Synthesis of a diversified combinatorial library of 1H-pyrazolo[1,2-b] phthalazine-5,10-dione derivatives applying sustainable carbon-based solid acid catalyst involving a domino four-component reaction

Article abstract of DOI:10.1007/s00706-014-1195-8

A SO₃H-bearing carbonaceous solid catalyst has been synthesized through sulfonation followed by the hydrothermal carbonization method from renewable resource polyethylene glycol. The biodegradable catalyst was characterized by XRD, TEM, FT-IR, and energy dispersive X-ray. The surface area and pore diameter of the catalyst were determined by a nitrogen adsorption-desorption isotherm experiment. A highly efficient multicomponent heteroannulation protocol for the synthesis of a library of 1H-pyrazolo[1,2-b] phthalazine-5,10-dione derivatives has been developed by applying the solid acid catalyst. This synthesis was established to follow the group-assistant- purification chemistry process avoiding traditional chromatography. The aqueous reaction medium, easy recovery of the catalyst, and high yield of the products make the protocol attractive, sustainable, and economic. This work may not only lead to environmentally benign systems, but also will provide a new aspect of organic chemistry in water.

Full text of DOI:10.1007/s00706-014-1195-8

Monatsh Chem
DOI 10.1007/s00706-014-1195-8
ORIGINAL PAPER
Synthesis of a diversified combinatorial library
of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives applying
sustainable carbon-based solid acid catalyst involving a domino
four-component reaction
•
Koyel Pradhan Sanjay Paul Asish R. Das
•
Received: 30 January 2014 / Accepted: 24 February 2014
Ó Springer-Verlag Wien 2014
Abstract A SO3H-bearing carbonaceous solid catalyst
has been synthesized through sulfonation followed by the
hydrothermal carbonization method from renewable
resource polyethylene glycol. The biodegradable catalyst
was characterized by XRD, TEM, FT-IR, and energy dis-
persive X-ray. The surface area and pore diameter of the
catalyst were determined by a nitrogen adsorption–
desorption isotherm experiment. A highly efficient multi-
component heteroannulation protocol for the synthesis
of a library of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives has been developed by applying the solid acid
catalyst. This synthesis was established to follow the
group-assistant-purification chemistry process avoiding
traditional chromatography. The aqueous reaction medium,
easy recovery of the catalyst, and high yield of the products
make the protocol attractive, sustainable, and economic.
This work may not only lead to environmentally benign
systems, but also will provide a new aspect of organic
chemistry in water.
Introduction
New developments in the chemical industries are driven by
environmental regulations, safety, energy efficiencies, and the
need for improved performance. The increasing environ-
mental regulations require the use of green technology in
various areas [1, 2]. Particularly, catalysts are attractive in
green technology because of their importance in petrochem-
icals and fine chemical synthesis. Usually chemical syntheses
involve homogeneous catalysts that are highly selective,
economical, and efficient. However, many homogeneous
catalytic systems cannot be commercialized because of dif-
ficulties associated with product isolation, equipment
corrosion, solvent recycling, and reusability of the catalyst.
The utilization of heterogeneous catalysts such as zeolites,
transition-metal ions, and strong acid cation exchange resins
has the potential to overcome some of the above limitations
because of the ease of separation of catalysts [3–8], but these
catalysts require a longer reaction time to carry out the
reactions because of their very low reactivity [9, 10].
Keywords PEG-SAC Á Heteroannulation Á
However, using heterogeneous catalysts such as meso-
porous materials could be more reactive owing to their high
surface-to-volume ratio leading to a larger number of
active sites. In recent years, mesoporous carbon material
consisting of small polycyclic aromatic carbon sheets with
a high density of sulfonic acid sites has gained prominence
[11, 12] because of their significant advantages over the
homogeneous catalytic systems such as increased activity,
selectivity, longer catalyst life, negligible equipment cor-
rosion, ease of product separation, reusability, and overall
environmentally safe disposal [13–16]. These carbon-based
catalysts, obtained by partial carbonization of organic
compounds (glucose, starch, and cellulose), followed by
sulfonation in fuming H2SO4 [17–19], have proven to be
highly active in various organic reactions [20, 21].
Group-assistant purification Á Pyrazolo[1,2-b]phthalazine
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-014-1195-8) contains supplementary
material, which is available to authorized users.
K. Pradhan Á S. Paul Á A. R. Das (&)
Department of Chemistry, University of Calcutta,
Calcutta 700009, India
e-mail: ardascuchem@gmail.com; ardchem@caluniv.ac.in;
ardas66@rediffmail.com
123

K. Pradhan et al.
Herein, we have demonstrated a two-step synthesis of
SO3H-bearing carbonaceous solids by hydrothermal car-
bonization using polyethylene glycol as the carbon
precursor in a reversed mode from previously reported
methods. In this protocol, the SO3H group was first intro-
duced into the carbon precursor polyethylene glycol by
using chlorosulfonic acid (step A, Fig. 1). Mesoporous
carbonaceous solid acid was then obtained through
incomplete carbonization of SO3H group functionalized
polyethylene glycol (step B, Fig. 1) at higher temperature.
Nitrogen-containing heterocyclic compounds are
employed as important skeletons in organic synthesis
owing to their tremendous application in biologically
active pharmaceuticals, agrochemicals, and functional
materials [22–25]. Pyrazole core-containing compounds,
including drugs such as celecoxib, viagra, pyrazofurine,
and many others, possess a variety of biological activities
[26–28]. Celecoxib (Fig. 2) occupies a unique position as a
potent and GI-safe anti-inflammatory and analgesic agent.
It is considered as a typical model of the diaryl heterocy-
cles template that is known to inhibit the COX-2 enzyme
selectively [29]. On the other hand, much attention has
been focused toward pyrazoles as antimicrobial [30],
antiviral [31], and anticancer [32, 33] agents after the
discovery of the natural pyrazole C-glycoside pyrazofurin
(Fig. 2). This antibiotic was reported to possess a broad
spectrum of antimicrobial and antiviral activities in addi-
tion to being active against several tumor cell lines [34].
Phthalazine derivatives (Fig. 2) exhibit properties such as
anticonvulsant [35], cardiotonic [36], vasorelaxant [37],
cytotoxic [38, 39], antihypoxic, antipyretic [40], antifungal
[41], anticancer [42], and anti-inflammatory [43]. It was
thought that molecules containing two active pharmaco-
phores, pyrazole and phthalazine, would produce novel
molecular templates that are likely to exhibit interesting
biological properties.
Quite a good number of methods have already been
reported in the literature for the synthesis of pyrazolo[1,2-
b]phthalazine derivatives [44–49]. However, these methods
suffer from one or more disadvantages, such as the use of
hazardous organic solvents, pollution discharge, high reaction
temperature, expensive moisture-sensitive catalysts, tedious
workup conditions, longer reaction times, or large volume of
catalyst loadings. Based on their extensive application and
lack of proper efficiency, and being inexpensive and envi-
ronmentally benign methods for the synthesis of this
heterocyclic scaffold, it is necessary to further develop more
convenient methods to construct such significant compounds.
SO3H-bearing amorphous carbon materials can function
as stable and highly active solid acid catalysts for various
acid-catalyzed reactions such as esterification, transesteri-
fication, and hydrolysis reactions [11, 12, 17–19]. In
continuation of our research program dedicated to the
design and synthesis of novel heterocyclic systems [50–
53], herein, we wish to disclose PEG-derived SO3H-bear-
ing amorphous carbon materials that catalyzed a general,
rapid, high yielding, green synthetic protocol for a variety
of pyrazolo[1,2-b]phthalazine derivatives.
Results and discussion
The carbon-based solid acid was prepared by hydrothermal
treatment of PEG-OSO3H. The mesoporous carbonaceous
Fig. 1 Synthesis of solid acid
catalyst PEG-SAC
O
O
Chlorosulfonic
acid
Pyrolysis&
Carbonization
OH
O
O
O
Sulphonation
B
HO
O
O
O
A
O
n
O
n
SO3 H group
Fig. 2 Biologically active
molecules containing pyrazole
and phthalazine nucleus
123

Synthesis of a diversified combinatorial library of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
PEG-derived solid acid catalyst was denoted PEG-SAC.
Figure 3 shows the XRD patterns of the PEG-SAC catalyst.
The XRD pattern exhibits a broad C (002) diffraction peak
(2h = 10°–30°) attributable to amorphous carbon, and it
also consists of a weak diffraction peak C (101) at
2h = 35°–50° because of the axis of the graphite structure
of the carbonaceous material. Hence, the XRD pattern
indicates that the amorphous carbon is composed of aro-
matic carbon sheets oriented in a random manner (Fig. 1).
The FT-IR spectra of PEG-SAC catalyst is shown in Fig. 4.
The strong peak at around 1,710 cm-1 and weak peak at
around 1,117 cm-1 could be typically assigned to the
stretching modes of the SO3H groups, which are regarded
as ‘‘active sites’’ of this catalyst [54].
from PEG-6000 by the hydrothermal method (Fig. 5).
Amorphous carbons were found on the HR-TEM images of
the catalyst. From the HR-TEM images, it is evident that
the carbonaceous material PEG-SAC has a sponge-like
morphology.
Two independent methods, acid–base back titration and
elemental analysis, have been applied to more or less come
up with the same result aiming at quantifying the acid
content of the catalyst. Elemental analyses of the as-syn-
thesized PEG-SAC catalyst were performed by energy
dispersive X-ray analysis (EDX) equipped onto TEM.
Quantitative EDX analysis in Fig. 6 clearly showed that C,
O, and S were the main elemental components of the cat-
alyst. The acid–base titration of the prepared catalyst was
performed using 0.03 M NaOH solution with a 50 cm3
dispersed solution (50 cm3 water was stirred with 1 g of
the catalyst for 30 min at rt) of the catalyst in water. From
the acid–base back titration, it was observed that the acid
density (–SO3H) is 1.52 mmol g-1, and elemental analysis
(EDX) revealed that the S content of the catalyst is
HR-TEM was used to study the morphology of the
surface of the solid acid catalyst PEG-SAC synthesized
1.48 mmol g-1
.
The surface area and pore diameter of the catalyst were
determined by nitrogen adsorption. Figure 7 shows the N2
adsorption-desorption isotherm by plotting the adsorbed
volume as a function of the gas pressure (P) normalized by
the adsorptive saturation pressure at 77 K (Po). The mea-
sured BET surface area and NLDFT pore diameter of the
PEG-SAC catalyst were 480 m2 g-1 and 6.1 nm, respec-
tively. According to the International Union of Pure and
Applied Chemistry (IUPAC), the hysteresis loop in Fig. 7
indicates the existence of mesoporous structures in the
PEG-SAC catalyst. The carbonaceous material PEG-SAC
is insoluble in most of the organic solvents (ethanol, DMF,
Fig. 3 XRD patterns of the catalyst
Fig. 4 FTIR analysis of the
catalyst
123

K. Pradhan et al.
Fig. 5 HR-TEM images of the
catalyst
methanol, toluene, DCM, DMSO), including water. Hence,
the synthesized carbonaceous material can be used as a
heterogeneous catalyst in a wide range of solvents.
We then focused on synthesizing 1H-pyrazolo[1,2-
b]phthalazine-5,10-dione derivatives by using the carbon-
based solid acid catalyst. During initial exploratory reac-
tions, to find an optimized condition we studied the
condensation among equimolar amounts of phthalimide,
hydrazine hydrate, malononitrile, and 3-nitrobenzaldehyde
(Scheme 1). Initially, that particular reaction was carried
out in the presence of various solvents such as toluene,
acetonitrile, DMF, DMSO, ethanol, and water at 60 °C
with 70 mg of PEG-SAC; results are summarized in
Table 1. The results clearly indicate that water showed
superiority over the other solvents. This phenomenon can
be attributed to the high ionization of the sulfonic acid
group functionalized catalyst to provide the H? ion in
aqueous medium. To find the optimized amount of solid
acid catalyst as shown in Table 1, the reaction was carried
out by varying the amount of the catalyst (35–90 mg) on
the model reaction. The conversion of 1H-pyrazolo[1,2-
b]phthalazine-5,10-dione derivative increased linearly with
the catalyst weight up to 70 mg and became almost steady
when the amount of catalyst was further increased beyond
this.
Fig. 6 Energy dispersive X-ray analysis (EDX) of the catalyst
In order to show the accessibility of this catalyst-solvent
system for the specific synthesis of 1H-pyrazolo[1,2-
b]phthalazine from phthalimide, hydrazine hydrate,
3-nitrobenzaldehyde and malononitrile, a comparative
study has been done with other reported methods (Table 2).
The study revealed that PEG-SAC in aqueous medium is
the most acceptable condition in every aspect, such as
lower temperature, less reaction time, ecofriendly solvent,
higher yield, as well as biodegradable and reusable
catalyst.
Having identified these optimal conditions, we set out to
explore the scope for this new reaction; the results are sum-
marized in Table 3. All reactions were performed under
Fig. 7 Nitrogen adsorption-desorption isotherms and pore size
distributions of the as-prepared PEG-SAC catalyst
123

Synthesis of a diversified combinatorial library of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
Scheme 1
Table 1 Standardization of reaction condition
at the benzene ring, such as fluoro, nitro and bromo, also
Entry
Catalyst loading/mg
Solvent
t/h
Yielda/%
reacted smoothly, providing highly substituted 1H-pyrazol-
o[1,2-b]phthalazine-5,10-diones (Table 3). Aliphatic and
acid-/base-sensitive heterocycles such as 2-thienyl and 2-furyl
groups are also compatible with this Brønsted acid-catalyzed
four-component reaction (products 1h, 1i, 1j, 2h). Not only
that, the one-pot, four-component reaction was also well
established with phthalic anhydride, but in that case the
desired products were obtained with a slight decrease in the
product yield.
1
70
70
70
70
70
70
35
45
55
80
90
Toluene
Acetonitrile
DMF
3.0
3.0
3.0
3.0
2.0
0.5
0.5
0.5
0.5
0.5
0.5
49
52
67
69
70
97
48
69
80
97
97
2
3
4
DMSO
Ethanol
H2O
5
6
7
H2O
8
H2O
So far, a number of methods have been reported for the
synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives using malononitrile and ethyl cyanoacetate as
the active methylene component. However, there is a
maiden report for the synthesis of carboxamide deriva-
tives installing cyanoacetamide as the active methylene
counterpart of the four-component reaction. To expand
the generality of this novel catalytic method, we have
applied cyanoacetamide as the active methylene part for
the first time under the optimized conditions; the results
are presented in Table 4. At the R position, a large
number of aryl groups were well tolerated to provide
multifunctionalized 1H-pyrazolo[1,2-b]phthalazine-5,10-
dione carboxamides. Besides, phthalic anhydride was also
studied and underwent smooth transformation, affording
the desired products in good yields. Under the optimized
condition, the carboxamide derivative synthesis is com-
pletely regio-controlled. The Brønsted acid PEG-SAC
catalyst entirely ruled out the probability of N-nucleo-
philic attack at the amide carbonyl center of the
intermediate IV (Scheme 2), and no trace of the 1H-pyr-
azolo[1,2-b]phthalazine-2-carbonitrile derivative (4) was
detected (Table 4).
9
H2O
10
11
H2O
H2O
Phthalimide (1 mmol) and hydrazine hydrate (1 mmol) were stirred in
5 cm3 solvent in the presence of PEG-SAC catalyst at 60 °C for first
10 min, and then 3-nitrobenzaldehyde (1 mmol) and malononitrile
(1 mmol) were added and stirred for the rest of the time
a
Isolated yield of the pure product
Table 2 Comparison of different catalysts for the synthesis of 1H-
pyrazolo[1,2-b]phthalazine-5,10-dione derivative 1b
Entry Catalyst
Solvent
T/°C t/h Yield/% References
1
2
3
4
5
6
Al-KIT-6 (33) Ethanol
Al-KIT-6 (33) Water
60 4.0 84
100 4.0 29
[44]
[44]
PTSA
[bmim]Br 100 3.8 92
[45]
NiCl2Á6H2O
NiCl2Á6H2O
PEG-SAC
Ethanol
Water
Water
80 4.0 90
100 4.0 75
60 0.5 97
[46]
[46]
Present work
standard conditions without individual optimization. A variety
of aromatic aldehydes was surveyed to prepare different 1H-
pyrazolo[1,2-b]phthalazine-5,10-dione carbonitriles and car-
boxylates. At the R position, various aryl rings containing
electron-donating and electron-withdrawing groups are com-
patible with the reaction conditions. Substrates possessing
electron-donating groups at the benzene ring reacted
smoothly and afforded the desired products in good yield
(Table 3, entries 6, 7, 16, 17). Unsubstituted aromatic alde-
hydes and aldehydes possessing electron-withdrawing groups
With these outstanding results in hand, we are now in a
position to propose the mechanism of the reaction
(Scheme 2). In the presence of PEG-SAC, at first
phthalimide/phthalic anhydride (I) and hydrazine hydrate
react to form phthalhydrazide (II). After that, aldehyde
and the active methylene compound undergo acid-cata-
lyzed Knoevenagel condensation to obtain the
intermediate (III), which is consumed by phthalhydrazide
via Michael type addition followed by cyclization to
123

K. Pradhan et al.
Table 3 Substrate scope for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
Entry
R
Y
Prod.
t/min
Yielda/%
Yieldb/%
M.p./°C
Lit m.p./°C
References
1
C6H5
CN
1a
1b
1c
1d
1e
1f
35
30
30
35
30
40
45
45
45
50
40
35
35
35
40
45
45
50
91
97
96
93
95
89
90
88
88
86
90
95
95
93
90
89
88
83
87
94
93
90
92
86
88
84
85
83
87
93
92
90
87
86
85
80
276–278
270–272
264–266
258–260
270–272
240–242
236–238
290–292
244–246
230–232
246–248
238–240
230–232
276–278
262–264
260–262
200–202
158–160
275–276
[48]
[48]
[48]
[48]
[48]
[46]
[46]
–
2
3-NO2-C6H4
4-F-C6H4
2-Cl-C6H4
4-Cl-C6H4
4-OCH3-C6H4
4-CH3-C6H4
2-Furyl
269–271
3
265–266
4
257–259
5
272–274
6
–
7
1g
1h
1i
–
8
–
9
2-Thienyl
Isobutyl
244–246
[49]
[49]
[46]
[45]
[46]
[44]
[48]
[44]
–
10
11
12
13
14
15
16
17
18
1j
228–230
C6H5
COOEt
2a
2b
2c
2d
2e
2f
–
3-NO2-C6H4
4-F-C6H4
4-Cl-C6H4
2,3-Cl2-C6H3
4-OCH3-C6H4
3-CH3-C6H4
Isobutyl
239–240
–
–
260–263
–
2g
2h
–
160–162
[49]
Phthalimide/phthalic anhydride (1 mmol) and hydrazine hydrate (1 mmol) were stirred in 5 cm3 water in the presence of 70 mg PEG-SAC at
60 °C for 10 min, and then aldehyde (1 mmol) and malononitrile/ethyl cyanoacetate (1 mmol) were added and stirred for rest of the time
a
Isolated yield of the pure product when X = –NH
b
Isolated yield of the pure product when X = –O
afford 1H-pyrazolo[1,2-b]phthalazine-5,10-dione deriva-
tives (P). The high surface area of the catalyst not only
reduces the reaction time, but also enhances the yield of
the chromene derivatives because of its very large number
of reaction sites.
with acetone, and dried under vacuum at 100 °C for 12 h.
As revealed in Table 5, the catalyst was recovered in
excellent yield after each new set of reaction. This recycled
catalyst was used for the synthesis of 1H-pyrazolo[1,2-
b]phthalazine-5,10-dione derivatives applying the devel-
oped protocol. For this purpose, the reusability of the
catalyst was tested for the reaction of phthalimide, hydra-
zine hydrate, malononitrile, and 3-nitrobenzaldehyde
(Scheme 1). The catalyst was found to be reusable for at
least six cycles without considerable loss of activity
(Table 5). The morphology of the recovered catalyst was
confirmed by the HR-TEM image of the six-times reused
catalyst, which clearly demonstrated the high stability of
the carbon-based solid acid catalyst (Fig. 9).
In all the cases, the progress of the reaction was moni-
tored by TLC. The structures of desired products were
characterized by 1H and 13C NMR, IR, and elemental
analysis. The X-ray crystal structure of 2d shown in Fig. 8
further confirmed the product identity.
After the completion of the reaction (monitored by
TLC), water was removed under reduced pressure from the
reaction mixture, and acetone was added to it for dissolu-
tion of the crude product. The catalyst was filtered, washed
123

Synthesis of a diversified combinatorial library of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
Table 4 Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione carboxamides
Entry
R
Product
t/min
Yielda/%
Yieldb/%
M.p./°C
1
2
3
4
5
6
7
C6H5
3a
3b
3c
3d
3e
3f
40
35
35
35
40
40
45
88
95
95
93
90
91
86
85
92
93
90
87
88
83
230–232
240–242
210–212
226–228
240–242
220–222
230–232
3-NO2-C6H4
4-F-C6H4
4-Cl-C6H4
2,3-Cl2-C6H3
4-Br-C6H4
3-CH3-C6H4
3g
Phthalimide/phthalic anhydride (1 mmol) and hydrazine hydrate (1 mmol) were stirred in 5 cm3 water in the presence of 70 mg PEG-SAC at
60 °C for 10 min, and then aldehyde (1 mmol) and cyanoacetamide (1 mmol) were added and stirred for the rest of the time
a
Isolated yield of the pure product when X = –NH
b
Isolated yield of the pure product when X = –O
Scheme 2
123

K. Pradhan et al.
Conclusion
In summary, we have developed a green, sustainable, and
economic protocol for the one-pot, four-component syn-
thesis of a combinatorial library of diversified 1H-
pyrazolo[1,2-b]phthalazine-5,10-dione fused heterocyclic
molecules with the aid of an SO3H-bearing carbonaceous
solid catalyst (PEG-SAC). The sulfonated carbon material
was prepared by low-temperature carbonization of PEG-
SO3H, resulting in a highly active, stable solid acid cata-
lyst. All the products were isolated by filtration, avoiding
the use of silica gel column chromatography. The reactions
showed a broad substrate scope and readily available,
inexpensive commercial starting materials. The catalysts
are composed of polycyclic aromatic carbon with an SO3H
group. The very high surface area and high acid density of
the catalyst would surely grab the attention of the biolog-
ical as well as pharmaceutical industries for the very good
replacement of homogeneous acid catalysts in achieving
the synthesis of organic molecules in the future.
Fig. 8 ORTEP diagram of compound 2d
Table 5 Reusability of PEG-SAC
Runs
Weight percentage of the recovered catalyst/%
Yielda/%
1
2
3
4
5
6
a
100
98
97
97
96
96
97
95
94
94
92
92
Experimental
PEG-6000 and chlorosulfonic acid were purchased from
Aldrich (98 % pure). Phthalimide/phthalic anhydride was
purchased from Aldrich (99 % pure), and malononitrile,
ethylcyanoacetate, cyanoacetamide, and various aldehydes
(98 % pure) were purchased from SRL Biochem/Spectro-
chem (India), Ltd., and were used without further
purification.
Isolated yield of the pure product 1b
Catalyst preparation
At 0 °C, chlorosulfonic acid (10 mmol) was added to a
solution of PEG-6000 (1 mmol) in 10 cm3 CH2Cl2, and the
resulting solution was stirred at room temperature over-
night. Then, the solution was concentrated under vacuum,
and ether was added to it. The resulting precipitate was
filtered and washed with ether three times to afford PEG-
OSO3H as a gummy solid.
Carbon-based solid acid was prepared by hydrothermal
treatment of PEG-OSO3H. Carbon and SO3H precursor
PEG-OSO3H (6 g) were heated at 200 °C in a 100-cm3
Teflon hydrothermal reactor. Conditions were maintained
for 6 h at autogenous pressure and then on cooling to room
temperature formed a black amorphous solid. The meso-
porous carbonaceous PEG-derived solid acid catalyst was
denoted as PEG-SAC.
Fig. 9 HR-TEM image of the recovered catalyst after the sixth run
123

Synthesis of a diversified combinatorial library of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
General procedure for the synthesis
(m, 3H), 8.45 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
d = 61.9, 83.5, 123.5, 123.7, 127.1, 127.6, 129.0, 129.6,
130.2, 134.0, 134.8, 141.8, 147.9, 149.1, 153.7, 156.7,
A mixture of phthalimide/phthalic anhydride (1 mmol) and
hydrazine hydrate (1 mmol) was stirred in 5 cm3 water in
the presence of 70 mg PEG-SAC at 60 °C for 10 min, and
then aldehyde (1 mmol) and active methylene component
(1 mmol) were added and stirred for the required period of
time (TLC). After completion of the reaction, water was
removed under reduced pressure from the reaction mixture,
and acetone was added to it for the dissolution of crude
product. The acetone solution was filtered to remove the
catalyst. The solid was obtained upon concentrating the
acetone solution of the crude product extract. The product
thus appearing was collected by filtration, washed with
chilled aqueous ethanol, and finally recrystallized from
ethanol to obtain pure product.
166.8 ppm; IR (KBr): vꢀ = 1,683, 1,526, 1,349 cm-1
.
3-Amino-1-(4-fluorophenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carboxamide
(3c, C18H13FN4O3)
1H NMR (300 MHz, DMSO-d6): d = 6.36 (s, 2H), 6.40 (s,
1H), 7.09 (t, J = 8.7 Hz, 2H), 7.51–7.61 (m, 4H), 7.88–
8.22 (m, 4H) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 61.8, 84.0, 115.2, 125.3, 126.9, 127.4, 128.9, 129.1,
130.1, 130.2, 133.7, 134.6, 135.5, 148.5, 153.2, 154.9,
166.7 ppm; IR (KBr): vꢀ = 1,684, 1,526, 1,343 cm-1
.
3-Amino-1-(4-chlorophenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carboxamide
(3d, C18H13ClN4O3)
1H NMR (300 MHz, DMSO-d6): d = 6.35 (s, 1H), 6.42 (s,
2H), 7.33 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 4.2 Hz, 2H),
7.63 (s, 2H), 7.88–8.22 (m, 4H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 61.6, 83.7, 126.7, 127.2, 128.1, 128.7,
129.0, 129.8, 132.6, 133.6, 134.4, 138.3, 148.4, 153.1, 156.2,
3-Amino-1-(furan-2-yl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile
(1h, C16H10N4O3)
1H NMR (300 MHz, DMSO-d6): d = 6.44 (dd, J1 = 3 Hz,
J2 = 1.8 Hz, 1H), 6.59 (d, J = 3.3 Hz, 1H), 7.61 (s, 1H),
7.95 (t, J = 4.5 Hz, 2H), 8.10 (t, J = 4.2 Hz, 3H), 8.20–
8.23 (m, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 56.7, 58.4, 110.1, 111.1, 116.2, 127.1, 127.8, 128.9,
134.3, 135.3, 143.7, 143.8, 149.5, 151.5, 154.2, 157.0 ppm;
166.5 ppm; IR (KBr): vꢀ = 1,680, 1,522, 1,349 cm-1
.
3-Amino-1-(2,3-dichlorophenyl)-5,10-dioxo-5,10-dihydro-
1H-pyrazolo[1,2-b]phthalazine-2-carboxamide
(3e, C18H12Cl2N4O3)
IR (KBr): vꢀ = 2,203, 1,659, 1,385 cm-1
.
1H NMR (300 MHz, DMSO-d6): d = 6.19 (s, 2H), 6.59 (s,
1H), 7.36 (t, J = 7.8 Hz, 1H), 7.59 (dd, J1 = 7.8 Hz,
J2 = 1.2 Hz, 1H), 7.73–7.79 (m, 3H), 7.96 (d, J = 4.5 Hz,
2H), 8.05–8.29 (m, 2H) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 62.4, 127.1, 127.6, 128.5, 128.7, 129.2, 130.7,
132.8, 134.2, 135.0, 138.4, 149.5, 153.4, 156.5, 166.7 ppm;
Ethyl 3-amino-5,10-dioxo-1-(m-tolyl)-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carboxylate
(2g, C21H19N3O4)
1H NMR (300 MHz, DMSO-d6): d = 1.02 (t, J = 7.2 Hz,
3H), 2.24 (s, 3H), 3.93–3.96 (m, 2H), 6.01 (s, 1H), 7.02 (d,
J = 5.7 Hz, 1H), 7.11–7.18 (m, 4H), 7.93–8.27 (m, 5H) ppm;
13C NMR (75 MHz, DMSO-d6): d = 14.2, 21.0, 58.7, 63.3,
81.9, 124.5, 126.7, 127.3, 127.7, 127.8, 128.3, 128.8, 128.9,
133.6, 134.7, 137.0, 139.8, 149.7, 153.2, 156.8, 164.1 ppm;
IR (KBr): vꢀ = 1,684, 1,526, 1,349 cm-1
.
3-Amino-1-(4-bromophenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carboxamide
(3f, C18H13BrN4O3)
IR (KBr): vꢀ = 1,694, 1,663, 1,289 cm-1
.
1H NMR (300 MHz, DMSO-d6): d = 6.33 (s, 1H), 6.42 (s,
2H), 7.46 (s, 4H), 7.62 (s, 2H), 7.88–8.22 (m, 4H) ppm; 13
C
3-Amino-5,10-dioxo-1-phenyl-5,10-dihydro-1H-pyrazolo
[1,2-b]phthalazine-2-carboxamide (3a, C18H14N4O3)
1H NMR (300 MHz, DMSO-d6): d = 6.34–6.40 (m, 3H),
7.21–7.29 (m, 3H), 7.48 (d, J = 6.9 Hz, 2H), 7.60 (s, 2H),
7.88–7.91 (m, 2H), 8.02–8.05 (m, 1H), 8.20 (t, J = 1.8 Hz,
1H) ppm; 13C NMR (75 MHz, DMSO-d6): d = 62.3, 84.2,
126.7, 127.2, 127.7, 128.0, 128.2, 128.8, 129.0, 133.6,
134.4, 139.4, 148.2, 153.0, 156.2, 166.6 ppm; IR (KBr):
NMR (75 MHz, DMSO-d6): d = 61.7, 83.7, 121.2, 126.7,
127.2, 128.7, 129.0, 130.1, 131.1, 133.6, 134.4, 138.7,
148.4, 153.1, 156.2, 166.5 ppm; IR (KBr): vꢀ = 1,683,
1,524, 1,349 cm-1
.
3-Amino-5,10-dioxo-1-(m-tolyl)-5,10-dihydro-1H-pyrazolo-
[1,2-b]phthalazine-2-carboxamide (3g, C19H16N4O3)
1H NMR (300 MHz, DMSO-d6): d = 2.23 (s, 3H), 6.29 (s,
1H), 6.35 (s, 2H), 7.15 (t, J = 8.1 Hz, 1H), 7.29 (d,
vꢀ = 1,686, 1,500, 1,337 cm-1
.
J = 6.3 Hz, 2H), 7.60 (s, 2H), 7.83–8.06 (m, 5H) ppm; 13
C
3-Amino-1-(3-nitrophenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carboxamide
(3b, C18H13N5O5)
1H NMR (300 MHz, DMSO-d6): d = 6.49 (s, 3H), 7.57 (t,
J = 8.1 Hz, 1H), 7.68 (s, 2H), 7.88–7.94 (m, 3H), 8.02–8.22
NMR (75 MHz, DMSO-d6): d = 21.4, 62.7, 84.5, 125.5,
127.0, 127.5, 128.4, 129.0, 129.1, 129.3, 132.9, 133.9,
134.7, 137.7, 139.6, 148.5, 153.3, 156.5, 166.9 ppm; IR
(KBr): vꢀ = 1,687, 1,503, 1,335 cm-1
.
123

K. Pradhan et al.
23. Bergstrom FW (1944) Chem Rev 35:77
X-ray crystal structure
24. Lichtenthaler FW (2002) Acc Chem Res 35:728
25. Nabid MR, Rezaei SJT, Ghahremanzadeh R, Bazgir A (2010)
Ultrason Sonochem 17:159
26. Terrett NK, Bell AS, Brown D, Ellis P (1996) Bioorg Med Chem
Lett 6:1819
27. Singh SK, Reddy PG, Rao KS, Lohray BB, Misra P, Rajjak SA,
Rao YK, Venkatewarlu A (2004) Bioorg Med Chem Lett 14:499
28. O’Hagan D (2010) J Fluor Chem 131:1071
29. Palomer A, Cabre F, Pascual J, Campos J, Trujillo MA, Entrena
A, Callo MA, Garcia L, Mauleon D, Espinosa A (2002) J Med
Chem 45:1402
Crystallographic data for the structure 2d (crystallized
from DMSO) have been deposited with Cambridge Crys-
tallographic Data Centre as supplementary publication no.
CCDC-925979. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK (fax: ?44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
30. Kucukguzel SG, Rollas S, Erdeniz H, Kiraz M, Ekinci AC, Vidin
A (2000) Eur J Med Chem 35:761
Acknowledgments We gratefully acknowledge the financial sup-
port from UGC, New Delhi, India, and University of Calcutta. K.P.
and S.P. thank UGC, New Delhi, India, for the grant of their Junior
and Senior Research Fellowships, respectively.
31. Genin MJ, Biles C, Keiser BJ, Poppe SM, Swaney SM, Tarpley
WG, Yagi Y, Romero DL (2000) J Med Chem 43:1034
32. Daidone G, Maggio B, Plescia S, Raffa D, Musiu C, Milia C,
Perra G, Marongiu ME (1998) Eur J Med Chem 33:375
33. Gamage SA, Spicer JA, Rewcastle GW, Milton J, Sohal S,
Dangerfield W, Mistry P, Vicker N, Charlton PA, Denny WA
(2002) J Med Chem 45:740
References
34. Comber RN, Gray RJ, Secrist JA (1991) Carbohydr Res 216:441
35. Grasso S, DeSarro G, Micale N, Zappala M, Puia G, Baraldi M,
Demicheli C (2000) J Med Chem 43:2851
1. Rothenberg G (2008) Catalysis: concepts and green applications.
Wiley-VCH, New York
2. Clark JH (1999) Green Chem 1:1
36. Nomoto Y, Obase H, Takai H, Teranishi M, Nakamura J, Kubo K
(1990) Chem Pharm Bull 38:2179
3. Ordomsky VV, van der Schaaf J, Schouten JC, Nijhuis TA (2012)
J Catal 287:68
37. Watanabe N, Kabasawa Y, Takase Y, Matsukura M, Miyazaki K,
Ishihara H, Kodama K, Adachi H (1998) J Med Chem 41:3367
38. Chebanov VA, Muravyova EA, Desenko SM, Musatov VI,
Knyazeva IV, Shishkina SV, Shishkin OV, Kappe CO (2008) J
Comb Chem 8:427
4. Zhang ZH, Liu B, Zhao ZB (2012) Carbohydr Polym 88:891
5. Yang Y, Hu CW, Abu-Omar MM (2012) Green Chem 14:509
6. Caes BR, Raines RT (2011) ChemSusChem 4:353
7. Kim B, Jeong J, Lee D, Kim S, Yoon HJ, Lee YS, Cho JK (2011)
Green Chem 13:1503
39. Dondoni A, Massi A, Sabbatini S, Bertolasi V (2002) J Org Chem
67:6979
8. Qi XH, Watanabe M, Aida TM, Smith RL (2008) Green Chem
10:799
40. Al’-Assar F, Zelenin KN, Lesiovskaya EE, Bezhan IP, Chakchir
BA (2002) Pharm Chem J 36:598
9. Carlini C, Giuttari M, Galletti AMR, Sbrana G, Armaroli T,
Busca G (1999) Appl Catal A Gen 183:295
41. Kim JS, Rhee HK, Park HJ, Lee SK, Lee CO, Cho H-YP (2008)
Bioorg Med Chem 16:4545
10. Carlini C, Patrono P, Galletti AMR, Sbrana G (2004) Appl Catal
A Gen 275:111
42. El-Sakka SS, Soliman AH, Imam AM (2009) Afinidad 66:167
43. Ryu CK, Park RE, Ma MY, Nho JH (2007) Bioorg Med Chem
Lett 17:2577
44. Karthikeyana G, Pandurangan A (2012) J Mol Catal A Chem
361–362:58
45. Ghahremanzadeh R, Shakibaei GI, Bazgir A (2008) Synlett
8:1129
46. Song S-H, Zhong J, He Y-H, Guan Z (2012) Tetrahedron Lett
53:7075
47. Raghuvanshi DS, Singh KN (2011) Tetrahedron Lett 52:5702
48. Shaterian HR, Mohammadnia M (2012) J Mol Liq 173:55
49. Reddy MV, Jeong YT (2013) Tetrahedron Lett 54:3546
50. Pradhan K, Paul S, Das AR (2013) Tetrahedron Lett 54:3105
51. Pradhan K, Bhattacharyya P, Paul S, Das AR (2012) Tetrahedron
Lett 53:5840
52. Paul S, Das AR (2012) Catal Sci Technol 2:1130
53. Pradhan K, Paul S, Das AR (2014) Catal Sci Technol 4:822
54. Zong M-H, Duan Z-Q, Lou W-Y, Smith TJ, Wu H (2007) Green
Chem 9:434
11. Hara M, Yoshida T, Takagaki A, Takata T, Kondo JN, Domen K,
Hayashi S (2004) Angew Chem Int Ed 43:2955
12. Toda M, Takagaki A, Okamura M, Kondo JN, Domen K, Hayashi
S, Hara M (2005) Nature 438:178
13. Corma A (1997) Curr Opin Solid State Mater Sci 2:63
14. Busca G (1998) Catal Today 41:191
15. Corma A, Garcia H (1997) Catal Today 38:257
16. Sikdar SK, Howell SG (1998) J Clean Prod 6:253
17. Okamura M, Takagaki A, Toda M, Kondo JN, Tatsumi T, Domen
K, Hara M, Hayashi S (2006) Chem Mater 18:3039
18. Fukuhara K, Nakajima K, Kitano M, Kato H, Hayashi S, Hara M
(2011) ChemSusChem 4:778
19. Hara M (2009) ChemSusChem 2:129
20. Ramesh K, Murthy SN, Karnakar K, Nageswar YVD, Vi-
jayalakhshmi K, Devi BLAP, Prasad RBN (2012) Tetrahedron
Lett 53:1126
21. Karnakar K, Murthy SN, Ramesh K, Nageswar YVD, Reddy VK,
Devi BLAP, Prasad RBN (2012) Tetrahedron Lett 53:1968
22. Franklin EC (1935) Chem Rev 16:305
123