A novel one-pot synthesis of 2-arylpyrazoloquinolinone derivatives

Article abstract of DOI:10.1016/j.tet.2012.04.093

Two regioisomers of 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones and 2-arylpyrazolo[4,3-c]quinolin-4(5H)-ones were synthesized by utilizing 3-arylsydnones, ethyl 3-bromopropynoate, and 2-aminophenylboronic acid pinacol ester in presence of catalytic agent Pd(PPh₃)₄. This efficient one-pot synthesis methodology involved 1,3-dipolar cycloaddition, Suzuki coupling reaction, and intramolecular cyclization three sequence steps.

Full text of DOI:10.1016/j.tet.2012.04.093

Tetrahedron 68 (2012) 5920e5924
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel one-pot synthesis of 2-arylpyrazoloquinolinone derivatives
,
En-Chiuan Chang b, Ya-Lan Wen c d, Chun-Hsi Chang a, Yun-Hwei Shen c, Shaw-Bing Wen d,
,
a,
*
Mou-Yung Yeh b , Fung Fuh Wong
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
b Department of Chemistry, National Cheng Kung University, No 1, Ta Hsueh Rd., Tainan 70101, Taiwan, ROC
c Department of Resources Engineering, National Cheng Kung University, No. 1, Ta Hsueh Rd., Tainan 70101, Taiwan, ROC
d Department of Nursing, Meiho University, No. 23, Ping Kuang Rd., Neipu Hsiang, Pingtung 912, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Two regioisomers of 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones and 2-arylpyrazolo[4,3-c]quinolin-4(5H)-
ones were synthesized by utilizing 3-arylsydnones, ethyl 3-bromopropynoate, and 2-aminophenylboronic
acid pinacol ester in presence of catalytic agent Pd(PPh3)4. This efficient one-pot synthesis methodology
involved 1,3-dipolar cycloaddition, Suzuki coupling reaction, and intramolecular cyclization three
sequence steps.
Received 9 January 2012
Received in revised form 6 April 2012
Accepted 24 April 2012
Available online 10 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Arylpyrazolo[3,4-c]quinolin-4(5H)-ones
2-Arylpyrazolo[4,3-c]quinolin-4(5H)-ones
3-Aryl sydnone
1,3-Dipolar cycloaddition
Suzuki coupling reaction
Adenosine receptor
1. Introduction
to 3-ethoxalylindole is an expensive restricted starting material and
requires tedious procedures for manufacture. For preparation of 2-
An endogenous adenosine modulates a wide range of physio-
logical processes in the nervous, cardiovascular, renal, and immune
systems, interacts with at least four cell surface receptor subtypes
classified as A1, A2A, A2B, and A3.1e4 In 2000 and 2007, Colotta et al.,3
reported that 2-arylpyrazolo[3,4-c]quinolin-4(5H)-one compounds
1 can be potent and selective binding activity at bovine A1, A2A AR,
and human cloned A3 as adenosine receptor antagonists (see
Fig. 1).5,6 Moreover, another structural isomers 2-arylpyrazolo[4,3-
c]quinolin-4(5H)-ones 2 were also synthesized to evaluate as po-
tent and selective A3 adenosine receptor antagonists by Baraldi
et al. (see Fig. 1).7 As a result, the pyrazoloquinolinone structure
have been extensively investigated the biological functions in the
central nervous and periphery system.
A few of methods were provided to prepare 2-arylpyrazolo[3,4-c]
quinolin-4(5H)-one and 2-arylpyrazolo[4,3-c]quinolin-4(5H)-one
two core compounds. Currently, Catarzi et al.8 reported an improved
microwave irradiation synthesis of 2-arylpyrazolo[3,4-c]quinolin-
4(5H)-one from 3-thoxalylindole. However, this methodology is
usually performed on a small scale and the special analogues owing
arylpyrazolo[4,3-c]quinolin-4(5H)-ones, the standard procedure
was the multiple synthetic pathways involving imination of the
corresponding phenylhydrazines,9 Vilsmeier reaction, oxidation,
esterification, and the sequential hydrogenation of nitro group and
intramolecular cyclization.7 Herein, we have successfully developed
the efficient one-pot synthesis methodology involved 1,3-dipolar
cycloaddition, Suzuki coupling reaction, and intramolecular cycli-
zation three steps to prepare 2-arylpyrazolo[3,4-c]quinolin-4(5H)-
ones 1 and 2-arylpyrazolo[4,3-c]quinolin-4(5H)-ones 2 two classes
products. After the further chromatography purification, the
R
R1
N
O
R2
N
R
N
N
N
N
R2
R1
O
1
2
* Corresponding authors. Tel.: þ886 4 2205 3366x5603; fax: þ886 4 2207 8083;
e-mail addresses: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F.F.
Wong).
Fig. 1. 2-Arylpyrazolo[3,4-c]quinolin-4(5H)-one compounds 1 and 2-arylpyrazolo[4,3-
c]quinolin-4(5H)-ones 2.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.093

E.-C. Chang et al. / Tetrahedron 68 (2012) 5920e5924
5921
corresponding two 2-arylpyrazoloquinolinone isomers products 1
and 2 were separated and obtained in 27e32% and 39e43% isolated
yields, respectively (total yields 68e75%).
substituted isomers (6aed) appeared 0.35e0.37 ppm upfield rela-
tive to the 4-carboethoxy-substituted isomers (7aed).12
The individual isolated regioisomeric pyrazole 6 or 7 was per-
formed the 3- or 4-arylation with 2-aminophenylboronic acid
pinacol ester13 under the optimal Suzuki cross-coupling reaction
condition.14 The efficient cross-coupling could be accomplished by
using 10 mol % amount of Pd(PPh3)4 as palladium source, K2CO3
(5 equiv) as base, and p-xylene/ethanol solvent under reflux, which
afforded the corresponding desired products 2-arylpyrazolo[3,4-c]
quinolin-4(5H)-ones 1aed in 73e82% or 2-arylpyrazolo[4,3-c]qui-
nolin-4-(5H)-ones 2aed in 78e82% isolated yields (see Table 1).
To evaluate the one-pot multicomponent processes for prepa-
ration of 2-arylpyrazoloquinolinone derivatives 1aed and 2aed,
compound 3-phenyl sydnone 3a was used as modeling case to
choose the optimal three sequence steps condition (see Scheme 2).
Initial studies involved using PdCl2(PPh3)2 or Pd(OAc)2 as Pd(0)
catalyst source in the presence of K2CO3 as base in toluene/EtOH
solvent under reflux, which gave compound 1a and 2a (from 3a) in
low total yield (<56%). However, the efficient standard condition
could be accomplished by switching to Pd(PPh3)4 (10 mol %), K2CO3
(5 equiv) as base, and p-xylene/EtOH/H2O co-solvent under reflux,
which afforded the corresponding 2-arylpyrazoloquinolinones 1a
and 2a in modest total yield (>70%, see Table 2). Furthermore, we
employed the same reaction condition to 3-aryl sydnone substrates
3bee bearing with meta-chloro and various para-substituted aryl
group substituents, including Me, OMe, and F, the one-pot synthesis
methodology was also smoothly performed to give the corre-
sponding 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones 1bee and 2-
arylpyrazolo[4,3-c]quinolin-4(5H)-ones 2bee products in 27e32%
and 39e43% yields, respectively (see Scheme 2 and Table 2).
2. Results and discussion
To evaluate the one-pot multicomponent processes for prepa-
ration of 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones
1 and 2-
arylpyrazolo[4,3-c]quinolin-4(5H)-ones 2, the step-by-step syn-
thesis methodology were preliminarily carried out to research the
modeling synthetic study (see Scheme 1). Sydnones 3 bearing with
various para-substituted aryl group substituents, including Me,
OMe, and F, were prepared as the starting materials by the pub-
lished procedure.10 They underwent smooth cycloaddition with
ethyl 3-bromopropynoate to give two isomer pyrazoles 6 and 7.11
The reaction involves a 1,3-diploar cycloaddition of the sydnones,
behaving like a N-bridged cyclic azomethine imine intermediates
(4 and 5, see Scheme 1).12 The initially formed cycloadducts readily
extrude carbon dioxide to produce a mixture of five-membered
regioisomeric pyrazoles (6 and 7, see Scheme 1). After the further
chromatography purification, the corresponding two isomers
products 6aed and 7aed were obtained in 43e49% and 33e41%
isolated yields, respectively (see Table 1). Moreover, the ratios of
regioisomers (6/7) were detected from 59/41 to 53/47 (see Table 1,
the ratios were identified by 1H NMR spectrometer technique). The
structure assignment of the regioisomers (6/7) was made on the
basis of their characteristic 1H NMR spectrum. Particular attention
was given to the chemical shift of the special proton at 5-position in
pyrazolic ring. The identical ring proton in the 3-carboethoxy-
Ar
Ar
N
O
Br
OEt
O
O
O
N
Br
O
OEt
+
R
R
N
N
O
O
p-xylene, at reflux
N
N
N
O
O
Br
5a-5d
EtO
3a-3d
4a-4d
O
Br
O
OEt
3a, 4a, 5a, 6a, 7a: R = H
N
+
R
N
3b, 4b, 5b, 6b, 7b: R = Me
3c, 4c, 5c, 6c, 7c: R = OMe
3d, 4d, 5d, 6d, 7d: R = F
OEt
N
Br
6a-6d
7a-7d
NH2
O
B
NH2
O
B
O
O
Pd(PPh3)4, K2CO3
p-xylene/EtOH, at reflux
Pd(PPh3)4, K2CO3
p-xylene/EtOH, at reflux
O
1a, 2a: R = H
1b, 2b: R = Me
1c, 2c: R = OMe
1d, 2d: R = F
N
N
NH
R
N
R
N
NH
O
1a-1d
2a-2d
Scheme 1. The step-by-step synthesis of 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones 1aed and 2-arylpyrazolo[4,3-c]quinolin-4-(5H)-ones 2aed.

5922
E.-C. Chang et al. / Tetrahedron 68 (2012) 5920e5924
Table 1
The result of step-by-step synthesis of 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones 1aed and 2-arylpyrazolo[4,3-c]quinolin-4-(5H)-ones 2aed
Sydnones
R
Pyrazoles
No.
Final products 1 and 2
Yields (6/7, %/%)a
The ratios of regioisomers 6/7b
No.
Yieldsc (%)
No.
Yieldsd (%)
3a
3b
3c
3d
H
6a/7a
6a/7a
6a/7a
6a/7a
48/41
49/41
49/33
43/38
54/46
56/44
59/41
53/47
1a
1b
1c
1d
82
78
73
80
2a
2b
2c
2d
80
82
79
78
Me
OMe
F
a
The yields of regioisomers 6/7 were detected by the individual isolated yields from the chromatography separation method.
The ratios of regioisomers 6/7 were detected by 1H NMR spectrometer technique.
The yields of products 1aed were based on the weight of individual isolated compounds 6aed.
The yields of products 2aed were based on the weight of individual isolated compounds 7aed.
b
c
d
Although this newly developed method can provide the convenient
NMR spectra were obtained on a Bruker (300 MHz) spectrometer
by use of CDCl3 and DMSO-d6 as solvent. Carbon-13 NMR spectra
were obtained on a Bruker (75 MHz) spectrometer by used of CDCl3
as solvent. Carbon-13 chemical shifts are referenced to the center of
and effective one-pot synthesis to give tricyclic pyrazoloquinolinone
products, the low regioselectivity was observed in multicomponent
reaction.
Furthermore, we tried to perform the sequential three-
component study. 3-Aryl sydnone 3 was simultaneously treated
with ethyl 3-bromopropynoate and 2-aminophenylboronic acid
pinacol ester in presence of catalytic agent Pd(PPh3)4 and p-xylene/
EtOH/H2O co-solvent under reflux. The reaction was continuously
stirred and monitored for more than 72 h. However, the starting
material sydnone was not totally consumed. When the reaction was
terminated and worked-up, only the low yield of the desired pyr-
azoloquinolinone product was obtained (<15% yield).
the CDCl3 triplet (d 77.0 ppm). Multiplicities are recorded by the
following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; J, coupling constant (hertz). Elemental analyses were
carried out on a Heraeus CHNeO RAPID element analyzer. ESI-MS
spectra were obtained from an Applied Biosystems API 300 mass
spectrometer. High-resolution mass spectra were obtained by
means of a JEOL JMS-HX110 mass spectrometer.
3.2. Standard procedure for synthesis of pyrazoles (6 and 7)
In conclusion, we have successfully developed the one-pot
method to prepare two arylpyrazoloquinolinone regioisomers by
treating 3-aryl sydnones, ethyl 3-bromopropynoate, and 2-
aminophenylboronic acid pinacol ester in presence of catalytic
agent Pd(PPh3)4. Through the convenient column chromatography
purification, the corresponding two arylpyrazolo[3,4-c]quinolinone
1 and arylpyrazolo[4,3-c]quinolinone 2 products were obtained in
27e32% and 39e43% isolated yields, respectively.
A solution of 3-aryl sydnone (3, 0.20 g, 1.0 equiv) in 4 mL
p-xylene was added ethyl 3-bromopropynoate (0.23 g, 1.05 equiv)
and heated to reflux for 5 h. When the reaction was completed, the
reaction mixture was concentrated under reduced pressure to
remove p-xylene. The residue solution was purified by column
chromatography on silica gel to give the corresponding pyrazoles (6
and 7) in 43e49% and 33e41% isolated yields, respectively.
3. Experimental section
3.1. General procedure
3.2.1. Ethyl 4-bromo-1-phenyl-1H-pyrazole-3-carboxylate (6a).
1H NMR (CDCl3, 300 MHz)
d
1.43 (t, J¼7.5 Hz, 3H, ArH), 4.46 (q,
J¼7.0 Hz, 2H, CH), 7.38 (t, J¼3.1 Hz, 1H, ArH), 7.47 (t, J¼7.5 Hz, 2H,
ArH), 7.68e7.70 (d, J¼5.9 Hz, 2H, ArH), 7.99 (s, 1H, CH); 13C NMR
All chemicals were reagent grade and used as purchased. All
reactions were carried out under nitrogen atmosphere and moni-
tored by TLC analysis. Flash column chromatography was carried
out on silica gel (230e400 mesh). Infrared (IR) spectra were mea-
sured on a Bomem Michelson Series FT-IR spectrometer. The
wavenumbers reported are referenced to the polystyrene
1601 cmꢀ1 absorption. Absorption intensities are recorded by the
following abbreviations: s, strong; m, medium; w, weak. Proton
(75 MHz, CDCl3) d 14.3, 61.4, 98.2, 119.9, 128.1, 129.6, 129.8, 139.0,
141.8, 161.0; Anal. Calcd for C12H11BrN2O2; C: 48.84; H: 3.76; N: 9.49;
found: C: 48.87; H: 3.73; N: 9.45.
3.2.2. Ethyl 3-bromo-1-phenyl-1H-pyrazole-4-carboxylate (7a).
1H NMR (CDCl3, 300 MHz)
d
1.38 (t, J¼7.5 Hz, 3H, CH), 4.35 (q,
J¼8.1 Hz, 2H, CH), 7.37 (t, J¼3.1 Hz, 1H, ArH), 7.47 (t, J¼7.5 Hz, 2H,
ArH), 7.66e7.68 (d, J¼5.9 Hz, 2H, ArH), 8.35 (s, 1H, CH); 13C NMR
O
R
N
NH
N
O
R
, p-xylene
Br
1.
1a-1e
O
OEt
N
O
N
NH2
O
B
R
2.
3a-3d
1a, 2a, 3a: R = H
1b, 2b, 3b: R = p-Me
1c, 2c, 3c: R = p-OMe
1d, 2d, 3d: R = p-F
1e, 2e, 3e: R = m-Cl
N
N
O
NH
Pd(PPh3)4, K2CO3
p-xylene/EtOH, at reflux
O
2a-2e
Scheme 2.

E.-C. Chang et al. / Tetrahedron 68 (2012) 5920e5924
5923
Table 2
The result of one-pot synthesis of 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones 1aee and 2-arylpyrazolo[4,3-c]quinolin-4(5H)-ones 2aee
O
N
The ratios of regioisomers (1 and 2)a
The isolated yields (%) of 1 and 2
O
N
Yields of 1/2b
Total yields (%)
R
3a
R¼p-H
1a/2a
1b/2b
1c/2c
1d/2d
1e/2e
45/55
32/40
32/43
29/39
27/43
30/42
72
75
68
70
72
3b
3c
3d
3e
R¼p-Me
R¼p-OMe
R¼p-F
42/58
43/57
38/62
41/59
R¼m-Cl
a
The ratios of regioisomers 1/2 were detected by 1H NMR spectrometer technique.
The yields of regioisomers 1/2 were detected by the individual isolated yields from the chromatography separation method.
b
(75 MHz, CDCl3)
d
14.3, 60.7, 115.6, 119.3, 128.0, 129.4, 129.6, 132.0,
for C12H10BrFN2O2; C: 46.03; H: 3.22; N: 8.95; found: C: 46.06; H:
3.19; N: 8.98.
138.7, 161.3; Anal. Calcd for C12H11BrN2O2; C: 48.84; H: 3.76; N:
9.49; found: C: 48.83; H: 3.75; N: 9.50.
3.2.3. Ethyl 4-bromo-1-(4-methylphenyl)-1H-pyrazole-3-
3.3. Standard procedure for synthesis of 2-arylpyrazolo[3,4-c]
quinolin-4(5H)-ones 1aed and 2-arylpyrazolo[4,3-c]quinolin-
4-(5H)-ones 2aed from pyrazoles (6 or 7) via of step-by-step
method
carboxylate (6b). 1H NMR (DMSO-d6, 300 MHz)
d
1.32 (t, J¼6.1 Hz,
3H, CH), 2.34 (s, 3H, ArCH), 4.33 (q, J¼6 Hz, 2H, CH), 7.32e7.34 (d,
J¼6.1 Hz, 2H, ArH), 7.72e7.74 (d, J¼6.1 Hz, 2H, ArH), 8.86 (s, 1H, CH);
13C NMR (75 MHz, DMSO-d6)
d 14.1, 20.5, 60.8, 97.0, 119.0, 130.1,
131.0, 136.4, 137.6, 140.6, 160.3; Anal. Calcd for C13H13BrN2O2; C:
50.50; H: 4.24; N: 9.06; found: C: 50.51; H: 4.20; N: 9.03.
A solution of (6 or 7, 100 mg, 1.0 equiv) in 8.0 mL p-xylene/EtOH
(1/1) was added 2-aminophenylboronic acid pinacol ester (820 mg,
1.1 equiv), Pd(PPh3)4 (39 m g, 0.1 equiv), and K2CO3 (2 mL, 2 M
aqueous solution). The solution was heated to reflux for 24 h. After
the reaction was completed, the reaction mixture was concentrated
under reduced pressure to remove p-xylene and EtOH. The residue
was added with 20 mL water, and extract with EtOAc (40 mL). The
organic layer was filtered to remove the insoluble substances, then
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue solution was purified by column chromatography
on silica gel to give the corresponding 2-arylpyrazolo[3,4-c]qui-
nolin-4(5H)-one products 1aed in 73e82% or 2-arylpyrazolo[4,3-c]
quinolin-4-(5H)-one products 2aed in 78e82% isolated yields.
3.2.4. Ethyl 3-bromo-1-(4-methylphenyl)-1H-pyrazole-4-
carboxylate (7b). 1H NMR (DMSO-d6, 300 MHz)
d
1.30
(t, J¼5.8 Hz, 3H, CH), 2.33 (s, 3H, CH), 4.27 (q, J¼5.8 Hz, 2H, CH),
7.30e7.32 (d, J¼5.8 Hz, 2H, ArH), 7.74e7.77 (d, J¼9.1 Hz, 2H, ArH),
9.02 (s, 1H, CH); 13C NMR (75 MHz, DMSO-d6)
d 14.2, 20.4, 60.2,
114.5, 118.9, 128.4, 130.0, 133.4, 136.1, 137.3, 160.7; Anal. Calcd for
C13H13BrN2O2; C: 50.50; H: 4.24; N: 9.06; found: C: 50.48; H: 4.20;
N: 9.09.
3.2.5. Ethyl 4-bromo-1-(4-methoxyphenyl)-1H-pyrazole-3-
carboxylate (6c). 1H NMR (CDCl3, 300 MHz)
d
1.35 (t, J¼6.1 Hz,
3H, CH), 3.74 (s, 3H, OCH), 4.37 (q, J¼6.9 Hz, 2H, CH), 6.84e6.87 (d,
J¼9.1 Hz, 2H, ArH), 7.48e7.51 (d, J¼9.1 Hz, 2H, ArH), 7.84 (s, 1H, CH);
3.4. Standard procedure for one-pot synthesis of 2-arylpyrazolo
[3,4-c]quinolin-4(5H)-ones 1aee and 2-arylpyrazolo[4,3-c]
quinolin-4-(5H)-ones 2aee
13C NMR (75 MHz, CDCl3)
d 14.0, 55.3, 61.0, 97.5, 114.3, 121.1, 129.6,
132.3, 141.0, 159.1, 160.8; Anal. Calcd for C13H13BrN2O3; C: 48.02; H:
4.03; N: 8.62; found: C: 47.98; H: 3.99; N: 8.67.
A solution of 3-phenyl sydnone (3, 100 mg, 1.0 equiv) in 4.0 mL
p-xylene was added ethyl 3-bromopropynoate (120 mg, 1.05 equiv)
and heated to reflux for 5 h. The residue was cooled down and
added 2-aminophenylboronic acid pinacol ester (820 mg,1.1 equiv),
Pd(PPh3)4 (39 mg, 0.1 equiv), K2CO3 (2 mL, 2 M aqueous solution),
and EtOH (4.0 mL). The reaction mixture was stirred at reflux for
24 h. When the reaction was completed, the reaction mixture was
concentrated under reduced pressure to remove p-xylene and
EtOH. The residue was added with 20 mL water, and extract with
EtOAc (40 mL). The organic layer was filtered to remove the in-
soluble substances, then dried over MgSO4, filtered, and concen-
trated under reduced pressure. The residue solution was purified by
column chromatography on silica gel to give the corresponding 2-
arylpyrazolo[3,4-c]quinolin-4(5H)-one 1bee and 2-arylpyrazolo
[4,3-c]quinolin-4(5H)-one 2bee products in 27e32% and 39e43%
yields, respectively.
3.2.6. Ethyl 3-bromo-1-(4-methoxyphenyl)-1H-pyrazole-4-
carboxylate (7c). 1H NMR (CDCl3, 300 MHz)
d
1.34 (t, J¼7.5 Hz,
3H, CH), 3.79 (s, 3H, OCH), 4.30 (q, J¼7.5 Hz, 2H, CH), 6.90e6.93 (d,
J¼8.8 Hz, 2H, ArH), 7.50e7.53 (d, J¼8.8 Hz, 2H, ArH), 8.21 (s, 1H,
CH); 13C NMR (75 MHz, CDCl3)
d 14.2, 55.4, 60.5, 114.5, 115.0, 120.9,
128.8, 131.8, 132.2, 159.1, 161.3; Anal. Calcd for C13H13BrN2O3; C:
48.02; H: 4.03; N: 8.62; found: C: 47.99; H: 4.04; N: 8.54.
3.2.7. Ethyl 4-bromo-1-(4-fluorophenyl)-1H-pyrazole-3-carboxylate
(6d). 1H NMR (CDCl3, 300 MHz)
d
1.43 (t, J¼7.5 Hz, 3H, CH), 4.46
(q, J¼7.1 Hz, 2H, CH), 7.17 (t, J¼8.9 Hz, 2H, ArH), 7.64e7.69 (m, 2H,
ArH), 7.94 (s, 1H, ArH); 13C NMR (300 MHz, CDCl3)
14.2, 61.5, 98.3,
d
116.3, 116.7, 121.8, 121.9, 132.1, 141.9, 160.4, 160.9, 163.7; Anal. Calcd
for C12H10BrFN2O2; C: 46.03; H: 3.22; N: 8.95; found: C: 45.97; H:
3.26; N: 8.91.
3.2.8. Ethyl 3-bromo-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate
3.4.1. 2-Phenylpyrazolo[3,4-c]quinolin-4(5H)-ones (1a). 1H NMR
(7d). 1H NMR (CDCl3, 300 MHz)
d
1.38 (t, J¼7.5 Hz, 3H, CH), 4.36
(q, J¼6.9 Hz, 2H, CH), 7.17 (t, J¼9.0 Hz, 2H, ArH), 7.63e7.67 (m, 2H,
ArH), 8.29 (s, 1H, CH); 13C NMR (75 MHz, CDCl3)
14.3, 60.8, 115.8,
116.4, 116.7, 121.3, 121.4, 129.5, 132.1, 160.3, 161.3, 163.6; Anal. Calcd
(DMSO-d6, 300 MHz)
ArH), 7.64 (t, J¼7.5 Hz, 2H, ArH), 7.96e8.05 (m, 3H, ArH), 9.49 (s, 1H,
CH), 11.49 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
114.9, 116.1,
119.8,122.3,122.6,123.5,123.8,127.8,128.1,129.8,136.1,139.4,141.6,
d
7.24 (t, J¼7.5 Hz, 1H, ArH), 7.35e7.51 (m, 3H,
d
d

5924
E.-C. Chang et al. / Tetrahedron 68 (2012) 5920e5924
156.9; Anal. Calcd for C16H11N3O; C: 73.55; H: 4.24; N: 16.08; found:
C: 73.58; H: 4.23; N: 16.09.
7.47e7.56 (m, 3H, ArH), 7.92e7.94 (d, J¼6.0 Hz, 1H, ArH), 8.02e8.04
(d, J¼6.0 Hz, 1H, ArH), 8.09e8.14 (m, 2H, ArH), 9.55 (s, 1H, CH), 11.51
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
d 114.8, 116.4, 116.7, 118.5,
3.4.2. 2-Phenylpyrazolo[4,3-c]quinolin-4(5H)-ones (2a). 1H NMR
119.8, 122.3, 122.9, 123.7, 126.6, 130.1, 131.2, 134.2, 138.2, 139.6, 141.1,
156.6; Anal. Calcd for C16H10ClN3O; C: 64.98; H: 3.41; N: 14.21;
found: C: 65.02; H: 3.45; N: 14.25.
(DMSO-d6, 300 MHz)
ArH), 8.13 (t, J¼7.5 Hz, 3H, ArH), 9.38 (s, 1H, CH), 11.26 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6)
113.7, 114.4, 116.3, 119.8, 122.2, 122.3,
d
7.26 (t, J¼7.5 Hz, 1H, ArH), 7.37e7.63 (m, 5H,
d
127.8, 128.5, 129.7, 138.2, 139.2, 149.1, 158.7; Anal. Calcd for
C16H11N3O; C: 73.55; H: 4.24; N: 16.08; found: C: 73.57; H: 4.26; N:
16.05.
3.4.10. 2-(3-Chlorophenylphenyl)pyrazolo[4,3-c]quinolin-4(5H)-ones
(2e). 1H NMR (DMSO-d6, 300 MHz)
d
7.22e7.24 (m, 1H, ArH),
7.38e7.61 (m, 4H, ArH), 8.12e8.22 (m, 3H, ArH), 9.44 (s, 1H, CH),
11.26 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
113.5, 114.6, 116.3,
d
3.4.3. 2-(4-Methylphenyl)pyrazolo[3,4-c]quinolin-4(5H)-ones
118.3,119.5,122.3,122.5,127.5,129.0,130.0,131.4,134.1,138.3,140.3,
149.3, 158.6; Anal. Calcd for C16H10ClN3O; C: 64.98; H: 3.41; N:
14.21; found: C: 65.01; H: 3.39; N: 14.19.
(1b). 1H NMR (DMSO-d6, 300 MHz)
d
2.40 (s, 3H, CH), 7.23e7.26 (m,
1H, ArH), 7.37e7.44 (m, 4H, ArH), 7.90e7.98 (m, 3H, ArH), 9.43 (s,
1H, CH), 11.48 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
20.5,
d
114.9, 116.1, 119.7, 122.2, 122.5, 123.3, 123.8, 127.7, 130.2, 136.1, 137.2,
137.6, 141.3, 156.9; Anal. Calcd for C17H13N3O; C: 74.17; H: 4.76; N:
15.26; found: C: 74.21; H: 4.74; N: 15.29.
Acknowledgements
We are grateful to the China Medical University (CMU100-
ASIA-17) and the National Science Council of Republic of China for
financial support (NSC-99-2320-B-039-014-MY3). This study is
also supported in part by Taiwan Department of Health Clinical
Trial and Research Center of Excellence (DOH100-TD-B-111-004).
3.4.4. 2-(4-Methylphenyl)pyrazolo[4,3-c]quinolin-4(5H)-ones
(2b). 1H NMR (DMSO-d6, 300 MHz)
d
2.39 (s, 3H, CH), 7.25 (t, J¼7.5 Hz,
1H, ArH), 7.38e7.51 (m, 4H, ArH), 7.97e8.00 (d, J¼8.9 Hz, 2H, ArH),
8.11e8.14 (d, J¼8.9 Hz, 1H, ArH), 9.31 (s, 1H, CH), 11.24 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6)
d 20.5,113.7,114.2,116.3,119.7,122.2,122.3,
128.1, 129.6, 130.1, 137.0, 137.3, 138.2, 148.9, 158.7; Anal. Calcd for
C17H13N3O; C: 74.17; H: 4.76; N: 15.26; found: C: 74.14; H: 4.743; N: 15.29.
Supplementary data
3.4.5. 2-(4-Methoxyphenyl)pyrazolo[3,4-c]quinolin-4(5H)-ones
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.04.093.
(1c). 1H NMR (DMSO-d6, 300 MHz)
d
3.85 (s, 3H, OCH), 7.16e7.26
(m, 3H, ArH), 7.37e7.39 (m, 2H, ArH), 7.93e7.97 (m, 3H, ArH), 9.36
(s, 1H, CH), 11.47 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
55.6,
d
114.9, 115.0, 116.1, 121.4, 122.3, 122.5, 123.3, 123.8, 127.7, 133.0, 136.1,
141.2, 157.0, 159.0; Anal. Calcd for C17H13N3O2; C: 70.09; H: 4.50; N:
14.42; found: C: 70.12; H: 4.48; N: 14.39.
References and notes
1. Fredhol, B. B.; IJzerman, A. P.; Jacobson, K. A.; Klotz, K. N.; Linden, J. Pharmacol.
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Trincavelli, L.; Lucacchini, A. J. Med. Chem. 2000, 43, 1158e1164.
6. Colotta, V.; Catarzi, D.; Varano, F.; Capelli, F.; Lenzi, O.; Filacchioni, G.; Martini,
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E.; Moro, S. J. Med. Chem. 2007, 50, 4061e4074.
3.4.6. 2-(4-Methoxyphenyl)pyrazolo[4,3-c]quinolin-4(5H)-ones
(2c). 1H NMR (DMSO-d6, 300 MHz)
d 3.83 (s, 3H, OCH), 7.10e7.13 (d,
J¼8.9 Hz, 2H, ArH), 7.23 (t, J¼7.4 Hz, 1H, ArH), 7.36e7.50 (m, 2H,
ArH), 7.98e8.01 (d, J¼8.9 Hz, 2H, ArH), 8.10e8.12 (d, J¼6.0 Hz, 1H,
ArH), 9.24 (s, 1H, CH), 11.23 (s, 1H, NH); 13C NMR (75 MHz, DMSO-
d6)
d 55.5, 113.8, 114.1, 114.7, 116.3, 121.4, 122.2, 122.3, 128.0, 129.5,
132.8, 138.1, 148.9, 158.7; Anal. Calcd for C17H13N3O2; C: 70.09; H:
4.50; N: 14.42; found: C: 70.12; H: 4.48; N: 14.48.
7. Baraldi, P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.; Fruttarolo, F.; Romeo
Romagnoli, R.; Zaid, N. A.; Moorman, A. R.; Varani, K.; Andrea Borea, P. A. J. Med.
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Arch. Pharm. (Weinheim, Ger.) 1997, 330, 383e386.
3.4.7. 2-(4-Fluorophenyl)pyrazolo[3,4-c]quinolin-4(5H)-ones
(1d). 1H NMR (DMSO-d6, 300 MHz)
d 7.22e7.26 (m, 1H, ArH),
7.35e7.52 (m, 4H, ArH), 7.94e7.96 (d, J¼6.2 Hz, 1H, ArH), 8.05e8.10
(m, 2H, ArH), 9.45 (s, 1H, CH), 11.50 (s, 1H, NH); 13C NMR (75 MHz,
9. Werbel, L. M.; Kesten, S. J.; Turner, W. R. Eur. J. Med. Chem. 1993, 28,
837e852.
DMSO-d6) d 114.8, 116.1, 116.5, 116.8, 121.9, 122.1, 122.3, 122.7, 123.8,
10. For the preparation of sydnones: (a) Yeh, M.-Y.; Tien, H.-J.; Huang, L.-Y.; Chen,
M.-H. J. Chin. Chem. Soc. 1983, 30, 29e37; (b) Thoman, C. J.; Voaden, D. J.;
Hunsberger, I. M. J. Org. Chem. 1964, 29, 2044e2045; (c) Dallacker, F.; Kern.
J. Chem. Ber. 1966, 99, 3830e3835; (d) Kuo, W.-F.; Lin, I.-T.; Sun, S.-W.; Yeh, M.-Y.
J. Chin. Chem. Soc. 2001, 48, 769e782; (e) Hans, G.; Friedemann, R. Liebigs Ann.
Chem. 1979, 1, 63e73; (Chem. Abstr. 90:203976).
11. (a) Delaunay, T.; Genix, P.; Es-Sayed, M.; Vors, J.-P.; Monteiro, N.; Balme, G. Org.
Lett. 2010, 12, 3328e3331; (b) Chang, E.-M.; Wong, F. F.; Chen, T.-H.; Chiang,
K.-C.; Yeh, M.-Y. Heterocycles 2006, 68, 1007e1015.
127.9, 136.0, 136.1, 141.6, 156.8; Anal. Calcd for C16H10FN3O; C:
68.81; H: 3.61; N: 15.05; found: C: 68.78; H: 3.57; N: 15.01.
3.4.8. 2-(4-Fluorophenyl)pyrazolo[4,3-c]quinolin-4(5H)-ones
(2d). 1H NMR (DMSO-d6, 300 MHz)
d
7.25 (t, J¼7.5 Hz, 1H, ArH),
7.37e7.52 (m, 4H, ArH), 8.12e8.16 (m, 3H, ArH), 9.35 (s, 1H, CH),
11.26 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
113.6, 114.4, 116.3,
d
12. Chang, E.-M.; Chen, T.-H.; Wong, F. F.; Chang, E.-C.; Yeh, M.-Y. Synlett 2006,
901e904.
13. Horn, J.; Li, H. Y.; Marsden, S. P.; Nelson, A.; Shearer, R. J.; Campbell, A. J.; House,
116.7, 122.0, 122.1, 122.3, 122.4, 128.7, 129.8, 135.8, 138.2, 149.2,
158.7; Anal. Calcd for C16H10FN3O; C: 68.81; H: 3.61; N: 15.05;
found: C: 68.85; H: 3.58; N: 15.08.
D.; Weingarten, G. G. Tetrahedron 2009, 62, 9002e9007.
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2961e2968; (b) Eskildsen, J.; éstergaard, N.; VedՓ, P.; Begtrup, M. Tetrahe-
dron 2002, 58, 7635e7644; (c) Susuki, A. J. Organomet. Chem. 1999, 576,
147e168.
3.4.9. 2-(3-Chlorophenyl)pyrazolo[3,4-c]quinolin-4(5H)-ones
(1e). 1H NMR (DMSO-d6, 300 MHz)
d
7.24 (t, J¼7.5 Hz, 1H, ArH),