Silica sulfuric acid-catalyzed one-pot synthesis, mechanism, and fluorescence properties of 2-(2-arylquinolin-4-(1H)-ylidene)malononitriles

Article abstract of DOI:10.1002/jhet.1577

A mild, one-pot synthesis of 2-(2-arylquinolin-4-(1H)-ylidene) malononitriles is developed via the silica sulfuric acid-catalyzed tandem condensation of 2-aminoacetophenone with malononitrile and aromatic aldehyde in ionic liquid. It is proposed that malononitrile acted as not only a reactant but also a promoter in the interesting process. The fluorescence properties screening showed a new compound has high fluorescence quantum yield.

Full text of DOI:10.1002/jhet.1577

Month 2013
Silica Sulfuric Acid-Catalyzed One-Pot Synthesis, Mechanism, and
Fluorescence Properties of 2-(2-arylquinolin-4-(1H)-ylidene)malononitriles
Yu Wan,a,b Wei Lin,a,b Hai-qiang Xin,a,b Rui Yuan,a,b Ling-ling Zhao,a,b Jing-jing Shi,a,b Chao Wang,a,b
Xiao-xiao Zhang,a,b and Hui Wua,b
*
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, China
bKey Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Jiangsu 221116, China
*
E-mail: wuhui72@yahoo.com.cn
Received September 28, 2010
DOI 10.1002/jhet.1577
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A mild, one-pot synthesis of 2-(2-arylquinolin-4-(1H)-ylidene)malononitriles is developed via the silica
sulfuric acid-catalyzed tandem condensation of 2-aminoacetophenone with malononitrile and aromatic
aldehyde in ionic liquid. It is proposed that malononitrile acted as not only a reactant but also a promoter in
the interesting process. The fluorescence properties screening showed a new compound has high fluorescence
quantum yield.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
mild, base-promoted cyclization of N-(o-ketoaryl) amides,
known as the Camps cyclization, is more attractive and has
been widely employed to synthesize a variety of quinolines.
However, the synthetic utility of the Camps cyclization is
restricted by the limited access to N-(o-ketoaryl)amides.
Some other synthesis of these compounds makes use of tran-
sition metals [9], including palladium-catalyzed carbonyla-
tion [10], titanium-mediated reductive coupling [11], and
ruthenium-catalyzed reduction reactions [12]. Although the
scope of copper and palladium-catalyzed amidation of aryl
halides is broad in general, aryl halides bearing a ketone
functional group have been reported to be incompatible
because of the competitive arylation of the ketone enolate [13].
Therefore, the development of more efficient methods for
preparing these kind of compounds with milder reaction con-
ditions is desired. Herein, we will describe a new and simple
approach to synthesize 2-(2-arylquinolin-4-(1H)-ylidene)
malononitriles (4) via the reaction of malononitrile (1) with
aromatic aldehydes (2) and 2-aminoacetophenone (3) in
ionic liquid promoted by catalytic amount of silica sulfuric
acid (SSA). (Scheme 1).
In the beginning, optimizations of the reaction con-
ditions, including reaction solvents, temperature, and
amount of SSA, were investigated using malononitrile (1),
3,4-dimethoxybenzaldehyde (2d), and 2-aminoacetophe-
none (3) as model reactants. As summarized in Table 1, the
results showed that this transformation could not run
smoothly except in the presence of SSA (Entries 1–4,
Table 1), other acids or bases such as HCl, NaHSO3, or
NaOH could not be employed as promoter. The important
role of SSA in this reaction may be attributed to its acidity
and ability to form H-bonds. The H-bond formation between
SSA and NH2 in 2-aminoacetophenone made SSA act as a
As the analogs of the plant-derived flavone, aza-flavone
(2-arylquinolin-4(1H)-one) and its derivatives represent a
major class of nitrogen-containing heterocycles frequently
found in naturally occurring alkaloids and synthetic biologi-
cally active molecules [1]. They exhibit antibacterial activity
and have emerged as potent antibiotics [2]. More recently,
certain 2-arylquinolin-4(1H)-one and compounds containing
these structures have been studied as potential treatments for
a range of diseases [3] as they exhibit antimitotic [4], antipla-
telet [3], and antiviral [3] activities and have positive cardiac
effects [3]. Quinolin-4-(1H)-ylidene malononitriles are also
versatile synthetic intermediates because of their facile
derivatization [5].
May be due to the passivation between 2-OH and acetyl
in it, generally, 2-aminoacetophenone could not be used
as reactant to react with aromatic aldehyde to synthesize
2-arylquinolin-4(1H)-one via the direct cascade Knovenger
condensation–intramolecular Micheal addition such as
2-hydroxyacetophenone, which has higher reactivity.
Although there are many synthesis methods of quinoline
derivatives, the synthesis of 2-(2-arylquinolin-4-(1H)-
ylidene)malononitrile derivatives has not been reported so
far. Among the methods reported for the synthesis of quino-
line derivatives, the most classical and common one is the
condensation of aniline with Meldrum’s acid (or its deriva-
tives) and trimethyl orthoformate to afford the corresponding
enamine. The enamine intermediate is then cyclized in high-
boiling solvents, such as diphenyl ether at high temperature
(250ꢀC) or under microwave (300ꢀC) conditions [6–8]. This
method suffers from not only the harsh reaction conditions
but also the limitation of substrate scope. Alternatively, the
© 2013 HeteroCorporation

Y. Wan, W. Lin, H.-Q. Xin, R. Yuan, L.-L. Zhao, J.-J. Shi, C. Wang, X.-X. Zhang, and H. Wu
Vol 000
Scheme 1
Table 1
Synthesis of 4d under different conditions.a
Entry
Solvent
Catalyst (g)
Time (h)
T (ꢀC)
Yield of 4d (%)b
1
2
3
4
5
6
7
8
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
H2O
THF
alcohol
DMF
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
HCl (0.5)
6
6
6
6
6
6
6
6
6
6
6
6
3
5
8
6
6
6
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
80
Nrc
Nrc
Nrc
69
NaHSO3 (0.4)
NaOH (0.2)
SSA (0.2)
SSA (0.2)
SSA (0.2)
SSA (0.2)
SSA (0.2)
SSA (0.05)
SSA (0.1)
SSA (0.3)
SSA (0.4)
SSA (0.2)
SSA (0.2)
SSA (0.2)
SSA (0.2)
SSA (0.2)
SSA (0.2)
Nrc
Nrc
Nrc
Nrc
50
9
10
11
12
13
14
15
16
17
18
66
66
67
35
45
69
Nrc
45
100
140
67
aAll reactions were carried out in the scale of 1.0mmol of 3,4-dimethoxybenzaldehyde 2d, 1.0mmol of malononitrile 1, and 1.0mmol of 2-aminoacetophenone
3 in 2.0 mL of given solvent.
bIsolated yield.
cNo reaction.
phase transformation catalyst and enhance the solubility of
reactants in solvent. Water and classic organic solvents such
as tetrahydrofuran (THF), N,N-dimethylformamide (DMF),
and alcohol could not be used as efficient solvents. Ionic
liquids [BMIM]BF4 could effectively promote this process
(Entries 4–8, Table 1). Increasing catalytic loading of SSA
from 0.05 to 0.2 g improved the yield of 4d from 50% to
69%, which showed that the catalyst concentration plays a
major role in the reaction.
To apply this reaction to a library synthesis, the scope of
the substrates was evaluated with a variety of substituted
benzaldehydes (Table 2). It appeared that the electronic
nature of substituted groups in benzene ring had not
influenced on the yield. It is noteworthy that no remarkable
steric hindrance on the reaction was observed; for example,
the desired products were obtained in moderate to good
yields when the ortho substitutes on the benzaldehyde
were used (Entries 2 and 10, Table 2).
However, the yield decreased unexpectedly when the
amount of catalyst was over 0.2 g. A possible explanation
for the decrease of yield was that the starting materials
or the product had been destroyed when an excess
amount of SSA was added; thus, 0.2 g of SSA was a
suitable choice for optimum yield of 4d (Entries 9–12).
Finally, when the temperature was increased to 120ꢀC
with [BMIM]BF4 as the solvent, the reaction proceeded
smoothly (Entries 11 16, and 17, Table 1), However,
prolonging the reaction time did not enhance the yield of
the product (Entry 18, Table 1).
The fluorescence properties of products were shown in
Table 3. The following are clear: (i) Compared with the
fluorescence data of 9,10-diphenylanthrance, the blue-
shifted lmax(ex) (224–229 nm) and red-shifted lmax(em)
(464–493 nm) of all products afforded wide range of
Stokes shifts (160–240 nm). It showed that all products
could be excited more easily than 9,10-diphenylanthrance,
and the lmax(em) of products appeared in the blue light
range, which mentioned their value as luminescence or
fluorescence probe. (ii) The electro and steric effects of
substituted group on aromatic aldehydes have little
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Silica Sulfuric Acid-Catalyzed One-Pot Synthesis, Mechanism, and Fluorescence
Properties of 2-(2-arylquinolin-4-(1H)-ylidene)malononitriles
Table 2
Scheme 2
Synthesis and fluorescence of 2-quinolin-4(1H)-ylidene malononitrile.a
Melting point
Entry
Compound
R
Yield (%)b
(ꢀC)
1
2
3
4
5
4a
4b
4c
4d
4e
4-OH
2-MeO
4-MeO
3,4-(MeO)2
3,4,5-(MeO)
75
78
74
69
65
281–283
>300
>300
>300
>300
X-ray single crystal structure was shown in Figure 1.
Compound (5) can not react with (2g) to afford the final
product (4g). Finally, the reaction of the Knoevenagel
condensation product, 4-fluorophenylidenemalonodinitrile
(derived from 4-fluorobenzaldehydes (2g) and malononitrile
(1)) with 2-aminoacetophenone (3), did still not give the
corresponding product (4g) (Scheme 4). These results
suggested that this interesting reaction came through an
abnormal procedure.
3
6
7
8
9
4f
4g
4h
4i
3-F
4-F
3-Br
4-Br
2,4-Cl2
72
76
71
75
63
>300
>300
>300
>300
>300
10
4j
aAll reactions were carried out in the scale of 0.2 g of silica sulfuric acid in
2 mL ionic liquid at 120ꢀC, and starting materials
(1:2:3 = 1.0:1.0:1.0 mmol) were completely consumed.
bIsolated yield.
So, we speculated that the formation of the products was
via a cascade procedure (Scheme 5): the rapidly condensa-
tion of 2-aminoacetophenone with malononitrile gave
intermediate A, then aromatic aldehyde attacked the
ÀNH2 of A to give B. Then, the high reactive –CH3 in
intermediate B caused by two –CN with strong electron-
withdrawing effect added to enamine followed by tandem
intramolecular cyclization to afford the final product. It
also indicated the presence of mutual passivation between
–NH2 and carbonyl in 2-aminoacetophenone.
In conclusion, we have disclosed a simple and one-pot
method to synthesize 2-(2-arylquinolin-4-(1H)-ylidene)
malononitriles through a novel domino reaction of
arylaldehyde, malononitrile, and 2-aminoacetophenone in
ionic liquid by using catalyzed SSA. The mechanism
research proposed that malononitrile acted as not only a
reactant but also a promoter in the interesting process.
The fluorescence properties screening showed one new
compound has high fluorescence quantum yield.
influence on the fluorescence properties, which clearly
showed that the luminescence of products came from their
framework directly. (iii) Only 4h exhibited stronger
fluorescence in DMF with the bigger fluorescence quantum
yield than that of 9,10-diphenylanthrance (0.660), which
showed its potential application as a new fluorescent probe
or luminescence material.
To verify the mechanism, we performed each step
individually. First, 1-(2-aminophenyl)-3-(4-fluorophenyl)
prop-2-en-1-one, the product of 4-fluorobenzaldehydes (2g)
and 2-aminoacetophenone (3), reacted with malononitrile
(1) did not give corresponding product (4g) (Scheme 2).
This may be due to the decrease of carbonyl’s reactivity
caused by the strong electron-donating ability of o-NH2.
Second, when 2-aminoacetophenone (3) was treated with
malononitrile (1) (Scheme 3), we obtain an unexpected
product 2-amino-4-methylquinoline-3-carbonitrile (5). Its
Table 3
Luminescence Properties of 4.
Compound
Emax(abs) (MÀ1.cmÀ1
)
l
abs (nm)
l
em (nm)
RFIa
9989
Stokes shift
Φb
9,10-diphenylan thrance
2.221
2.379
2.261
2.017
2.576
2.547
2.144
2.179
3.501
2.420
2.169
261
227
227
226
229
229
226
226
237
227
224
408
464
481
448
485
472
486
477
477
485
493
147
160
179
149
240
174
177
168
149
172
177
0.660
0.010
0.070
0.020
0.060
0.060
0.275
0.344
0.670
0.531
0.211
4a
4b
4c
4d
4e
4f
4g
4h
4i
123.2
78.89
261.1
63.78
56.53
3660
4137
6433
5752
2549
4j
aRelative fluorescence intensity.
bRelative fluorescence quantum yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Wan, W. Lin, H.-Q. Xin, R. Yuan, L.-L. Zhao, J.-J. Shi, C. Wang, X.-X. Zhang, and H. Wu
Vol 000
Scheme 3
CH3
CN
N
NH2
5
Figure 1. ORTEP diagram of 5.
Scheme 4
Scheme 5. The possible reaction mechanism.
General procedure for the synthesis of compounds 4.
A
EXPERIMENTAL
mixture of substitution-2-hydroxyacetophenone (1.0 mmol),
aromatic aldehyde (1.0 mmol), malononitrile (1.0 mmol), and
0.2 g of silica sulfuric acid was stirred in ionic liquid (2 mL) at
120ꢀC. The reaction was monitored by TLC. The crude product
was precipitated by the addition of water and purified by flash
column chromatography (petroleum ether : ethyl acetate = 3:1).
The analytical data for represent compounds are shown below.
4a. 2-(2-(4-hydroxyphenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.82 (s, 1H), 10.32 (1H, s), 8.90–8.88 (1H, d, J =8.0 Hz),
7.96 (1H, s), 7.93 (1H, s), 7.86–7.84 (1H, t), 7.76 (s, 1H), 7.73
All reagents were purchased from commercial sources and
used without further purification. Melting points were determined
in the open capillaries and were uncorrected. TLC analysis was
performed with glass backed plates precoated with silica gel and
examined under UV (254 nm). NMR spectra were measured in
DMSO-d6 with Me4Si as the internal standards on a Bruker
Advance DPX-400 at room temperature. IR spectra were recorded
on Bruker FTIR spectrometer; absorbance were reported in cmÀ1
.
SSA was equipped with chlorosulfonic acid and silica at room
temperature [14].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Silica Sulfuric Acid-Catalyzed One-Pot Synthesis, Mechanism, and Fluorescence
Properties of 2-(2-arylquinolin-4-(1H)-ylidene)malononitriles
(s, 1H), 7.57–7.53 (1H, t), 7.03 (1H, s), 7.01 (1H, s), 6.93
(1H, s). HRMS (ESI): m/z calcd for C18H11N3O, 285.0902;
found, 285.0874.
12.68 (1H, s), 8.67 (1H, s), 8.56–8.54 (1H, d, J = 8.0 Hz),
8.52–8.50 (1H, d, J = 8.0 Hz), 8.20 (1H, s), 7.99 (1H, s),
7.81–7.78 (3H, m), 7.66–7.61 (1H, m), 7.59–7.57 (3H, m),
7.38–7.36 (1H, m). IR (cmÀ1): 6285, 3202, 3063, 2225,
1611, 1565, 1426, 1330, 757. HRMS (ESI): m/z calcd for
C18H10BrN3, 347.0855; found, 347.0919.
4i. 2-(2-(4-bromophenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.16 (1H, s), 8.59–8.57 (1H, d, J = 8.0 Hz ), 8.38–8.36 (1H,
d, J = 8.0Hz), 8.26 (1H, s), 7.79 (1H, s), 7.77 (1H, s), 7.65–7.61
(1H, t), 7.53–7.51 (1H, d, J = 8.0Hz), 7.35–7.31 (1H, t), 6.96 (2H,
s).IR (cmÀ1): 3488, 3329, 3165, 3129, 3058, 2206, 1627, 1605,
1432, 823, 807, 761. HRMS (ESI): m/z calcd for C18H10BrN3,
347.0855; found, 347.19104.
4j. 2-(2-(2,4-dichlorophenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.22 (1H, s), 8.34 (1H, t ), 7.95 (1H, s), 7.84–7.81 (1H, d,
J = 12.0 Hz ), 7.72–7.65 (2H, m), 7.63–7.62 (1H, d, J = 4.0 Hz),
7.62–7.60 (1H, m), 7.54–7.52 (1H, d, J = 8.0 Hz), 7.54–7.52
(1H, d, J = 8.0 Hz), 7.31–7.28 (1H, d, J = 12.0 Hz), 7.00–6.98
(2H, t) IR (cmÀ1): 3329, 3204, 2203, 1628, 1606, 1579, 1277,
808, 760. HRMS (ESI): m/z calcd for C18H9Cl2N3, 337.0314;
found, 337.0387.
4b. 2-(2-(2-methoxyphenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, 281–284ꢀC, 1H NMR (400 MHz, DMSO-d6):
d 13.14–13.13 (1H, m), 8.93–8.91 (1H, t), 7.86–7.85 (1H, t),
7.64–7.58 (1H, m), 7.30–7.28 (1H, d, J = 8.0 Hz), 7.20–7.16 (1H,
t), 6.88 (1H, s), 3.85 (1H, s). IR (cmÀ1): 3261, 3167, 2998,
2197, 1629, 1595, 1516, 1433, 1335, 1306, 1260, 1159, 1014.
853, 775. HRMS (ESI): m/z calcd for C19H13N3O, 299.1059;
found, 299.0910.
4c. 2-(2-(4-methoxyphenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.90 (1H, s), 8.89–8.87 (1H, d, J = 8.0 Hz), 7.96–7.94 (1H,
d, J = 8.0 Hz), 7.87–7.83 (3H, m), 7.57–7.53 (1H, m), 7.22 (1H,
s), 7.20 (1H, s), 6.94 (1H, s), 3.88 (3H, s). 13C NMR
(100 MHz, DMSO-d6): d 161.82, 153.29, 147.64, 138.19,
133.03, 129.51, 125.10, 124.60. 124.22, 120.13, 119.02,
114.77, 105.12, 55.59, 46.92. IR (cmÀ1): 3263, 3162, 3002,
2197, 1597, 1517, 1441, 1343, 1281, 1186, 1156, 1027.
HRMS (ESI): m/z calcd for C19H13N3O, 299.1059; found,
299.1038.
4d. 2-(2-(3,4-dimethoxyphenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.87 (1H, s), 8.91–8.89 (1H, d, J = 8.4 Hz), 7.95–7.93 (1H, d,
J = 8.0 Hz), 7.89–7.87 (1H, t), 7.59–7.54 (1H, m), 7.46–7.44
(2H, m), 7.24–7.21 (1H, d, J = 12.0 Hz), 6.96 (1H, s), 3.90
(3H, s), 3.87 (3H, s). 13C NMR (100 MHz, DMSO-d6): d
153.23, 151.51, 148.95, 147.85, 138.09, 133.03, 125.11,
124.76, 124.21, 121.15, 120.06, 119.01, 112.06, 115.05,
105.37, 55.85, 55.78, 46.90. IR (cmÀ1): 3258, 3210, 3161,
3140, 3002, 2950, 2839, 3193, 1631, 1603, 1583, 1516, 1449,
1023, 833, 776. HRMS (ESI): m/z calcd for C20H15N3O2,
329.1164; found, 329.1175.
Acknowledgments. We are grateful to the Natural Sciences
Foundation of China (No. 20772103), Natural Sciences Foundation
of University in Jiangsu Province (No. 10KJA430050), Surpassing
Project in Jiangsu Province (No. 08QLT001), the Innovation
Project of Post-graduate Student in Xuzhou Normal University
(No. 2010YLA003), Post-graduate Innovation Project in
Jiangsu Province (No. CX10S-551z), and the Natural Sciences
Foundation in Xuzhou Normal University (No. 09XLA17) for
financial support.
4e. 2-(2-(3,4,5-trimethoxyphenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.94 (1H, s), 8.90–8.88 (1H, d, J = 8.0 Hz), 7.93–7.86 (2H,
m), 7.59–7.55 (1H, m), 7.15 (2H, s), 6.95 (1H, s), 3.91 (6H,
s), 3.77 (3H, s). 13C NMR (100 MHz, DMSO-d6): d 153.32,
153.27, 148.03, 140.01, 138.02, 133.16, 128.22, 125.26, 124.25,
120.15, 119.04, 105.97, 105.73, 60.25, 55.34, 47.44. IR (cmÀ1):
3266, 3177, 3205, 2991, 2972, 2942, 2835, 2193, 2167, 1628,
1517, 1434, 1357, 1320, 834, 774. HRMS (ESI): m/z calcd for
C21H17N3O3, 359.1270; found, 359.1248.
4f. 2-(2-(3-fluorophenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.17 (1H, s), 8.62–8.60 (1H, d, J = 8.0 Hz), 8.24–8.21 (1H,
d, J = 12.0 Hz), 7.65–7.59 (2H, m), 7.53–7.51 (1H, d,
J = 8.0 Hz), 7.40–7.32 (2H, m), 6.97 (2H, s). IR (cmÀ1):
3475, 3402, 3330, 3179, 2209, 2098, 1647, 1606, 1520,
1431, 786, 761. HRMS (ESI): m/z calcd for C18H10FN3,
287.0859; found, 287.0917.
4g. 2-(2-(4-fluorophenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
12.12(1H, s), 8.59–8.57 (1H, d, J = 8.0 Hz), 8.49–8.45 (1H,
m), 8.24 (1H, s), 7.65–7.61 (1H, q), 7.53–7.51 (1H, d,
J = 8.0 Hz), 7.43–7.35 (2H, q), 7.35–7.31 (1H, t), 6.92 (1H, s).
IR (cmÀ1): 3494, 3373, 3128, 3060, 2969, 2897, 2205, 1649,
1513, 1435, 1226, 829, 806, 765. HRMS (ESI): m/z calcd for
C18H10FN3, 287.0859; found, 287.0803.
REFERENCES AND NOTES
[1] Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chem., 3rd
ed.; John Wiley and Sons: New York 1995, Chapter 6.
[2] (a) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. In
Heterocycles In Life and Society; John Wiley and Sons: New York
1997, pp 135–164. (b) Andriole, V. T. The Quinolones; Academic Press:
California 1988.
[3] (a) Osawa, T.; Ohta, H.; Akimoto, K.; Harada, K.; Soga, H.;
Jinno, Y. Eur. Patent. 1994. (b) Huang, L. J.; Hsieh, M. C.; Teng, C.
M.; Lee, K. H.; Kuo, S. C. Bioorg Med Chem 1998, 6, 1657. (c) Takami,
H.; Kishibayashi, N.; Ishii, A.; Kumazawa, T. Bioorg Med Chem 1998, 6,
2441. (d) Lee, H. Z.; Lin, W. C.; Yeh, F. T.; Wu, C. H. Eur J Pharmacol
1998, 354, 205. (e) Jackson, S. P.; Robertson, A. D.; Kenche, V.;
Thompson, P.; Prabaharan, H.; Anderson, K.; Abbott, B.; Goncalves, I.;
Nesbitt, W.; Schoenwaelder, S.; Saylik, D. PCT Int. Patent 016607,
2004. (f) Llina`s-Brunet, M.; Bailey, M. D.; Ghiro, E.; Gorys, V.; Halmos,
T.; Poirier, M.; Rancourt, J.; Goudreau, N. J Med Chem 2004, 47, 6584.
(g) Wu, F. X. H.; Nakajima, S.; Lu, Z. H.; Sun, Y.; Miao, Z.; Wang, Z.
PCT Int. Patent 010029, 2005. (h) Pal, M.; Khanna, I.; Subramanian,
V.; Padakanti, S.; Pillarisetti, S. PCT Int. Patent 058201, 2006. (i) Frutos,
R. P.; Haddad, N.; Houpis, I. N.; Johnson, M.; Smith-Keenan, L. L.;
Fuchs, V.; Yee, N. K.; Farina, V.; Faucher, A.-M.; Brochu, C.; Hache´,
B.; Duceppe, J.-S.; Beaulieu, P. Synthesis 2006, 36: 2563.
[4] (a) Kuo, S. C.; Lee, H. Z.; Juang, J. P.; Lin, Y. T.; Wu, T.-S.;
Chang, J. J.; Lednicer, D.; Paull, K. D.; Lin, C. M.; Hamel, E.; Lee, K. H.
