Green and efficient synthesis of pyrazolo[3,4-b]quinolin-5-ones derivatives by microwave-assisted multicomponent reaction in hot water medium

Article abstract of DOI:10.1002/jhet.586

Novel simple, efficient, and eco-friendly synthetic procedure for preparation of pyrazolo[3,4-b]quinolin-5-ones based on three-component microwaves-assisted heterocyclization reaction of 5-aminopyrazoles, aromatic aldehydes, and dimedone in hot-water medi

Full text of DOI:10.1002/jhet.586

March 2011
Green and Efficient Synthesis of Pyrazolo[3,4-b]quinolin-5-ones
Derivatives by Microwave-Assisted Multicomponent Reaction in
Hot Water Medium
365
Anastasiya Yu. Andriushchenko, Sergey M. Desenko, Vitaliy N. Chernenko,
and Valentin A. Chebanov*
State Scientific Institution ‘‘Institute for Single Crystals" of National Academy of Sciences of
Ukraine, Lenin ave., 60, Kharkiv 61001, Ukraine
*E-mail: chebanov@isc.kharkov.com
Received March 17, 2010
DOI 10.1002/jhet.586
Published online 22 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
Novel simple, efficient, and eco-friendly synthetic procedure for preparation of pyrazolo[3,4-b]quino-
lin-5-ones based on three-component microwaves-assisted heterocyclization reaction of 5-aminopyra-
zoles, aromatic aldehydes, and dimedone in hot-water medium was developed. The new method allows
obtaining target heterocycles in good and excellent yields and with high degree of purity.
J. Heterocyclic Chem., 48, 365 (2011).
INTRODUCTION
highly desirable to develop efficient methods that use al-
ternative energy sources such as microwave irradiation,
to facilitate chemical reactions. Recently, the combina-
tion of these two prominent green chemistry principles,
‘‘microwaves’’ and ‘‘water,’’ has become very popular
and received substantial interest [6].
The concept of ‘‘green chemistry’’ is now widely
adopted to meet the fundamental scientific challenges of
protecting the human health and environment with
simultaneously achieving commercial viability [1,2].
One of the key areas of green chemistry is the elimina-
tion of solvents in chemical processes or the replace-
ment of hazardous solvents.
Nitrogen-containing heterocycles are abundant in na-
ture and are of great significance to life because their
structural subunits exist in many natural products such
as vitamins, hormones, antibiotics, and alkaloids as well
as pharmaceuticals, herbicides, and dyes [7]. Developing
efficient, selective, and eco-friendly synthetic methods
for applications in complex organic preparations of het-
erocyclic compounds is the ultimate goal of several
research groups. For example, there were reported green
and efficient synthesis of several fused pyrimidine deriv-
atives by microwave-assisted reactions in water [8],
three-component, aqueous one-pot synthesis of fused
pyrazoles [9(a)], synthesis of benzimidazoles in ‘‘hot
water’’ [9(b)], environmentally benign aqueous micro-
wave Biginelli protocol [10], and an approach to pyr-
ano[2,3-c]pyrazoles in aqueous media [11].
Among alternative media, water is very benign and,
compared with organic solvents, is abundant, nontoxic,
and eco-friendly. In many examples of ‘‘aqueous reac-
tions,’’ organic cosolvents are employed to increase the
solubility of organic reactants in water [3]. However,
chemical processing in pure water is also possible under
‘‘superheated conditions’’ (>100ꢀC) in sealed vessels, as
the so-called near-critical water (150–300ꢀC) possesses
properties very different from those of ambient liquid
water [4]. Therefore, water has become an attractive me-
dium for many organic reactions, not only for the advan-
tages concerning the avoidance of the expensive solvents
but also for some unique reactivity and selectivity [5].
In the most chemical processes, major adverse effects
toward the environment are due to the consumption of
energy for heating. To overcome this problem, it is
Recently, much attention has been devoted to pyra-
zolo-annelated heterocycles because this fragment is a
key moiety in numerous biologically active compounds,
C
V
2010 HeteroCorporation

