One-pot four-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10- dione derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.10.063

The synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by NiCl₂-catalyzed novel one-pot four-component condensation reaction of phthalimide, hydrazine, malononitrile (or ethyl cyanoacetate), and aromatic aldehydes was reported. This work provides a simple, efficient, and eco-friendly method for the construction of pyrazolo[1,2-b]phalazine-5,10-dione derivatives.

Full text of DOI:10.1016/j.tetlet.2012.10.063

Tetrahedron Letters 53 (2012) 7075–7077
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot four-component synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
⇑
⇑
Shi-Hua Song, Jun Zhong, Yan-Hong He , Zhi Guan
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2012
Revised 7 October 2012
Accepted 16 October 2012
Available online 23 October 2012
The synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by NiCl2-catalyzed novel one-pot
four-component condensation reaction of phthalimide, hydrazine, malononitrile (or ethyl cyanoacetate),
and aromatic aldehydes was reported. This work provides a simple, efficient, and eco-friendly method for
the construction of pyrazolo[1,2-b]phalazine-5,10-dione derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Green synthesis
Phthalazine derivative
One-pot
Introduction
For example, the use of strong acid probably results in pollution
discharge and flammable, explosive, and expensive catalysts were
Nitrogen-containing heterocyclic compounds are widespread in
nature, and their applications in biologically active pharmaceuti-
cals, agrochemicals, and functional materials are getting more
and more important.1–4 Furthermore pyrazoles are usually the core
fragment of many biologically active compounds, such as
Celecoxib, Viagra, Pyrazofurine, and so on.5–8 Recently, heterocy-
cles containing a phthalazine moiety have attracted extensive
attentions. Phthalazine derivatives have been reported to possess
anticonvulsant,9 cardiotonic,10 vasorelaxant,11 cytotoxic,12 antimi-
crobial,13 antifungal,14 anticancer,15 and anti-inflammatory
activities.16 In addition, the titled compounds, pyrazolo[1,2-
b]phthalazine-diones, were also found to have analgesic, anti-
hypoxic, and anti-pyretic activities.17 Therefore, the development
of simple methods for the synthesis of pyrazolo[1,2-b]phthal-
azine-5,10-diones is very important. Multicomponent reactions
were employed as a powerful tool to synthesize diverse and com-
plex heterocyclic compounds due to their advantages of the intrin-
sic atom economy, simpler procedures, structural diversity, energy
savings, and reduced waste.18–20 To our knowledge, there are only
several literatures about the multicomponent synthesis for
1H-pyrazolo [1,2-b] phthalazine-5,10-dione derivatives, which
were synthesized by a one-pot three-component reaction of
phthalhydrazide, aromatic aldehydes, and malononitrile or ethyl
cyanoacetate catalyzed by p-TSA,21 Et3N4 or [Bmim]OH.22
However, the present methods have more or less shortcomings.
employed. Herein we wish to report the synthesis of 1H-pyrazol-
o[1,2-b]phthalazine-5,10-dione derivatives by a one-pot four-com-
ponent condensation reaction of phthalimide, hydrazine hydrate,
aromatic aldehydes, and malononitrile or ethyl cyanoacetate cata-
lyzed by Lewis acid NiCl2Á6H2O.
Results and discussion
Initially, we carried out the one-pot four-component reaction of
phthalimide (1), hydrazine hydrate (2), malononitrile (3a), and 4-
nitrobenzaldehyde (4) in refluxing ethanol as a model reaction.
Different Lewis acids were tested, and results are listed in Table 1.
As shown in Table 1, all tested Lewis acids had catalytic effects on
the four-component condensation reaction. Under the same exper-
imental conditions, NiCl2Á6H2O showed an excellent catalytic
activity, which gave product 5a1 in a yield of 94% (Table 1, entry
6). When using MnCl2 and SnCl2Á2H2O as catalysts, we got 5a1 in
moderate yields of 76% and 70%, respectively (Table 1, entries 2
and 5). The reactions catalyzed by ZnI2 or CoCl2Á6H2O could give
product 5a1 in 80% or 81% yield, respectively (Table 1, entries 1
and 4). However, only 65% yield of product was obtained from
the reaction catalyzed by FeCl2Á4H2O (Table 1, entry 3). Therefore,
NiCl2Á6H2O was chosen as the catalyst for the further study. Mean-
while, water was tested as a reaction medium of model reaction
catalyzed by NiCl2Á6H2O, but just 75% yield of product was isolated
(Table 1, entry 7). The effect of temperature on the reaction was
also investigated (Table 1, entries 6, 8 and 9). After examining
the reaction in ethanol at 30 °C, 50 °C and at the boiling point of
⇑
Corresponding authors. Tel./fax: +86 23 68254091.
E-mail addresses: heyh@swu.edu.cn (Y.-H. He), guanzhi@swu.edu.cn (Z. Guan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.063

7076
S.-H. Song et al. / Tetrahedron Letters 53 (2012) 7075–7077
Table 1
The effect of different conditions on the model reactiona
NO2
CHO
O
O
O
Lewis Acid
CN
CN
N
N
CN
NH2NH2• H2O
+
+
+
NH
EtOH/refluxing
NH2
O
1
NO2
4
2
3a
5a1
Entry
Cat.
Cat. (mol %)
Solvent
T/°C
Yieldb (%)
1
2
3
4
5
6
7
8
ZnI2
MnCl2
10
10
10
10
10
10
10
10
10
5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
EtOH
EtOH
EtOH
EtOH
Refluxing
Refluxing
Refluxing
Refluxing
Refluxing
Refluxing
Refluxing
30
80
76
65
81
70
94
75
N.D.
56
70
93
FeCl2Á4H2O
CoCl2Á6H2O
SnCl2Á2H2O
NiCl2Á6H2O
NiCl2Á6H2O
NiCl2Á6H2O
NiCl2Á6H2O
NiCl2Á6H2O
NiCl2Á6H2O
9
10
11
50
Refluxing
Refluxing
15
a
Reaction conditions: phthalimide (1.0 mmol), hydrazine hydrate (1.0 mmol), Lewis acid, solvent (3.0 mL), 2 h; then adding 4-nitrophenylaldehyde (1.0 mmol), malon-
onitrile (1.0 mmol), 2 h.
b
Isolated yields.
Table 2
NiCl2Á6H2O catalyzed synthesis of phthalazinetrione derivativesa
O
O
Ar
O
NiCl2 6H O
·
2
X
CN
N
N
NH2NH2• H2O
ArCHO
X
+
+
+
NH
EtOH/refluxing
NH2
O
3a X=CN
3b X=CO2Et
1
2
4
5
Entry
X
Ar
Product
Time/h
Yieldb (%)
1
2
3
4
5
6
7
8
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
C6H5
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-FC6H4
3-ClC6H4
4-BrC6H4
C6H5
5a1
5a2
5a3
5a4
5a5
5a6
5a7
5a8
5a9
5a10
5a11
5a12
5b1
5b2
5b3
5b4
5b5
2
4
4
4
6
5
5
6
6
3
6
6
4
5
5
6
5
94
90
85
82
80
85
80
91
82
87
81
92
84
71c
83
80
84
9
10
11
12
13
14
15
16
17
a
Reaction conditions: phthalimide (1.0 mmol), hydrazine hydrate (1.0 mmol), NiCl2Á6H2O (0.1 mmol), ethanol (3.0 mL), refluxing 2 h; then adding aromatic aldehyde
(1.0 mmol), malononitrile or ethyl cyanoacetate (1.0 mmol), refluxing. For general procedure, please see ref. 23.
b
Isolated yields.
c
Reaction conditions: phthalimide (1.0 mmol), hydrazine hydrate (1.0 mmol), NiCl2Á6H2O (0.1 mmol), ethanol (3.0 mL), refluxing 2 h; then adding ethanol (3.0 mL) in order
to stir smoothly, 4-fluoro benzaldehyde (1.0 mmol), ethyl cyanoacetate (1.0 mmol), refluxing 5 h.
ethanol, it was found that the best result was obtained from the
reaction in refluxing ethanol. Then the catalyst loading on the
model reaction was investigated. When 5 mol % of catalyst was
used, the product 5a1 was obtained only in 70% yield (Table 1, en-
try 10). The catalyst loading of 10 mol % led to an excellent yield of
94 % (Table 1, entry 6), however no obvious improvement was ob-
served by further increasing the catalyst loading to 15 mol %,
which gave a yield of 93% (Table 1, entry 11). Therefore, 10 mol %
of NiCl2Á6H2O was used as the optimized catalyst for further
research.
The generality of this four-component reaction was studied
under optimal conditions by varying the structures of aldehydes.
The results are summarized in Table 2. Generally, the reactions
that employed aromatic aldehydes bearing electron-withdrawing
or electron-donating functional groups at different positions
produced the corresponding products 5 in good to excellent
yields within 6 h. The steric and electronic properties of the
aldehydes affected the reaction yields obviously. For example,
reacting with phthalimide, hydrazine hydrate, and malononitrile,
4-nitrobenzaldehyde gave an excellent yield of 94% (Table 2,

S.-H. Song et al. / Tetrahedron Letters 53 (2012) 7075–7077
7077
Ni2+
O
O
O
2
NH2NH2.H2O
NiCl2.6H2O
Ni2+
NH NH2
NH2
NH
NH
O
O
O
1
O
Ni2+
-NH3
NH
NH
O
O
Ar
6
O
N
Ar
-NiCl2.6H2O
X
N
N
X
O
3
NH CN
NiCl2.6H2O
X
CN
NH
NC
O
CHAr
+
Ni2+
X
7
ArCHO
4
O
O
Ar
N
N
X
5
NH2
Scheme 1. A plausible reaction mechanism.
entry 1); while 3-nitrobenzaldehyde and 2-nitrobenzaldehyde
provided the product in 90% and 85% yields, respectively (Table 2,
entries 2 and 3). The decrease of yields was likely that the steric
effect of nitro group increased from para position to ortho
position. Similarly, 3-chlorobenzaldehyde gave a better yield than
2-chlorobenzaldehyde (Table 2, entries 6 and 7). This trend also
was found using 4-bromobenzaldehyde and 3-bromobenzaldehyde
(Table 2, entries 8 and 9). However there was an exception that
4-chlorobenzaldehyde provided a relatively low yield of 80%
(Table 2, entry 5) than 3-chlorobenzaldehyde. Overall this
procedure was applicable to various F, Cl, and Br substituted
benzaldehydes which gave satisfactory yields (Table 2, entries
4–9). The high yields of products could be obtained from
benzaldehyde and aromatic aldehydes bearing electron-donating
groups as well. In addition, the four-component reactions
using ethyl cyanoacetate (Table 2, entries 13–17) instead of
malononitrile generally gave good yields except reacting with
4-fluorobenzaldehyde (Table 2, entry 14).
A plausible mechanism was proposed for the formation of 1H-
pyrazolo[1,2-b]phthalazine-5,10-diones from the four-component
condensation reaction of phthalimide, hydrazine hydrate, malono-
nitrile, and aromatic aldehydes (Scheme 1). In the presence of a
catalyst, phthalimide 1 reacts with hydrazine hydrate 2 to generate
phthalhydrazide 6. Meanwhile, the Knoevenagel condensation
of malononitrile or ethyl cyanoacetate 3 with aldehyde 4
produces intermediate 7. Subsequently, Michael-type addition of
phthalhydrazide 6 and intermediate 7 followed by cyclization
affords the corresponding product 5.
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.10.063.
References and notes
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Conclusion
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In summary, we have developed a one-pot four-component
reaction for the synthesis of pyrazolo[1,2-b]phthalazine-5,10-
diones from readily available starting materials. This method has
the advantages of being concise, highly efficient, friendly to the
environment, and inexpensive.
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23. General procedure for the synthesis of phthalazine derivatives 5: A mixture of
phthalimide (1.0 mmol), hydrazine hydrate (1.0 mmol), and NiCl2Á6H2O
(0.1 mmol) in ethanol (3.0 mL) was stirred under reflux for 2 h. Then
aromatic aldehyde (1.0 mmol), malononitrile, or ethyl cyanoacetate
(1.0 mmol) were added, and the mixture was refluxed for a specified time.
The reaction was monitored by TLC. After the reaction completed, the reaction
mixture was allowed to cool to rt. The residue precipitated during the process
was separated from the solution by filtration, and the filter cake was washed
with ethanol to yield NMR pure 5.
Acknowledgments
Financial support from 2011 Select Project in Scientific and
Technological Activities for Returned Scholars of Chongqing Per-
sonnel Bureau, and the Doctoral Foundation of Southwest Univer-
sity (SWU112019) is gratefully acknowledged.