J Med Chem 1993, 36, 1146. (b) Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T.
S.; Lednicer, D.; Lin, C. M.; Hamel, E.; Lee, K. H. J Med Chem 1994, 37,
1126. (c) Sui, Z.; Nguyen, V. N.; Altom, J.; Fernandez, J.; Hilliard, J. J.;
Bernstein, J. I.; Barrett, J. F.; Ohemeng, K. A. Eur J Med Chem 1999, 34,
4h. 2-(2-(3-bromophenyl)quinolin-4(1H)-ylidene) malononitrile.
Yellow crystal, >300ꢀC, 1H NMR (400 MHz, DMSO-d6): d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Wan, W. Lin, H.-Q. Xin, R. Yuan, L.-L. Zhao, J.-J. Shi, C. Wang, X.-X. Zhang, and H. Wu
Vol 000
[7] Torii, S.; Okumoto, H.; Xu, L. H.; Sadakane, M.;
Shostakovsky, M. V.; Ponomaryov, A. B.; Kalinin, V. N. Tetrahedron
1993, 49(31), 6773.
[8] Fürstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J Org Chem
1994, 59(18), 5215.
[9] (a) Tang, J.; Huang, X. Synth Commun 2003, 33, 3953. (b)
Beifuss, U.; Ledderhose, S. Synlett 1997, 2: 313. (c) Strekowski, L.;
Wydra, R. L.; Cegla, M. T.; Czarny, A.; Harden, D. B.; Patterson, S. E.;
Battiste, M. A.; Coxon, J. M. J Org Chem 1990, 55, 4777.
[10] Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov, A. B. Tet-
rahedron Lett 1992, 33, 373.
381. (d) Xia, Y.; Yang, Z. Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu,
J. H.; Lee, K. H. J Med Chem 2001, 44, 3932. (e) Hadjeri, M.; Peiller, E.-L.;
Beney, C.; Deka, N.; Lawson, M. A.; Dumontet, C.; Boumendjel, A. J Med
Chem 2004, 47, 4964. (f) Hradil, P.; Krejcı´, P.; Hlava´c, J.; Wiederman-
nova´, I.; Lycka, A.; Bertolasi, V. J Heterocycl Chem 2004, 41, 375.
(g) Lai, Y. Y.; Hung, L. J.; Lee, K. H.; Xiao, Z.; Bastow, K. F.; Yamori,
T.; Kuo, S. C. Bioorg Med Chem 2005, 13, 265. (h) Ferlin, M. G.; Chiar-
elotto, G.; Gasparotto, V.; Via, L. D.; Pezzi, V.; Barzon, L.; Palu, G.;
Castagliuolo, I. J Med Chem 2005, 48, 3417. (i) Gasparotto, V.; Casta-
gliuolo, I.; Chiarelotto, G.; Pezzi, V.; Montanaro, D.; Brun, P.; Palu,
G.; Viola, G.; Ferlin, M. G. J Med Chem 2006, 49, 1910.
[11] Fu¨rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J Org Chem
1994, 59, 5215.
[12] Tollari, S.; Cenini, S.; Ragaini, F.; Cassar, L. J Chem Soc
1994, 1741.
[13] Yin, J.; Buchwald, S. L. J Am Chem Soc 2002, 124, 6043.
[14] Wu, H.; Shen, Y.; Wan, Y.; Shi, D. Q. Tetrahedron 2007, 63,
2404.
[5] (a) Raafat, M.; Shaker, A. J Chem Soc 2006, 59. (b) Jan, S. J
Chem Soc 1988, 2053. (c) VanAllan, J. A.; Petropoulos, C. C.; Reynolds,
G. A.; Maier, D. P. J Heterocycl Chem 2009, 7, 495. (d) Xia, Y.; Yang, Z.
Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S. C.; Hamel, E.; Hackl,
T.; Lee, K. H. J Med Chem 1998, 41, 1155.
[6] Madrid, P. B.; Sherrill, J.; Liou, A. P.; Weisman, J. L.; DeRisi,
J. L.; Guy, R. K. Bioorg Med Chem Lett 2005, 15, 1015.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet