A highly efficient green synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10- dione derivatives and their photophysical studies

Article abstract of DOI:10.1016/j.tetlet.2011.08.111

A task-specific ionic liquid, [Bmim]OH, has been used for an efficient synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones by one-pot cyclocondensation reaction of phthalhydrazide, aromatic aldehydes, and malononitrile or ethyl cyanoacetate under microwave irradiation. The advantages of this method include the use of green catalyst, no organic solvent, easy work-up and excellent yields. The photophysical properties for some 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives have been investigated for the first time.

Full text of DOI:10.1016/j.tetlet.2011.08.111

Tetrahedron Letters 52 (2011) 5702–5705
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A highly efficient green synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives and their photophysical studies
⇑
Dushyant Singh Raghuvanshi, Krishna Nand Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A task-specific ionic liquid, [Bmim]OH, has been used for an efficient synthesis of 1H-pyrazolo[1,2-
b]phthalazine-5,10-diones by one-pot cyclocondensation reaction of phthalhydrazide, aromatic alde-
hydes, and malononitrile or ethyl cyanoacetate under microwave irradiation. The advantages of this
method include the use of green catalyst, no organic solvent, easy work-up and excellent yields. The
photophysical properties for some 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives have been
investigated for the first time.
Received 28 February 2011
Revised 18 August 2011
Accepted 20 August 2011
Available online 25 August 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Green approach
Pyrazolophthalazine
Microwave
Ionic liquid
Optical studies
Diversity-oriented synthesis (DOS) continues to be an area of
importance at the interface of organic synthesis and chemical biol-
ogy/material science.1 At the heart of DOS are the methods needed
for an efficient generation of functionally and diverse small
molecules, especially those possessing skeletons found in natural
products, drug-like molecules and materials.2 Perhaps the most
promising and powerful method for generating such molecules is
by sequential multicomponent reactions (MCRs) with further
increase in molecular complexity and diversity.3 There is great
current interest in microwave assisted organic synthesis (MAOS),4
because such environmentally benign chemical methodologies are
strongly required in the light of the paradigm shift to ‘Green
Chemistry’. According to the current synthetic requirements,
environmentally benign multi-component procedures employing
microwave (MW) methodology are particularly welcome due to
their intrinsic advantages.5 The use of a benign and recyclable cat-
alyst/solvent with high activity and selectivity is an interesting and
rapidly growing area of synthetic chemistry. Owing to their green
credentials, ionic liquids (ILs) have attracted considerable interest
as environmentally benign reaction media,6–9 catalysts9–11 and
reagents.12
biologically active compounds, including blockbuster drugs such
as celecoxib, viagra, pyrazofurine, and many others.16–19 Similarly,
heterocycles containing a phthalazine moiety are of current inter-
est due to their pharmacological and biological activities,20–22 for
example, pyrazolo[1,2-b]phthalazine-dione is described as anti-
inflammatory, analgesic, anti-hypoxic, and anti-pyretic agent.21
Phthalazine derivatives are also found to possess anticonvulsant,23
cardiotonic24 and vasorelaxant25 activities. Present communication
reports a one pot multicomponent, efficient and green synthesis of
some 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives. The
photophysical properties of some selected derivatives have also
been studied showing medium to strong optical behavior.
A perusal of literature reveals that there exist only two multi-
component reports by Bazgir et al. for the synthesis of pyrazolo-
[1,2-b]phthalazine-diones employing PTSA/BmimBr (100 °C, 3 h)
and sonochemistry in the presence of Et3N/EtOH (50 °C, 1 h).26
However, the generality of the existing reports is somewhat viti-
ated by the severe reaction conditions, and the catalysts and
solvents used are not acceptable in the context of green synthesis.
Thus, the development of a new, efficient and green approach for
the preparation of heterocycles containing a phthalazine ring frag-
ment is highly desirable. In view of the above and as a part of our
ongoing programme on multicomponent reactions,27 an efficient
and convenient synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-
dione has been accomplished by the multicomponent reaction of
phthalhydrazide, aromatic aldehydes, and malononitrile using con-
trolled MW irradiation in the presence of [Bmim]OH at an ambient
temperature of 45 °C (Scheme 1).
Nitrogen-containing heterocyclic compounds are widespread in
nature, and their applications to pharmaceuticals, agrochemicals,
and functional materials are becoming more and more impor-
tant.13–15 Pyrazoles are an important class of compounds for new
drug development, as they are the core structure of numerous
⇑
In order to optimize the reaction conditions, the catalytic activ-
ity of [Bmim]OH was tested for a typical multicomponent reaction
Corresponding author. Tel.: +91 542 6702485; fax: +91 542 2368127.
E-mail addresses: knsingh@bhu.ac.in, knsinghbhu@yahoo.co.in (K.N. Singh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.111

D. S. Raghuvanshi, K. N. Singh / Tetrahedron Letters 52 (2011) 5702–5705
5703
and temperature did not improve the product yield. It is interesting
to note that the reactants, when simply stirred in [Bmim]OH at
room temperature for 30 min, resulted in a sizable conversion to
the product (50%).
O
O
O
Ar
[Bmim]OH
CN
X
NH
NH
N
N
ArCHO
X
MW, 100W ,45°C
4-5min.
X= CN,
COOEt
3
NH2
O
4
Under the optimized set of controlled MW reaction conditions
(100 W and 45 °C), a number of aromatic aldehydes 2 were al-
lowed to undergo multicomponent reaction with malononitrile 3
and phthalylhydrazide 1 in a molar ratio of 1:1:1 in ionic liquid
[Bmim]OH (0.2 mL) affording 1H-pyrazolo[1,2-b]phthalazine-
5,10-diones 4a–z in excellent yields in 4–5 min (Table 1).28 The
physical and spectral data of all the products are in full agreement
with the assigned structures. It is worthwhile to mention that the
ionic liquid [Bmim]OH was recycled up to five times without any
loss and diminution in its amount and efficacy. After each and
every recycle, the purity of the ionic liquid was affirmed by spec-
troscopic data.
Electronic absorption and photoluminescent properties: out of
all the 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 4a–z synthe-
sized, eight representative derivatives having variant structural
features viz 4a, 4g, 4k, and 4m with cyano functionality; and 4n,
4t, 4y, and 4z containing ester linkage, were subjected to their pos-
sible photophysical studies. The photo physical parameters includ-
ing the quantum yield and Stokes shift for all the examined
compounds are given in Table 2.
2
1
Scheme 1. [Bmim]OH catalyzed synthesis 1H-pyrazolo[1,2-b]phthalazine-5,
10-dione derivatives.
Table 1
[Bmim]OH mediated synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione deriva-
tives 4a–za
Entry
Ar-CHO
Ar
CN-CH2-X
X
Product
Time (min)
Yields (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Ph
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4
4
5
4
5
5
4
4
5
5
5
5
5
4
5
5
4
5
5
4
5
5
4
5
5
5
94
92
93
96
90
91
97
95
94
92
91
89
92
95
92
91
93
91
92
98
95
95
93
90
91
93
4-BrC6H4
3-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-FC6H4
4-MeC6H4
4-MeOC6H4
2-Thienyl
Ph
4-BrC6H4
3-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-FC6H4
The 5 Â 10À5 M DMSO solution of compounds 4a, 4g, 4k, and
4m showed absorption bands at 360, 355, 351, and 354 nm,
respectively (Fig. 1). Moreover, when these compounds were ex-
cited at their respective wavelengths, all the compounds (4a, 4k,
and 4m) except 4g exhibited a medium to strong photolumines-
cent emissions. Compound 4a emits at two wavelengths at 438
and 522 nm, while 4k and 4m showed strong emission bands at
524 and 446 nm with a weak shoulder at 450 and 521 nm, respec-
tively. The weak emission band (575 nm) observed in the case of
4g is attributed to the electron-withdrawing nature of nitro
substituent.
The photophysical behavior of the compounds containing the
ester group is almost similar to that of the compounds with cyano
substituent ( Fig. 2). The compound 4n showed two absorption
bands at 310 and 364 nm, whereas 4z absorbs at 332 and
365 nm. The compound 4x absorbs strongly at 325 nm with a weak
shoulder at 365 nm. Contrary to 4n, 4x, and 4z; the compound 4t
absorbs at a single wavelength of 358 nm. When excited at
310 nm, 4n emits at 519 nm; 4x also emits around the same region
at 517 nm upon excitement at 325 nm. Moreover, the excitation of
4t at 358 nm showed comparatively weak intensity at 510 nm. The
compound 4z (thienyl substituent) showed an altogether different
fluorescent behavior with two different emission bands at wave-
lengths 439 and 516 nm. In this series too, 4t with the nitro substi-
tuent emits weakly in comparison to other examined derivatives.
As evident from Table 2, a large Stokes shift and low quantum
yield for all the examined derivatives are observed. The Stokes shifts
CN
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
4s
4t
4u
4v
4w
4x
4y
4z
4-MeC6H4
4-MeOC6H4
2-Thienyl
a
Microwave heating performed on 100 W at 45 °C.
Isolated yield.
b
of phthalhydrazide 1, benzaldehyde 2a, and malononitrile 3 under
controlled microwave in the presence and absence of ethanol. The
use of [Bmim]OH (20 mol %) in ethanol promoted the reaction to a
reasonable extent (70%) at 100 W and 80 °C; whereas the use of
[Bmim]OH alone brought about an excellent conversion (92%) un-
der the same set of MW conditions. Intrigued by this observation,
the reaction was investigated in detail under controlled microwave
by varying MW power (80, 100 and 150 W) and temperature (40,
45, 60 and 80 °C) in [Bmim]OH alone. It was observed that the
maximum conversion to product 4a (94%) was achieved using
100 W power output at 45 °C. A further increase in the MW power
Table 2
UV-Visible and fluorescence data of the examined derivatives of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
Compound
kabs (nm)
kext (nm)
kem (nm)
e
(MÀ1 cmÀ1
)
D
m
(cmÀ1
)
Ufa
s (l
s)b
4a
4g
4k
4m
4n
4t
360
355
351
360
355
351
354
310
358
325
332
438, 522
25000
13000
25400
17400
16800
22400
30000
20200
4946.73, 8620.69
10857.29
9085.04, 5946.79
6068.51, 9296.17
12990.24
8325.12
11426.87
7341.44, 10740.64
0.057
0.051
0.045
0.080
0.136
0.049
0.063
0.075
328
227
279
225
225
212
222
227
575
524, 450 (s)
446, 521 (s)
519
510
517
439, 516
354
310, 364 (s)
358
325, 365 (s)
332, 365 (s)
4x
4z
kabs = absorbance maxima, kext = excitation wavelength, kem = fluorescence maxima,
e
= molar absorptivity,
D
m
= Stoke’s lines, Uf = quantum yield.
a
Quantum yield was calculated with respect to naphthalene in DMSO.
b
Fluorescence decay time was carried out at room temperature using the 355 nm wavelength from a 7 ns pulsed Nd:YAG laser (Innolas, Spitlight 600, Germany) and the
data were acquired using an oscilloscope (analog digital scope-HM1507) with software SP107.

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D. S. Raghuvanshi, K. N. Singh / Tetrahedron Letters 52 (2011) 5702–5705
90
1.35
1.20
1.05
0.90
0.75
0.60
0.45
0.30
0.15
0.00
4a
4g
4k
80
70
60
50
40
30
20
10
0
4a
4g
4k
4m
4m
450
500
550
600
650
300
350
400
450
500
Wavelength, nm
Wavelength, nm
Figure 1. Absorption and emission spectra of 4a, 4g, 4k and 4m derivatives.
1.6
1.2
0.8
0.4
0.0
125
4n
4t
4n
4t
4x
4z
4x
4z
100
75
50
25
0
400 425 450 475 500 525 550 575 600 625
300
325
350
375
400
425
450
Wavelength, nm
Wavelength, nm
Figure 2. Absorption and emission spectra of 4n, 4t, 4x and 4z derivatives.
E = Eabs À Eflu (in cmÀ1
)
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have been determined as the difference
D
and have been found to range from 4946.73 to 10857.29 cmÀ1 for
the cyano derivatives 4a, 4g, 4k, and 4m, and from 7341.44 to
12990.24 cmÀ1 for the ester derivatives 4n, 4t, 4y, and 4z. Thus,
the Stokes shifts for the cyano compounds are lower as compared
to that of the ester derivatives. This may be explained as a conse-
quence of involvement of amino group in hydrogen bonding with
the O-atom of the ester group, which is absent in the case of first
series of compounds.
In conclusion, a one-pot high yielding synthetic protocol has
been developed for achieving 1H-pyrazolo[1,2-b]phthalazine-
5,10-diones using an environmentally benign and recyclable cata-
lyst [Bmim]OH. The observed fluorescent behavior of these deriva-
tives further opens its amenability as a new series of fluorescent
molecules.
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Acknowledgments
The authors are thankful to the Department of Biotechnology,
New Delhi for the research project and to the CSIR, New Delhi for
SRF to DSR. Thanks are also due to Professor S. B. Rai, Department
of Physics, BHU, Varanasi for measuring the fluorescence lifetimes.
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(1 mmol) and [Bmim]OH (0.2 mL) were put in a pressure regulation 10-mL
pressurized vial with ‘snap-on’ cap and the reaction mixture was subjected to
irradiation in a single-mode microwave synthesis system at 100 W power and
45 °C for 4–5 min. After completion of the reaction as indicated by TLC, water
(5 mL) was added and the product was extracted with EtOAc (3 Â 10 mL). The
combined organic phase was dried over anhydrous Na2SO4, evaporated under
reduced pressure and recrystallized from ethanol to afford pure 1H-
pyrazolo[1,2-b]phthalazine-5,10-diones 4. After isolation of the product, the
remaining aqueous layer containing the ionic liquid was washed with ether
(10 mL) to remove any organic impurity, and then dried under vacuum at 90–
95 °C for 15 h to afford [Bmim]OH, which was used in the subsequent runs
without further purification.
28. General procedure for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione:
Phthalhydrazide (1 mmol), aromatic aldehyde (1 mmol), malononitrile