366
A. Y. Andriushchenko, S. M. Desenko, V. N. Chernenko, and V. A. Chebanov
Vol 48
Scheme 1
Table 1
Screening of the catalyst type for the synthesis of 4a
(MW, H2O, 130ꢀC).
Entry
Catalyst
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
None
HOAc
p-TSA
HCl
NaOH
K2CO3
Et3N
10
10
10
10
10
10
10
10
40
43
46
36
30
42
65
55
among them are prominent drug molecules such as Viagra,
Celebrex, Analginum, and many others [12]. Interested in
biological activity of a significant number of compounds
containing condensed pyrazole ring system, in broad pro-
gram of developing efficient, selective, and eco-friendly
synthetic methods, we started exploring the use of water as
reaction medium in combination with microwave irradia-
tion as a useful, environmentally benign alternative.
Piperidine
reaction temperature, the synthesis of 4a was performed
in water with 1.2 equivalents of Et3N at 130–200ꢀC
with an increment of 10ꢀC. It was established that
within a range 130–170ꢀC, the yield of quinolinone 4a
raised up with increasing the temperature (Table 2). The
temperature growth allowed also shortening the reaction
time from 15 to 10 min without influence on yield and
purity. However, no significant changes in the yield of
4a were observed, when the reaction temperature was
raised from 170 to 200ꢀC. Therefore, the temperature of
170ꢀC was chosen as the most suitable to carry out the
multicomponent reaction studied in the water medium.
With the application of the elaborated optimized reac-
tion conditions (H2O/Et3N, MW, 170ꢀC, 10 min), a
21-membered library of pyrazolo[3,4-b]quinolin-5-ones
4a–u was easily synthesized by the three-component
treatment of equimolar amounts of pyrazol-5-amines
1a–c, aldehydes 2a–g, and dimedone 3 (Scheme 2 and
Table 3). The reaction products were isolated in good
and excellent yields as stable crystalline solids.
Here, we report direct synthesis of well-known substi-
tuted pyrazolo[3,4-b]quinolin-5-ones using high-temper-
ature water and microwave heating via one-pot three-
component reaction of 3-substituted 5-aminopyrazols,
aromatic aldehydes, and dimedone. In earlier publica-
tions [13], it was shown that direction of this treatment
sufficiently depended on conditions and, thereby, such
multicomponent reaction is a challenge object for devel-
opment of eco-friendly synthetic methodology based on
application of hot water medium.
RESULTS AND DISCUSSION
The algorithm of choosing appropriate reaction
parameters, being of crucial importance for successful
organic synthesis, includes search for optimal medium
and catalytic system, temperature regime, reaction time,
activation method, etc. To elaborate efficient microwave-
assisted synthesis of target pyrazolo[3,4-b]quinolinones 4
in water medium the three-component reaction of 3-phe-
nyl-1H-pyrazol-5-amine 1a, 4-metoxybenzaldehyde 2a,
and dimedone 3 was selected as a model treatment for
searching optimal reaction conditions (Scheme 1).
It was established that wide range of aromatic alde-
hydes containing diverse types of substituents can be
efficiently used in the new microwave-assisted eco-
friendly protocol to produce target heterocycles 4 in
excellent yields and purity. However, when the aliphatic
aldehydes were applied, no product of heterocyclization
was isolated from the reaction mixture.
First, different types of acidic and basic catalysts were
screened at the fixed temperature (130ꢀC) and the con-
stant microwave (MW) power of 375 W. It was estab-
lished (Table 1) that multicomponent reaction of equimo-
lar mixture of 1a, 2a, and 3 in water under MW heating
was the most efficient in the presence of 1.2 equivalents
Et3N, whereas application of other basic or acidic cata-
lysts gave worse results. Moreover, in the case of HOAc,
HCl, NaOH, and K2CO3, a sufficient resinification of the
reaction mixture was observed.
Table 2
Temperature optimization for the synthesis of 4a (MW, H2O).
Entry
T (ꢀC)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
130
140
150
160
170
180
190
200
15
15
13
13
10
10
10
10
65
68
70
77
82
80
80
78
However, when the catalyst was absent, only starting
materials were quantitatively isolated. To optimize the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Green and Efficient Synthesis of Pyrazolo[3,4-b]quinolin-5-ones Derivatives by
Microwave-Assisted Multicomponent Reaction in Hot Water Medium
367
whose structure was proven by spectroscopic methods (1H
NMR, 13C NMR, and MS). The spectral and analytical data
were identical to previously published [13].
Scheme 2
REFERENCES AND NOTES
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lengton, 2007, p 1.
CONCLUSION
Thus, the simple, efficient, and eco-friendly synthetic
method was developed for preparation of pyrazolo[3,4-b]qui-
nolin-5-ones by microwaves-assisted multicomponent heter-
ocyclization reaction of 5-aminopyrazoles, aromatic alde-
hydes, and dimedone in hot-water medium in the presence of
triethylamine. All target heterocyclic compounds were
obtained in good to excellent yields and purity of >95%.
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The near-critical water microwave-assisted experiments
were carried out in a MARS multimode reactor from CEM
Corporation (Matthews, NC) equipped with fiber-optic temper-
ature probe.
General procedure for the synthesis of 4a–u. Pyrazol-5-
amine 1a–c (1.0 mmol), aldehyde 2a–g (1.0 mmol), dimedone
3 (1.0 mmol), triethylamine (1.2 mmol), and 3 mL of water
were placed in 10 mL Xpress vial which then was capped.
The mixture was irradiated at 170ꢀC (375 W) for 10 min with
intensive magnetic stirring. After cooling to room temperature,
3 mL of EtOH-H2O mixture (1:1) was added to the crude reac-
tion mixture and stirred for 10 min. The precipitate was col-
lected by filtration, washed with EtOH–H2O (1:1), and dried
at room temperature to produce the desired pyrazoloquinoli-
none 4a–u. In all the cases, the reaction gave a single product
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Table 3
Synthesis of compounds 4a-u.
Compound
R
R1
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
Ph
Ph
4-CH3OC6H4
4-CH3C6H4
4-BrC6H4
4-ClC6H4
4-C2H5OC6H4
Ph
3,4-(CH3O)2C6H3
4-CH3OC6H4
4-CH3C6H4
4-BrC6H4
4-ClC6H4
4-C2H5OC6H4
Ph
82
83
83
90
84
80
76
80
80
85
86
86
82
74
86
86
86
82
77
75
77
Ph
Ph
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warlu, A. Bioorg Med Chem Lett 2004, 14, 499; (c) Penning, T. D.;
Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R.
S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J.
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Ph
Ph
Ph
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
CH3
3,4-(CH3O)2C6H3
4-CH3OC6H4
4-CH3C6H4
4-BrC6H4
CH3
CH3
CH3
CH3
4-ClC6H4
4-C2H5OC6H4
Ph
3,4-(CH3O)2C6H3
4t
4u
CH3
CH3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet