, ketone and ester groups. These methods not only
afford significant improvements in reaction rates and yields but
also present a more straightforward and easy work-up proce-
dure, thus providing a very efficient alternative to traditional
processes.
Entry
Quinoline 3
Time/min
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3a
3b
3c
3d
3e
3f
3g
3h
3i
3
3
3
3
3
3
5
5
10
10
5
5
5
5
5
5
3
90
93
94
94
95
92
95
93
90
91
90
93
89
86
96
94
94
95
92
95
94
95
Experimental
3j
3k
3l
General
Melting points were determined on an XT-4 apparatus and
were uncorrected. IR spectra were taken on a Bruker Vector-
3m
3n
3o
3p
3q
3r
3s
3t
1
22 spectrometer in KBr pellets and reported in cm−1. H NMR
spectra were recorded at 300 MHz on a Bruker Avance-300
spectrometer in CDCl3 with chemical shifts (d) given in ppm
relative to TMS as an internal standard. 13C NMR spectra were
recorded on a Bruker Avance-300 (75.5 MHz) spectrometer with
complete proton decoupling; chemical shifts are reported in ppm
relative to the solvent resonance as the internal standard (CDCl3,
d 77.16 ppm). All intensities in the 13C NMR spectral data are 1C
except where indicated. High-resolution mass spectra (HRMS)
were obtained on a Micromass GCT mass spectrometer with a
positive EI mode.
3
3
3
4
3u
3v
4
By comparison of the data in Tables 4 and 5, it can be
seen that the microwave irradiation protocol is generally faster
than conventional heating at the same temperature to reach
a comparable yield. For the microwave-assisted reactions in a
SANYO E-350S microwave oven (Table 3), the reaction time
required could be even shorter than that in a monomodal EmrysTM
Creator. The possible reason is that the temperature in a SANYO
E-350S microwave oven was uncontrolled and likely reached at a
temperature higher than 100 ◦C. Furthermore, the test tubes were
uncapped and the water formed could evaporate from the reaction
mixture at a higher temperature, thus providing extra driving force
for the reactions. One can see from the results in Tables 3 and 5 that
the good yields in a commercially available and cheap SANYO E-
350S domestic microwave oven can be reproduced in a monomodal
EmrysTM Creator and thus can be transferred to a more modern
microwave synthesizer.
General procedure for the synthesis of compound 3 with
microwave irradiation in a SANYO EM-350S microwave oven
2-Aminoarylketone or 2-aminoarylaldehyde 1 (1 mmol) and car-
bonyl compound 2 (1 mmol) were mixed with the given amount of
p-TsOH or other catalyst and introduced into a test tube (10 mL).
Then the mixture was subjected to microwave irradiation at an
output of 300 W or 150 W for a given time. When it was cooled
to room temperature, water (3 mL) was added to the reaction
mixture. The resulting suspension was neutralized with 0.4 mL of
10% NaOH. Then the mixture was stirred for 5 min and the solid
was collected by Bu¨chner filtration, washed with H2O (6 mL ×
3) and dried in a desiccator to give the product as a white or
slightly yellow powder. For the oil or low-melting-point products,
the purification procedure was different. The neutralized mixture
was extracted with ethyl acetate (5 mL × 2). The organic layer
was separated out and dried over anhydrous MgSO4. Evaporation
of the solvent afforded the crude product as a slightly yellow
oil, which was further purified by column chromatography when
necessary.
Conclusion
In summary, we have developed a rapid and efficient version
of the Friedla¨nder annulation for the synthesis of various poly-
substituted quinolines assisted by p-TsOH. All the reactions were
conducted under completely solvent-free conditions using either
Table 5 Synthesis of poly-substituted quinolines 3 assisted by p-TsOH under microwave irradiation conditions using a monomodal EmrysTM Creator
Substrate 1
Substrate 2
Quinoline 3
Time/min
Temp/◦C
Power/W
Yield (%)
1a
1a
1b
1b
1c
1c
2a
2h
2a
2h
2a
2h
3a
3h
3k
3p
3q
3v
0.5
3
1
3
1
100
100
100
100
100
100
300
300
300
300
150
150
94
96
92
95
94
96
4
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General procedure for the synthesis of compound 3 with
conventional heating
(d, J = 8.4 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 198.09,
1
162.43 (d, JC–F = 246.6 Hz), 162.33, 150.40, 148.81, 133.43 (d,
3
4JC–F = 3.7 Hz), 131.88, 129.93 (d, JC–F = 8.0 Hz, 2C), 128.73,
A mixture containing 2-aminoarylketone or 2-aminoarylaldehyde
1 (1 mmol), carbonyl compound 2 (1 mmol) and p-TsOH (1 mmol)
was introduced into a test tube (10 mL) and stirred at 100 ◦C
(oil bath temperature) for the designated time. When the reaction
was completed (monitored by TLC), the subsequent work-up
procedure was the same as that of the above microwave irradiation
conditions.
2
128.00, 127.60, 126.66, 124.09, 115.34 (d, JC–F = 21.7 Hz, 2C),
40.75, 34.69, 21.43; FT-IR (KBr) 3065, 2949, 1691, 1552, 1513,
1489, 1220, 1162, 852, 770, 540 cm−1; HRMS (+EI) calcd for
C19H14FNO (M+): 291.1059, found: 291.1057.
3,3-Dimethyl-9-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-acridinone
(3h). 1H NMR (300 MHz, CDCl3) d 1.16 (s, 6H), 2.57 (s, 2H),
3.28 (s, 2H), 7.12–7.23 (m, 4H), 7.40–7.48 (m, 2H), 7.78 (ddd,
J = 8.3, 6.2, 2.2 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3) d 198.16, 162.48 (d, 1JC–F = 246.6 Hz), 161.29,
General procedure for the synthesis of compound 3 with microwave
irradiation in a monomodal EmrysTM Creator microwave
synthesizer
150.06, 149.19, 133.41 (d, 4JC–F = 3.5 Hz), 131.86, 129.98 (d, 3JC–F
=
7.9 Hz, 2C), 128.79, 128.09, 127.58, 126.73, 123.00, 115.40 (d,
2JC–F = 21.7 Hz, 2C), 54.40, 48.52, 32.36, 28.4 (2C); FT-IR (KBr)
3063, 2958, 1686, 1556, 1487, 1215, 777, 550 cm−1; HRMS (+EI)
calcd for C21H18FNO (M+): 319.1372, found: 319.1370.
All reactions were performed in a monomodal EmrysTM Cre-
ator from Personal Chemistry, Uppsala, Sweden. Typically,
in a 10 mL EmrysTM reaction vial, 2-aminoarylketone or 2-
aminoarylaldehyde 1 (1 mmol), carbonyl compound 2 (1 mmol)
and p-TsOH (1 mmol) were mixed and then capped. The mixture
was irradiated at 300 W or 150 W and at 100 ◦C for a given
time. The subsequent work-up procedure was the same as that in
a SANYO EM-350S microwave oven.
4-(4-Fluorophenyl)-2-phenylquinoline (3i). 1H NMR (300 MHz,
CDCl3) d 7.23–7.28 (m, 2H), 7.45–7.57 (m, 6H), 7.73–7.80 (m,
2H), 7.86 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 6.7 Hz, 2H), 8.29 (d,
J = 7.0 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 163.07 (d,
1JC–F = 248.1 Hz), 157.03, 148.94, 148.26, 139.65, 134.49 (d,
1-[2-Methyl-4-(4-fluorophenyl)quinolin-3-yl]ethanone (3d). 1H
NMR (300 MHz, CDCl3) d 2.04 (s, 3H), 2.70 (s, 3H), 7.23 (tt,
J = 8.7, 2.1 Hz, 2H), 7.33–7.38 (m, 2H), 7.47 (ddd, J = 8.3, 6.8,
1.2 Hz, 1H), 7.58 (dd, J = 8.3, 1.2 Hz, 1H), 7.74 (ddd, J = 8.3,
6.8, 1.4 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H); 13C NMR (75.5 MHz,
3
4JC–F = 3.5 Hz), 131.40 (d, JC–F = 8.2 Hz, 2C), 130.34, 129.77,
129.57, 128.99 (2C), 127.72 (2C), 126.62, 125.89, 125.49, 119.53,
2
115.81 (d, JC–F = 21.6 Hz, 2C); FT-IR (KBr) 3053, 1608, 1492,
1224, 840, 764, 698 cm−1; HRMS (+EI) calcd for C21H14FN (M+):
299.1110, found: 299.1113.
1
CDCl3) d 205.56, 163.15 (d, JC–F = 249.6 Hz), 153.57, 147.66,
2-(4-Chlorophenyl)-4-(4-fluorophenyl)quinoline (3j). 1H NMR
(300 MHz, CDCl3) d 7.23–7.29 (m, 2H), 7.48–7.56 (m, 5H), 7.73–
7.78 (m, 2H), 7.86 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 6.6 Hz, 2H),
8.22 (d, J = 8.5 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 163.13 (d,
1JC–F = 248.5 Hz), 155.68, 148.92, 148.51, 138.05, 135.83, 134.36
(d, 4JC–F = 3.5 Hz), 131.39 (d, 3JC–F = 8.2 Hz, 2C), 130.32, 129.95,
129.19 (2C), 128.97 (2C), 126.85, 125.96, 125.55, 119.08, 115.87
142.82, 135.19, 132.00 (d, 3JC–F = 8.2 Hz, 2C), 131.17 (d, 4JC–F
=
=
3.5 Hz), 130.28, 129.12, 126.79, 125.93, 125.15, 116.03 (d, 2JC–F
21.7 Hz, 2C), 32.11, 23.93; FT-IR (KBr) 3044, 1697, 1604, 1573,
1511, 1488, 1404, 1392, 1212, 1159, 1095, 858, 766 cm−1; HRMS
(+EI) calcd for C18H14FNO (M+): 279.1059, found: 279.1053.
9-(4-Fluorophenyl)-2,3-dihydro-1H-cyclopenta[b]quinoline (3e).
1H NMR (300 MHz, CDCl3) d 2.18 (quintet, J = 7.5 Hz, 2H), 2.90
(t, J = 7.4 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H), 7.19–7.27 (m, 2H),
7.32–7.42 (m, 3H), 7.58–7.66 (m, 2H), 8.07 (d, J = 7.9 Hz, 1H);
13C NMR (75.5 MHz, CDCl3) d 167.53, 162.64 (d, 1JC–F = 247.4
Hz), 148.09, 141.80, 133.94, 132.75 (d, 4JC–F = 3.7 Hz), 131.15 (d,
3JC–F = 8.1 Hz, 2C), 129.04, 128.44, 126.34, 125.76, 125.46, 115.74
(d, 2JC–F = 21.5 Hz, 2C), 35.30, 30.44, 23.62; FT-IR (KBr) 3064,
2959, 1607, 1495, 1382, 1221, 1159, 840, 764, 562 cm−1; HRMS
(+EI) calcd for C18H14FN (M+): 263.1110, found: 263.1101.
2
(d, JC–F = 21.6 Hz, 2C); FT-IR (KBr) 3068, 1604, 1492, 1224,
1091, 832, 760 cm−1; HRMS (+EI) calcd for C21H1335ClFN (M+):
333.0721, found: 333.0719.
3,3-Dimethyl-9-methyl-1,2,3,4-tetrahydro-1-acridinone (3p).
1H NMR (300 MHz, CDCl3) d 1.14 (s, 6H), 2.67 (s, 2H), 3.08 (s,
3H), 3.19 (s, 2H), 7.57 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.77 (ddd,
J = 8.4, 6.9, 1.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.22 (d, J =
8.4 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 200.32, 160.94,
149.56, 148.12, 131.33, 129.09, 127.55, 126.28, 125.41, 124.05,
54.74, 48.43, 31.97, 28.20 (2C), 15.81; FT-IR (KBr) 2955, 2968,
1682, 1560,1494, 1373, 1280, 1215, 762 cm−1; HRMS (+EI) calcd
for C16H17NO (M+): 239.1310, found: 239.1308.
9-(4-Fluorophenyl)-1,2,3,4-tetrahydroacridine (3f). 1H NMR
(300 MHz, CDCl3) d 1.76–1.84 (m, 2H), 1.93–2.01 (m, 2H), 2.59 (t,
J = 6.4 Hz, 2H), 3.20 (t, J = 6.6 Hz, 2H), 7.21–7.36 (m, 6H), 7.61
(ddd, J = 8.4, 6.2, 2.1 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3) d 162.54 (d, 1JC–F = 246.9 Hz), 159.26, 146.43,
145.65, 133.06 (d, 4JC–F = 3.7 Hz), 131.00 (d, 3JC–F = 7.9 Hz, 2C),
Ethyl 6,8-dibromo-2-methyl-3-quinolinecarboxylate (3q). 1H
NMR (300 MHz, CDCl3) d 1.46 (t, J = 7.1 Hz, 3H), 3.03 (s,
3H), 4.45 (q, J = 7.1 Hz, 2H), 8.00 (t, J = 2.0 Hz, 1H), 8.20
(d, J = 2.0 Hz, 1H), 8.62 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
d 165.66, 160.01, 144.14, 138.98, 137.48, 130.06, 127.42, 125.42,
125.27, 119.47, 61.77, 26.96, 14.35; FT-IR (KBr) 3075, 2989, 1709,
1601, 1582, 1284, 1254, 1068, 870, 786 cm−1; HRMS (+EI) calcd
for C13H1179Br2NO2 (M+): 370.9157, found: 370.9162.
128.80, 128.60, 128.58, 126.87, 125.70, 125.66, 115.87 (d, 2JC–F
=
21.4 Hz, 2C), 34.33, 28.21, 23.14, 23.00; FT-IR (KBr) 3058, 2930,
2860, 1603, 1512, 1491, 1218, 1156, 847, 758, 564 cm−1; HRMS
(+EI) calcd for C19H16FN (M+): 277.1267, found: 277.1261.
9-(4-Fluorophenyl)-1,2,3,4-tetrahydro-1-acridinone (3g). 1H
NMR (300 MHz, CDCl3) d 2.26 (quintet, J = 6.5 Hz, 2H), 2.71
(t, J = 6.6 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 7.14–7.23 (m, 4H),
7.42–7.44 (m, 2H), 7.78 (ddd, J = 8.4, 6.2, 2.2 Hz, 1H), 8.07
1
1-(6,8-Dibromo-2-methylquinolin-3-yl)ethanone (3r). H NMR
(300 MHz, CDCl3) d 2.71 (s, 3H), 2.93 (s, 3H), 7.97 (d, J = 2.1 Hz,
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1H), 8.18 (d, J = 2.1 Hz, 1H), 8.32 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) d 199.45, 159.11, 143.98, 137.64, 137.04, 132.75, 130.07,
127.60, 125.48, 119.78, 29.54, 25.90; FT-IR (KBr) 3073, 2923,
1678, 1603, 1581, 1540, 1244, 943, 758 cm−1; HRMS (+EI) calcd
for C12H979Br2NO (M+): 340.9051, found: 340.9056.
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and Y.-G. Si, J. Org. Chem., 2002, 67, 9449.
5,7-Dibromo-2,3-dihydro-1H-cyclopenta[b]quinoline (3s). 1H
NMR (300 MHz, CDCl3) d 2.22 (quintet, J = 7.5 Hz, 2H), 3.10
(t, J = 7.5 Hz, 2H), 3.21 (t, J = 7.6 Hz, 2H), 7.74 (s, 1H), 7.82 (t,
J = 1.9 Hz, 1H), 8.02 (d, J = 1.9 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) d 169.89, 143.39, 137.71, 134.42, 129.50, 129.36, 129.33,
124.99, 118.35, 34.85, 30.44, 23.53; FT-IR (KBr) 3069, 2967, 1629,
1590, 1462, 1390, 1274, 1184, 1078, 868 cm−1; HRMS (+EI) calcd
for C12H979Br2N (M+): 324.9102, found: 324.9107.
5,7-Dibromo-1,2,3,4-tetrahydro-1-acridinone (3u). 1H NMR
(300 MHz, CDCl3) d 2.28 (quintet, J = 6.5 Hz, 2H), 2.82 (t, J =
6.6 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 8.05 (d, J = 2.0 Hz, 1H),
8.22 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) d 197.31, 163.58, 145.37, 138.35, 136.50, 131.33, 128.72,
127.56, 125.39, 119.86, 39.13, 33.67, 21.62; FT-IR (KBr) 3060,
2924, 1692, 1600, 1584, 1459, 1252, 1222, 1173, 1012, 937, 870, 787,
686 cm−1; HRMS (+EI) calcd for C13H979Br2NO (M+): 352.9051,
found: 352.9058.
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5,7-Dibromo-3,3-dimethyl-1,2,3,4-tetrahydro-1-acridinone (3v).
1H NMR (300 MHz, CDCl3) d 1.16 (s, 6H), 2.67 (s, 2H), 3.27 (s,
2H), 8.06 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H);
13C NMR (75.5 MHz, CDCl3) d 197.39, 162.38, 145.73, 138.19,
135.85, 131.32, 128.65, 126.51, 125.36, 119.79, 52.55, 47.22, 32.80,
28.45 (2C); FT-IR (KBr) 3058, 2953, 1688, 1599, 1586, 1462, 1228,
953, 865, 782, 701 cm−1; HRMS (+EI) calcd for C15H1379Br2NO
(M+): 380.9364, found: 380.9370.
11 (a) D. R. Sliskovic, J. A. Picard, W. H. Roark, B. D. Roth, E. Ferguson,
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Acknowledgements
We are grateful for financial support from the National Science
Fund for Distinguished Young Scholars (20125205), Fund for
Innovative Research Groups of National Science Foundation
of China (20321101) and Anhui Provincial Bureau of Human
Resources (2001Z019).
13 (a) Y. Fujikawa, M. Suzuki, H. Iwasaki, M. Sakashita and M. Kitahara,
Eur. Pat. Appl., EP 0304063, 1989; Y. Fujikawa, M. Suzuki, H. Iwasaki,
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Fujikawa, M. Kitahara, M. Sakashita and R. Sakoda, Bioorg. Med.
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