Polyethylene glycol (PEG-400): An efficient and recyclable reaction medium for the synthesis of pyrazolo[3,4-b]quinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.03.135

A simple, efficient, and eco-friendly synthetic protocol has been developed via one pot three-component reaction between aldehyde, amino pyrazole, and 1,3-cyclohexanedione by using recyclable polyethylene glycol (PEG)-400 as a reaction medium. Utilizing t

Full text of DOI:10.1016/j.tetlet.2012.03.135

Tetrahedron Letters 53 (2012) 2897–2903
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Polyethylene glycol (PEG-400): an efficient and recyclable reaction
medium for the synthesis of pyrazolo[3,4-b]quinoline derivatives
K. Karnakar a, S. Narayana Murthy a, K. Ramesh a, G. Satish a, Jagadeesh Babu Nanubolu b,
Y.V.D. Nageswar a,
⇑
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 607, India
b X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient, and eco-friendly synthetic protocol has been developed via one pot three-component
reaction between aldehyde, amino pyrazole, and 1,3-cyclohexanedione by using recyclable polyethylene
glycol (PEG)-400 as a reaction medium. Utilizing this protocol a variety of pyrazolo[3,4-b]quinoline deriv-
atives were synthesized in excellent yields.
Received 13 February 2012
Revised 30 March 2012
Accepted 31 March 2012
Available online 5 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
PEG-400
Pyrazolo[3,4-b]quinoline
Aldehydes
Amino pyrazole
1,3-Cyclohexanedione
Recyclability
In recent years, scientists have started exploring environmen-
tally benign synthetic organic transformations. The green chemis-
try has attracted the attention of the academia as well as industry.1
Research for finding other alternate reaction media, which can sub-
stitute the hazardous, toxic, and inflammable organic solvents,
which pose a serious threat to the environment, is gaining pro-
gress.2 Many environmentally compatible reaction media like flu-
orous phases,3 supercritical fluids,4 and ionic liquids5 are being
used for several organic reactions. Each has its own advantages
and is dependent on external factors like lipophilicity, pressure,
and viscosity.
Over the years, polyethylene glycol (PEG) and modified polyeth-
ylene glycol derivatives have become more popular alternate reac-
tion media, due to their interesting properties like non-toxicity,
bio-compatibility, and bio-degradability when compared to other
‘neoteric solvents’ such as ionic liquids, super-critical fluids, and
micellar systems.6 PEG is a polymerized compound of ethylene
oxide, which is hydrophilic in nature. It has benign characteristic
properties with respect to environment and chemical industry
such as low cost, reduced flammability, reduced toxicity, recycla-
bility, facile degradability, and miscibility with various organic
solvents likes toluene, dichloromethane, alcohol, and acetone.7
Several organic transformations like substitution reactions,8
oxidation and reduction reactions,9 Heck reaction,10 asymmetric
dihydroxylation,11 Suzuki cross-coupling reaction,12 Wacker reac-
tion,13 and partial reductions of alkynes14 were reported, using
PEG as a recyclable medium.
Pyrazolo[3,4-b]quinoline derivatives are significant for their
pharmacological activities. In particular, they exhibited potential
antiviral,15 antimalarial,16 and antiinflammatory properties. These
are also known for parasiticidic properties,17 antibacterial, antitu-
mor, hypotensive, and vasodilation activities.18 Pyrazolo-annelated
heterocyclic frame is the core moiety in numerous biologically ac-
tive compounds, such as Celebrex, Analginum, Viagra, BAY 41-
2272, and WYE-354 (Fig. 1) etc.19
Friedlander prepared pyrazolo[3,4-b]quinoline by the condensa-
tion of o-amino benzaldehyde with suitable pyrazoline-5-one.20
This reaction affords several by-products along with pyrazoloquin-
oline. To overcome shortcomings, several methods are reported for
the synthesis of pyrazolo[3,4-b]quinolines.21 Recently Shi and Yang
synthesized pyrazoloquinolines by using ionic liquid,22 and Cheba-
nov co-workers prepared these derivatives in the presence of
microwave irradiation.23 However, these reported protocols suffer
from one or more drawbacks such as use of expensive reagents,
harsh reaction conditions, prolonged reaction times, cumbersome
product isolation procedures and low yields. Exploring a mild,
efficient, and environmentally benign protocol for the synthesis of
pyrazolo[3,4-b]quinoline derivatives is highly desirable.
⇑
Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.135

2898
K. Karnakar et al. / Tetrahedron Letters 53 (2012) 2897–2903
In continuation of our research toward the development of no-
O
N
vel heterocyclic compounds,24 employing environmentally benign
reaction medium, herein we envisaged a simple and efficient
one-pot three-component protocol for the synthesis of pyrazol-
o[3,4-b]quinoline derivatives in moderate to high yields, using
environment friendly polyethyelene glycol (PEG) as a recyclable
reaction medium (Scheme 1). Initially, a model reaction was
conducted by taking 4-methoxy benzaldehyde (1.0 mmol), 1,3-
cyclohexanedione (1.0 mmol), and 5-amino-3-methyl-1-phenyl-
pyrazole (1.0 mmol) at a temperature of 50–60 °C and the desired
product was obtained in 36% yield only along with the unreacted
starting materials, even after prolonged reaction time (24 h). This
result prompted us to explore the ideal reaction condition to get
maximum product yield. The reaction temperature was increased
to 80–90 °C affording a better yield (74%). During further optimiza-
tion study it was observed that 100–110 °C as the ideal tempera-
ture for the reaction and beyond 130 °C the reaction resulted in
undesired side products. After optimizing the experimental
conditions, 3,4,5-trimethoxy benzaldehyde (1.0 mmol), 5,5-di-
O
NH2
N
HN
N
Br
N
N
N
N
N
H
N
HN
F
N
N
HO
N
O
O
O
O
BAY41-2272
WYE-354
Figure 1. Biologically active pyrazolo[3,4-b]quinolines.
R
N
O
H3C
O
H3C
N
PEG-400
R-CHO
+
+
N
NH2
R1
R1
R1
R1
N
Ph
100-110ºC
N
O
Ph
methyl-1,3-cyclohexanedione
(1.0 mmol),
and
5-amino-3-
R= Aryl, Hetero aryl
R1 = H, CH3
methyl-1-phenyl-pyrazole (1.0 mmol) were reacted in the
presence of recyclable polyethylene glycol (PEG)-400, resulting in
the formation of the desired pyrazolo[3,4-b]quinoline derivative
Scheme 1. Synthesis of pyrazolo[3,4-b]quinolines using PEG-400.
Table 1
Synthesis of pyrazolo[3,4-b]quinoline derivatives by using PEG-400a
S. No.
Aldehyde
1,3-Dione
Pyrazolo amine
Product
Time (h)
Yieldb (%)
CHO
O
O
1
N
4
86
NH2
N
Ph
N
N
Ph
O
N
CHO
O
O
2
4
87
N
NH2
N
Ph
N
N
Ph
O
N
OCH3
CHO
O
N
N
N
O
NH2
3
4
87
N
Ph
O
N
N
Ph
OCH3
N
OCH3
CHO
O
O
NH2
N
Ph
4
4
90
O
N
N
Ph
OCH3
N
CHO
O
O
NH2
5
4
89
N
Ph
O
N
N
Ph
N

K. Karnakar et al. / Tetrahedron Letters 53 (2012) 2897–2903
2899
Table 1 (continued)
S. No.
Aldehyde
1,3-Dione
Pyrazolo amine
Product
Time (h)
Yieldb (%)
F
CHO
O
N
O
NH2
6
7
8
9
N
Ph
4
88
85
87
O
N
N
Ph
F
N
Br
CHO
Br
O
N
O
NH2
N
Ph
4
4
4
O
N
N
Ph
N
OCH3
OCH3
CHO
O
N
N
O
NH2
N
Ph
OCH3
O
N
N
Ph
OCH3
N
CHO
O
Ph
NH2
N
Ph
O
O
89
Ph
N
N
Ph
N
OPh
O
CHO
O
N
N
10
4
84
NH2
N
Ph
N
N
Ph
OPh
O
N
OPh
O
CHO
O
11
4
85
NH2
N
Ph
N
N
Ph
OPh
CHO
O
N
N
N
HN
O
O
O
12
13
4
4
83
N
H
N
N
NH2
N
N
Ph
N
Ph
O
HN
O
CHO
84
N
H
N
N
Ph
NH2
N
Ph
O
(continued on next page)

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K. Karnakar et al. / Tetrahedron Letters 53 (2012) 2897–2903
Table 1 (continued)
S. No.
Aldehyde
1,3-Dione
Pyrazolo amine
Product
Time (h)
Yieldb (%)
CHO
O
O
14
4
85
N
NH2
N
N
Ph
N
O
N
N
Ph
CHO
F
O
F
O
15
4
83
N
NH2
N
Ph
N
O
N
Ph
OCH3
H3CO
OCH3
CHO
O
N
O
NH2
N
16
17
18
4
90
H3CO
OCH3
O
Ph
N
OCH3
N
N
Ph
OCH3
OCH3
H3CO
CHO
O
N
O
NH2
NH2
NH2
NH2
N
Ph
4
92
H3CO
OCH3
OCH3
O
N
N
N
Ph
OH
CHO
OH
O
N
N
O
O
N
Ph
4
91
O
N
N
Ph
N
O
CHO
O
O
N
Ph
19
4
86
O
N
N
Ph
N
O
CHO
O
O
N
N
O
O
N
20
4
88
O
Ph
N
N
Ph
N
NO2
CHO
NO2
O
NH2
N
21
4
75
O
Ph
N
N
Ph
N

K. Karnakar et al. / Tetrahedron Letters 53 (2012) 2897–2903
2901
Table 1 (continued)
S. No.
Aldehyde
1,3-Dione
Pyrazolo amine
Product
Time (h)
Yieldb (%)
NO2
CHO
O
N
O
NH2
N
Ph
22
4
76
O
N
N
Ph
NO2
N
CHO
O
O
23
4
80
N
NH2
N
N
N
O
Ph
N
N
Ph
S
O
CHO
CHO
S
S
S
S
S
O
24
4
82
N
NH2
N
Ph
O
N
N
Ph
S
S
O
N
O
O
25
4
84
NH2
N
Ph
O
N
N
Ph
N
N
S
O
CHO
CHO
26
4
4
82
83
S
S
N
NH2
N
Ph
N
N
Ph
O
S
O
O
27
N
NH2
N
Ph
N
N
Ph
N
O
a
Reaction conditions: aldehyde (1.0 mmol), 1,3-cyclohexanedione (1.0 mmol), amino pyrazole (1.0 mmol), and PEG-400 at 110 °C.
Isolated yields.
b
in excellent yield (Table 1, entry 17). The scope of this protocol was
matic aldehydes containing thiophene, pyrrole, and bithiophene
also provided good yields (Table 1, entry 12 and 13, 24–27). Alde-
hydes with the substituents of phenoxy and allyloxy groups also
transformed into the expected products (Table 1, entry 10 and
11, 19 and 20). Slightly diminished yields were obtained when ni-
tro benzaldehyde was reacted (Table 1, entry 21 and 22). Scope of
the reaction was also extended by reacting 1,3-cyclohexanedione
as well as 5,5-dimethyl-1,3-cyclohexanedione.
The possible mechanism is described in Scheme 2. Initially,
Knoevenagel condensation occurs between aldehyde and 1,3-
cyclohexanedione, resulting in the adduct (A), which upon
nucleophilic attack by amino pyrazole produces the Michael
extended by reacting a variety of substituted aldehydes, resulting
in a range of diversely substituted pyrazolo[3,4-b]quinoline deriv-
atives. Aromatic aldehydes carrying either electron donating (Table
1, entries 3–5, 8, 16–18) or electron withdrawing (Table 1, entries
21 and 22) substituents reacted very well, affording moderate to
high yields of pyrazoloquinoline derivatives (Table 1). Acid-sensi-
tive aldehyde such as 2-thiophenecarboxaldehyde also reacted
well and gave the corresponding pyrazoloquinoline derivative in
satisfactory yields (Table 1, entry 26 and 27). Reaction was also
conducted with bulky aromatic aldehydes having biphenyl, anthra-
cene, and bithiophene groups (Table 1, entry 9, 23–25). Hetero aro-

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K. Karnakar et al. / Tetrahedron Letters 53 (2012) 2897–2903
O
References and notes
CH3
R
O
O
R
O
R1
R1
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Low, J. N. Tetrahedron 2001, 57, 6947.
Figure 2. ORTEP diagram of compound 8 (30% probability).
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23. Andriushchenko, A. Y.; Desenko, S. M.; Cherneko, V. N.; Chebanov, V. A. J.
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adduct, as an intermediate (B). This intermediate on further
cyclization, dehydration, and aromatization yields the final prod-
uct as reported in the literature25 and it was further supported
by X-ray crystallography26 (Fig. 2). All products were characterized
by spectroscopic and analytical methods.27,28
In conclusion, we have demonstrated a mild and highly efficient
protocol for the synthesis of pyrazolo[3,4-b]quinoline derivatives
in excellent yields by using recyclable polyethylene glycol
(PEG)-400 as a reaction medium. Environmental acceptability, eco-
nomic viability, high yields, easy work-up, cleaner reaction pro-
files, and recyclability of PEG are the important features of this
protocol.
24. (a) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. V. D. Helv.
Chim. Acta 2009, 92, 2118; (b) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K.
R.; Nageswar, Y. V. D. Tetrahedron 2009, 65, 5251; (c) Madhav, B.; Murthy, S. N.;
Reddy, V. P.; Rao, K. R.; Nageswar, Y. V. D. Tetrahedron Lett. 2009, 50, 6025; (d)
Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Tetrahedron Lett.
2010, 51, 3649; (e) Shankar, J.; Karnakar, K.; Srinivas, B.; Nageswar, Y. V. D.
Tetrahedron Lett. 2010, 51, 3938; (f) Murthy, S. N.; Madhav, B.; Nageswar, Y. V.
D. Tetrahedron Lett. 2010, 51, 5252; (g) Ramesh, K.; Murthy, S. N.; Nageswar, Y.
V. D. Tetrahedron Lett. 2011, 52, 2362; (h) Anil Kumar, B. S. P.; Madhav, B.;
Harsha Vardhan Reddy, K.; Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52, 2862.
25. Dommock, J. R.; Raghavan, S. K.; Bigam, G. E. Eur. J. Med. Chem. 1988, 23, 111.
26. X-ray data for the compound (Table 1, entry 8) was collected at room
temperature using a Bruker Smart Apex CCD diffractometer with graphite
monochromated Mo
Ka radiation (k = 0.71073 Å) with x-scan method.
Preliminary lattice parameters and orientation matrices were obtained from
four sets of frames. Unit cell dimensions were determined using 5040
reflections in the range of 2.41 < h < 27.86° for AM42. Integration and scaling
of intensity data were accomplished using SAINT program. The structure was
solved by direct methods using SHELXS97 and refinement was carried out by
full-matrix least-squares technique using SHELXL97. Anisotropic displacement
parameters were included for all non-hydrogen atoms. All H atoms were
positioned geometrically and treated as riding on their parent C atoms, with C–
H distances in the range of 0.93–0.97 Å and Uiso(H) values of 1.5Ueq(C) for
methyl H atoms and 1.2Ueq(C) for all other H atoms. Crystal data for AM42:
Acknowledgments
We thank the CSIR, New Delhi, India, for fellowships to K.K.,
S.N.M., G.S. and the UGC for fellowship to K.R.
Supplementary data
C
25H23N3O3, M = 413.46, Monoclinic, space group P21/c, a = 16.1526(12) Å,
b = 8.4512(6) Å, c = 19.2357(10) Å, b = 125.526(4)°, V = 2137.0(2) Å3, Z = 4,
Dcalc = 1.285 g/cm3, T = 294(2) K, = 0.086 mmÀ1
F(000) = 872, Mo
radiation, k = 0.71073 Å, 19,783 reflections collected, 3749 unique
(Rint = 0.0182), 3312 with I >2 (I), R1 = 0.0390, wR2 = 0.1122, Final
GooF = 1.035. Intensity data were measured on Bruker Smart Apex with CCD
l
,
Ka
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
135.
r

K. Karnakar et al. / Tetrahedron Letters 53 (2012) 2897–2903
2903
area detector. CCDC 866149 contains supplementary crystallographic data for
the structure. The crystallographic data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/data_request/cif.
3243, 3111, 2930, 1709, 1649, 1223, 1089 cmÀ1
;
1H NMR (300 MHz, CDCl3,
TMS) d = 8.26 (d, J = 7.5 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H),
7.15 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H), 3.22 (s, 2H), 2.51 (s,
2H), 1.95 (s, 3H), 1.14 (s, 6H) ppm. 13C NMR (75 MHz, CDCl3, TMS) d 197.3,
163.4, 159.1, 150.3, 148.6, 145.5, 139.0, 129.2, 128.8, 128.4, 125.7, 120.9, 116.3,
113.3, 55.1, 54.0, 48.4, 32.1, 28.1, 14.4 ppm. ESI–MS: 412 (M+H)+; C26H26N3O2.
3,7,7-Trimethyl-1-phenyl-4-(3,4,5-trimethoxyphenyl)-7,8-dihydro-1H-pyrazolo
[3,4-b]quinolin-5(6H)-one (Table 1, entry 17): White crystals, mp 316–319 °C. IR
27. General procedure for the synthesis of Pyrazolo[3,4-b]quinoline derivatives: To a
stirred solution of polyethylene glycol (PEG)-400 (5 mL), aldehyde (1.0 mmol),
1,3-cyclohexadione (1.0 mmol) and amino pyrazole (1.0 mmol) were added
and stirred at 100–110 °C, until the reaction was complete as indicated by TLC.
After completion of the reaction as indicated by TLC, ether (5 mL) was added
and stirred for a while and cooled to À50 °C. At this temperature the PEG
became solid and the ether layer saturated with product was separated and
evaporated. The crude product was recrystallized in ethanol to get analytically
pure products in excellent yields. The recovered PEG was reused for further
cycles.
(KBr) 3241, 3113, 2924, 1709, 1652, 1227, 1085 cmÀ1 1H NMR (300 MHz,
;
CDCl3 + DMSO-d6, TMS) d = 8.24 (d, J = 8.3 Hz, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.31
(t, J = 7.3 Hz, 1H), 6.44 (s, 2H), 3.94 (s, 3H), 3.84 (s, 6H), 3.24 (s, 2H), 2.55 (s, 2H),
1.99 (s, 3H), 1.15 (s, 6H) ppm. 13C NMR (75 MHz, CDCl3 + DMSO-d6, TMS) d
197.1, 163.5, 152.9, 150.3, 148.4, 145.5, 138.9, 137.4, 132.8, 128.9, 125.9, 121.0,
119.8, 116.1, 104.5, 61.0, 56.0, 54.0, 48.5, 32.3, 28.1, 14.1 ppm. ESI–MS: 472
(M+H)+; C28H30N3O4.
28. 4-(4-Methoxyphenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]-
quinolin-5(6H)-one (Table 1, entry 4): White crystals, mp 295–297 °C. IR (KBr)