Three-component one-pot synthesis of pyrazolo[3,4-b]quinolin- 5(6H)-one derivatives in aqueous media

Article abstract of DOI:10.1002/jhet.781

A series of 4-aryl-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b] quinolin- 5(6H)-ones were synthesized by the three-component reaction of aromatic aldehydes, 3-methyl-1-phenyl-1H-pyrazol-5- amine, and 5,5-dimethyl-1,3-cyclohexandione in the pres

Full text of DOI:10.1002/jhet.781

212
Three-Component One-Pot Synthesis of Pyrazolo[3,4-b]quinolin-
5(6H)-One Derivatives in Aqueous Media
Vol 49
Hui-Yan Wang and Da-Qing Shi*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
People’s Republic of China
*E-mail: dqshi@suda.edu.cn
Received September 27, 2010
DOI 10.1002/jhet.781
Published online 15 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of 4-aryl-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin- 5(6H)-ones were
synthesized by the three-component reaction of aromatic aldehydes, 3-methyl-1-phenyl-1H-pyrazol-5-
amine, and 5,5-dimethyl-1,3-cyclohexandione in the presence of sodium 1-dodecanesulfonate in aqueous
medium. Compared to the previous methods, this new protocol has the advantages of convenient opera-
tion, higher yields, lower cost, and environmentally benign procedure.
J. Heterocyclic Chem., 49, 212 (2012).
INTRODUCTION
Pyrazole derivatives exhibit pharmacological activities
such as hypotensive, antibacterical, anti-inflammatory,
and antitumor properties. In particular, fused pyrazole
are known for various biological activities, e.g., pyra-
zolo[3,4-b]quinolines as potential antiviral [7], antima-
larial [8], and lowering of serum cholesterol. A number
of methods are available for the synthesis of pyrazolo
[3,4-b]quinolines [9]; the most efficient and commonly
used method involves the reaction of aromatic aldehyde,
1,3-dicarbonyl compound, and aminopyrazole in organic
solvent such as EtOH [10]. Each of the above methods
has its own merits; however, these methods are also
plagued by limitation of poor yields, difficult work-up,
and effluent pollution. As part of our current studies on
the developments of new routes to heterocyclic system
in aqueous media [11], we herein described a clean
synthesis of pyrazolo[3,4-b]quinoline-5(6H)-one deriva-
tives by the three-component reaction of aromatic
aldehyde, 5,5-dimethyl-1,3-cyclohexanedione, and 3-
methyl-1-phenyl-1H- pyrazol-5-amine using water as
reaction medium (Scheme 1).
The need to reduce the amount of toxic waste and by-
products arising from chemical processes requires
increasing emphasis on the use of less toxic and envi-
ronmentally compatible materials in the design of new
synthetic methods [1]. One of the most promising
approaches uses water as the reaction medium [2]. Ride-
out and Breslow, who showed that hydrophobic effects
could strongly enhance the rate of several organic reac-
tions, rediscovered the use of water as a solvent in or-
ganic reactions in 1980s [3]. In recent years, there has
been increasing recognition that water is an attractive
medium for many organic reactions [4]. The aqueous
medium with respect to organic solvent is less expen-
sive, less dangerous, and environment friendly. Gener-
ally, the low solubility of most reagents in water is not
an obstacle to the reactivity, which on the contrary, is
reduced with the use of cosolvents.
Multicomponent reactions (MCRs), in which multiple
reactions are combined into one synthetic operation,
have been used extensively to form carbon-carbon
bonds in the synthetic chemistry [5]. Such reactions
offer a wide range of possibilities for the efficient con-
struction of highly complex molecules in a single pro-
cedural step, thus avoiding the complicated purification
operations and allowing savings of both solvents and
reagents. In the past decade, there have been tremen-
dous developments in three- and four-component reac-
tions and grant efforts continue to be made to develop
new MCRs [6].
RESULTS AND DISCUSSION
Choosing an appropriate solvent is of crucial impor-
tance for the successful organic synthesis. To search for
the optimum reaction solvent, the reaction of 4-hydroxy-
benzaldehyde (1a), 5,5-dimethyl-1,3-cyclohexanedione
(2), and 3-methyl-1-phenyl-1H-pyrazol-5-amine (3) was
examined using H2O, acetone, 95% ethanol, DMF and
C
V
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January 2012
Three-Component One-Pot Synthesis of Pyrazolo[3,4-b]quinolin-5(6H)-one
Derivatives in Aqueous Media
213
Scheme 1.
chloroform as solvent, respectively. The results were
summarized in Table 1.
reaction occurs via an initial formation of the a,b-unsatu-
rated ketone, from the condensation of aldehyde and 5,5-
dimethyl-1,3-cyclohexanedione as shown in Scheme 2,
which suffers nucleophilic attack to give the Michael
adduct [A]. The intermediate [A] then isomerizates,
cyclizes, dehydrates, and subsequently losses a hydrogen
molecule to afford the fully aromatized compound. This
type of hydrogen loss is well documented [12].
From Table 1, it can be seen that this reaction using
water as solvent exhibited the most excellent yield.
Therefore, water was chosen as the solvent for this reac-
tion. To examine the efficiency and the applicability of
this three-component reaction, a series of different aro-
matic aldehydes were tested in aqueous media. As
shown in Table 2, this protocol could be applied to the
aromatic aldehydes with either electron-withdrawing
groups (such as halide groups) or electron-donating
groups (such as alkyl and alkoxyl groups). The products
were different from those literature reported [10].
Apart from the mild conditions of the process and its
excellent results, the simplicity of product isolation and
the possibility to recycle the reaction solution offer a sig-
nificant advantage. Because SDS is soluble in water and
the desired product is less soluble in water, the products
can be directly separated by cooling to room temperature
and filtering after the reaction is completed. The remain-
ing reaction solution can be recycled. Studies using 1a,
2, and 3 as model substrates showed that the recovered
reaction solution could be successively recycled in subse-
quent reaction without any decrease of yield (Table 3).
The structures of the products were established on the
spectroscopic data. The structure of compound 4k was
further confirmed by X-ray diffraction analysis. The
molecular structure of the product 4k is shown in
Figure 1. The crystallographic data of compound 4k is
summarized in Table 4.
In summary, we developed an efficient three-compo-
nent reaction of aromatic aldehydes, 5,5-dimethyl-1,3-
cyclohexanedione, and 3-methyl-1-phenyl-1H-pyrazol-5-
amine for the synthesis of pyrazolo[3,4-b]quinolne-5-
one derivatives using water as reaction medium.
Compared to the previous methods, this new protocol
has the advantages of convenient operation, higher
yields, low cost, and environmentally benign procedure.
EXPERIMENTAL
Melting points are uncorrected. IR Spectra were recorded on
a FT-IR Temsor 27 spectrometer in KBr with absorptions in
.
cmꢀ1 1H-NMR spectra were determined on a Bruker DPX-
400 MHz spectrometer using DMSO-d6 solutions. Chemical
shifts are expressed in ppm downfield from internal tetrame-
thylsilane. High resolution mass spectra were obtained using
TOF-MS instrument.
General procedure for the synthesis of 4-aryl-3,7,7-tri-
methyl-1-phenyl-7,8-dihydro-1H-pyrazolo [3,4-b]quinolin-
5(6H)-ones 4. A mixture of aromatic aldehyde 1 (2 mmol),
5,5-dimethyl-1,3-cyclohexanedione 2 (2 mmol), 3-methyle-1-
phenyl-1H-pyrazol-5-amine 3 (2 mmol), and SDS (0.2 g) in
Although the detailed mechanism of this reaction has
not been clarified yet, the formation of 4 can be explained
by the possible mechanism presented in Scheme 2. The
Table 2
The synthesis of 4 in aqueous medium.
Entry Product
Ar
Time (h) Isolated yield (%)
Table 1
1
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-HOC6H4
2-ClC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-CH3C6H4
4-BrC6H4
4-(CH3)2NC6H4
3,4-Cl2C6H3
3,4-OCH2OC6H3
4-CH3OC6H4
10
16
10
12
9
15
12
17
6
96
86
93
95
95
97
98
98
84
98
97
Solvent optimization for the synthesis of 4a.
3
4
Reaction
temperature (ꢁC)
Time
(h)
Isolated
yield (%)
5
6
Entry
Solvent
1
2
3
4
5
H2O/SDS
CH3COCH3
EtOH
90
11
11
11
11
11
98
0
7
8
Reflux
Reflux
90
35
18
12
9
DMF
CHCl3
10
11
4j
4k
11
12
Reflux
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

214
H.-Y. Wang and D.-Q. Shi
Vol 49
Table 3
Studies on the reuse of reaction solution in the preparation of 4a.
Table 4
Crystallographic data of compound 4k.
Round
Yield (%)
1
96
2
95
3
94
4
92
5
92
Empirical formula
C26H25N3O2
411.49
293(2) K
Formula weight
Temperature
Wavelength
˚
0.71073 A
Monoclinic
Crystal system
Space group
Unit cell dimensions
H2O (10 mL) was stirred for 6–17 h at 90ꢁC, then cooled to
room temperature. The crystalline powder formed was col-
lected by filtration, washed with water. The crude products
were purified by recrystallization from DMF to give 4.
Pn
˚
ꢁ
a ¼ 14.101(9) A a ¼ 90
ꢁ
˚
b ¼ 7.584(5) A b ¼ 122.73(3)
ꢁ
˚
c ¼ 23.376(11) A c ¼ 90
3
˚
2103(2) A
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
4-(4-Hydroxyphenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4a). M.p.: 281–283ꢁC
(ref. 13; M.p.: 277–279ꢁC); IR (potassium bromide): 3304,
3058, 1666, 1613, 1593, 1512, 1456, 1437, 1385, 1264, 1172,
4
1.300 Mg/m3
0.083 mmꢀ1
872
1026, 849, 758 cmꢀ1 1H-NMR (DMSO-d6) d: 1.07 (6H, s, 2
;
Crystal size
0.29 ꢂ 0.18 ꢂ 0.11 mm3
ꢂ CH3), 1.88 (3H, s, CH3), 2.51 (2H, s, CH2), 3.19 (2H, s,
CH2), 6.84 (2H, d, J ¼ 8.4 Hz, ArH), 7.07 (2H, d, J ¼ 8.4
Hz, ArH), 7.35 (1H, t, J ¼ 8.0 Hz, ArH), 7.57 (2H, t, J ¼ 8.0
Hz, ArH), 8.24 (2H, d, J ¼ 8.0 Hz, ArH), 9.60 (1H, s, OH).
4-(2-Chlorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4b). M.p.: 156–158ꢁC; IR
(potassium bromide): 3056, 1682, 1593, 1569, 1498, 1479,
Theta range for data
collection
Limiting indices
1.84ꢁ to 25.01ꢁ
ꢀ16 ꢃ h ꢃ 16, ꢀ8 ꢃ k ꢃ 9,
ꢀ19 ꢃ l ꢃ 27
Reflections collected
10637
3687 [R(int) ¼ 0.0712]
Independent reflections
Data/restraints/paramenters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
3687/0/281
1.004
1384, 1268, 1125, 853, 753 cmꢀ1 1H-NMR (DMSO-d6) d:
;
R1 ¼ 0.0524, wR2 ¼0.1056
1.06 (3H, s, CH3), 1.11 (3H, s, CH3), 1.81 (3H, s, CH3), 2.58
(2H, s, CH2), 3.29 (2H, s, CH2), 7.34–7.40 (2H, m, ArH),
7.44–7.53 (2H, m, ArH), 7.57–7.61 (3H, m, ArH), 8.25 (2H, d,
J ¼ 7.6 Hz, ArH); HRMS [Found: m/z: 415.1457 (Mþ); Calcd
for C25H3252ClN3O: M 415.1451].
R1 ¼ 0.1316, wR2 ¼ 0.1365
ꢀ3
˚
Largest diff. peak and hole
0.192 and ꢀ0.210 eꢄA
4-(4-Fluorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4c). M.p.: 170–172ꢁC (ref.
13; M.p.: 172–174ꢁC); IR (potassium bromide): 3062, 1678,
1596, 1561, 1509, 1470, 1455, 1382, 1260, 1158, 1093, 848,
4-(3-Chlorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4d). M.p.: 163–165ꢁC; IR
(potassium bromide): 3063, 1685, 1599, 1509, 1483, 1382,
1
1265, 1128, 985, 758, 736 cmꢀ1; H-NMR (DMSO-d6) d: 1.09
753 cmꢀ1
;
1H-NMR (DMSO-d6) d: 1.08 (6H, s, 2 ꢂ CH3),
(6H, s, 2 ꢂ CH3), 1.83 (3H, s, CH3), 2.53 (2H, s, CH2), 3.22
(2H, s, CH2), 7.27 (1H, d, J ¼ 7.2 Hz, ArH), 7.37 (1H, t, J ¼
7.2 Hz, ArH), 7.43 (1H, s, ArH), 7.48–7.65 (4H, m, ArH),
8.2þ4 (2H, d, J ¼ 8.0 Hz, ArH); HRMS [Found: m/z: 415.1445
(M ); Calcd for C25H3225ClN3O: M 415.1451].
1.84 (3H, s, CH3), 2.51 (2H, s, CH2), 3.22 (2H, s, CH2), 7.28–
7.39 (5H, m, ArH), 7.59 (2H, t, J ¼ 8.0 Hz, ArH), 8.24 (2H,
d, J ¼ 8.0 Hz, ArH).
4-(4-Chlorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4e). M.p.: 181–183ꢁC (ref.
13; M.p.: 180–183ꢁC); IR (potassium bromide): 3060, 1680,
1
1595, 1489, 1455, 1386, 1264, 1126, 844, 752 cmꢀ1; H-NMR
(DMSO-d6) d: 1.08 (6H, s, 2 ꢂ CH3), 1.84 (3H, s, CH3), 2.51
(2H, s, CH2), 3.21 (2H, s, CH2), 7.32–7.38 (3H, m, ArH), 7.53
(2H, d, J ¼ 8.4 Hz, ArH), 7.58 (2H, t, J ¼ 8.0 Hz, ArH), 8.24
(2H, d, J ¼ 8.0 Hz, ArH).
4-(4-Methylphenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4f). M.p.: 182–184ꢁC (ref.
13; M.p.: 184–186ꢁC); IR (potassium bromide): 3021, 1677,
1591, 1560, 1499, 1455, 1386, 1263, 1126, 803, 752 cmꢀ1
;
1H-NMR (DMSO-d6) d: 1.08 (6H, s, 2 ꢂ CH3), 1.81 (3H, s,
CH3), 2.42 (3H, s, CH3), 2.51 (2H, s, CH2), 3.21 (2H, s, CH2),
7.16 (2H, d, J ¼ 8.0 Hz, ArH), 7.27 (2H, d, J ¼ 8.0 Hz,
ArH), 7.36 (1H, t, J ¼ 8.0 Hz, ArH), 7.58 (2H, t, J ¼ 8.0 Hz,
ArH), 8.24 (2H, d, J ¼ 8.0 Hz, ArH).
4-(4-Bromophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4g). M.p.: 184–186ꢁC (ref.
13; M.p.: 188–189ꢁC); IR (potassium bromide): 3069, 1679,
1592, 1569, 1558, 1498, 1455, 1416, 1386, 1264, 1174, 1099,
909, 843, 752 cmꢀ1; H-NMR (DMSO-d6) d: 1.06 (6H, s, 2 ꢂ
1
CH3), 1.88 (3H, s, CH3), 2.51 (2H, s, CH2), 3.21 (2H, s, CH2),
Figure 1. The X-ray crystal structure of compound 4k.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Three-Component One-Pot Synthesis of Pyrazolo[3,4-b]quinolin-5(6H)-one
Derivatives in Aqueous Media
215
Scheme 2. The possible mechanism for the synthesis of compound 4.
7.27 (2H, d, J ¼ 8.4 Hz, ArH), 7.37 (1H, t, J ¼ 7.6 Hz, ArH),
7.58 (2H, t, J ¼ 7.6 Hz, ArH), 7.67 (2H, t, J ¼ 8.4 Hz, ArH),
8.24 (2H, d, J ¼ 8.0 Hz, ArH).
cmꢀ1
;
1H-NMR (DMSO-d6) d: 1.07 (6H, s, 2 ꢂ CH3), 1.85
(3H, s, CH3), 2.51 (2H, s, CH2), 3.20 (2H, s, CH2), 3.84 (s,
3H, CH3O), 7.02 (2H, d, J ¼ 8.4 Hz, ArH), 7.20 (2H, d, J ¼
8.4 Hz, ArH), 7.36 (1H, t, J ¼ 7.6 Hz, ArH), 7.58 (2H, t, J ¼
8.0 Hz, ArH), 8.24 (2H, d, J ¼ 8.0 Hz, ArH).
4-(4-Dimethylaminophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihy-
dro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4h). M.p.: 195–
197ꢁC (ref. 13; M.p.: 194–196ꢁC); IR (potassium bromide):
3066, 1687, 1612, 1567, 1506, 1473, 1419, 1385, 1283, 1260,
Acknowledgments. Financial support from the Major Basic
Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049) and
the Foundation of Key Laboratory of Organic Synthesis of
Jiangsu Province (No. JSK0812).
1
1201, 1130, 983, 816, 790, 766 cmꢀ1; H-NMR (DMSO-d6) d:
1.07 (6H, s, 2 ꢂ CH3), 1.92 (3H, s, CH3), 2.51 (2H, s, CH2),
2.99 (6H, s, (CH3)2N), 3.19 (2H, s, CH2), 6.78 (2H, d, J ¼
8.4 Hz, ArH), 7.09 (2H, d, J ¼ 8.8 Hz, ArH), 7.35 (1H, t, J
¼ 7.6 Hz, ArH), 7.57 (2H, t, J ¼ 8.0 Hz, ArH), 8.25 (2H, d,
J ¼ 7.6 Hz, ArH).
REFERENCES AND NOTES
4-(3,4-Dichorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4i). M.p.: 176–178ꢁC
(ref. 13; M.p.: 179–181ꢁC); IR (potassium bromide): 3062,
1683, 1598, 1568, 1509, 1482, 1439, 1419, 1385, 1309, 1291,
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(2H, s, CH2), 7.14 (1H, dd, J1 ¼ 2.0 Hz, J2 ¼ 8.0 Hz, ArH),
7.34 (1H, d, J ¼ 7.2 Hz, ArH), 7.38 (1H, d, J ¼ 2.0 Hz,
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180ꢁC (ref. 13; M.p.: 175–177ꢁC); IR (potassium bromide):
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(DMSO-d6) d: 1.08 (6H, s, 2 ꢂ CH3), 1.93 (3H, s, CH3), 2.51
(2H, s, CH2), 3.20 (2H, s, CH2), 6.12 (2H, s, OCH2O), 6.72
(1H, d, J ¼ 7.6 Hz, ArH), 6.89 (1H, s, ArH), 7.00 (1H, d, J ¼
7.6 Hz, ArH), 7.36 (1H, t, J ¼ 7.6 Hz, ArH), 7.58 (2H, t, J ¼
7.6 Hz, ArH), 8.24 (2H, d, J ¼ 8.0 Hz, ArH).
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1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4k). M.p.: 139–141ꢁC
(ref. 13; M.p.: 138–140ꢁC); IR (potassium bromide): 3017,
2956, 2868, 2834, 1676, 1608, 1581, 1556, 1514, 1467, 1439,
1410, 0382, 1305, 1292, 1244, 1175, 906, 842, 808, 751, 687
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Vol 49
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DOI 10.1002/jhet