InCl3-catalyzed green synthesis of 1H-pyrazolo[1,2-b] phthalazine-5,10-diones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2013.04.109

A simple, efficient, and green practical approach to 1H-pyrazolo[1,2-b] phthalazine-5,10-diones from phthalhydrazide, aldehydes, and malononitrile/ethyl cyanoacetate has been developed that uses inexpensive and readily available InCl₃ as a catalyst in solvent-free one-pot three-component cyclo condensation reaction. This method should provide high yields, shorter reaction time, easy work-up, purification of products by nonchromatographic method, and cleaner reaction. It is a new strategy for N-fused heterocycles synthesis, which haswider application in organic and medicinal chemistry.

Full text of DOI:10.1016/j.tetlet.2013.04.109

Accepted Manuscript
InCl3-Catalyzed green synthesis of 1H-pyrazolo[1,2-b] phthalazine-5,10-diones
under solvent-free conditions
Mudumala Veeranarayana Reddy, Yeon Tae Jeong
PII:
S0040-4039(13)00715-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.04.109
TETL 42877
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Reddy, M.V., Jeong, Y.T., InCl3-Catalyzed green synthesis of 1H-pyrazolo[1,2-b]
phthalazine-5,10-diones under solvent-free conditions, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.04.109
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InCl3-Catalyzed green synthesis of 1H-
pyrazolo[1,2-b] phthalazine-5,10-diones
under solvent-free conditions
Leave this area blank for abstract info.
Mudumala Veeranarayana Reddy and Yeon Tae Jeong*
O
O
O
NH2
N
N
InCl3
NH
X
NC
X
+ R CHO
(2a-y)
+
NH
Solvent-Free
80 C
R
O
(1)
(4a-y)
(3)

2
Tetrahedron Letters
journal homepage: www.elsevier.com
InCl3-Catalyzed green synthesis of 1H-pyrazolo[1,2-b] phthalazine-5,10-diones under
solvent-free conditions
Mudumala Veeranarayana Reddy and Yeon Tae Jeong*
Department of Image Science and Engineering, Pukyong National University,
Busan, Korea, 608-737
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple, efficient and green practical approach to 1H-pyrazolo[1,2-b]phthalazine-5,10-diones
from phthalhydrazide, aldehydes, and malononitrile/ ethyl cyanoacetate has been developed that
uses inexpensive and readily available InCl3 as a catalyst in solvent-free one-pot three-
component cyclo condensation reaction. This method should provide high yields, shorter
reaction time, easy work-up, purification of products by non-chromatographic method and
cleaner reaction. It’s a new strategy for N-fused heterocycles synthesis, whose are having a
wider applications in organic and medicinal chemistry.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
1H-pyrazolo[1,2-b]phthalazine-5,10-diones
InCl3
Solvent-free reaction
1. Introduction
and greatly removing the ecologically harmful and flammable
organic solvents which are create a large quantities of wastage.
The molecules which are containing heterocyclic unit(s)
have profound interest in medicinal chemistry because their wide
range of biological activities.1 These potential drug candidates
synthesis with privileged heterocycles are a crucial issue in
diversity oriented synthesis (DOS), and combinatorial chemistry.
Most of the nitrogen-containing fused pyrazolo[1,2-b]
phthalazines heterocycles are showing multiple biological
activities.2-7 Even though establishing various methodologies for
Reduction of these global warming now-a-days explorations of
solvent-free reactions has gained an important role in synthetic
organic chemistry21-31 by virtue of experimental simplicity, less
energy requirement, and producing high yields of products by
almost quantitative reactivity of the substrates.
literature feedback the merits of readily availability,
non-toxicity, inexpensiveness, moisture stability, air and water
compatibility, and Lewis acidic nature of indium chloride (InCl3)
as catalyst in synthetic organic chemistry for various organic
transformations to get highly selective products.32-36 Because of
its acidic nature enhance this usage towards catalytic amount
from stoichiometric. In addition to these numerous advantages it
also has merits of recyclability, operational simplicity, and
remarkable ability to suppress side reactions in acid sensitive
substrates are encouraging as eco-friendly catalyst in green
chemistry and supporting for a wide variety of reactions.37-41
Moreover, solvent-free and InCl3 combination reactions are well
known in organic transformation.42-45 Solvent-free reaction
endorsed InCl3 reactions are well known as environmentally
benign methods that also usually provide improved selectively,
enhanced reaction rates, cleaner products and manipulative
simplicity. This area has also attracted considerable attention in
recent years.42-45 We therefore became interested in devising
more general and green methods for the synthesis of 1H-pyrazolo
[1,2-b] phthalazine-5,10-diones.
these
important
biologically
active
pharmaceuticals,
agrochemicals, and functional materials which are resemblances
with naturally occurring nitrogen-containing heterocyclic (N-
heterocyclic) compounds, still there is challenging to
development of new methodologies for modern synthetic organic
chemists. Only a few methods have been reported the one-pot
synthesis of 1H-pyrazolo [1,2-b] phthalazine-5,10-diones, based
on catalysts such as Et3N,8 Mesoporous solid acid catalysts (Al-
KIT-6),9 [bmim]Br/PTSA,10 [Bmim]OH11 and NiCl2•6H2O.12
However, these procedures also are limited in scope, because of
relatively long reaction times and the use of an organic solvent,
expensive ionic liquids and catalysts. Therefore, the development
of an easy and efficient method for the preparation of 1H-
pyrazolo [1,2-b] phthalazine-5,10-diones is still a challenging
task.
Now-a-days from the view point of green and
sustainable chemistry13-16 solvent-free organic synthesis is the
best eco-friendly methodology to overcome the problems17-20 in
green chemical synthesis of various biologically active
compounds by considering fewer or no toxic substances
Our literature survey at this stage revealed that there are
no reports on the synthesis of 1H-pyrazolo [1,2-b] phthalazine-
5,10-diones under solvent-free at 80 °C mediated by InCl3. Our
main target is to develop a green organic reaction methodology.
As part of our ongoing research program on the development of
———
Corresponding author.
 Tel.: +82-51-629-6411; fax: +82-51-629- 6408;
e-mail: ytjeong@pknu.ac.kr

green protocols,46-48 herein, we report a facile one-pot synthesis
of 1H-pyrazolo [1,2-b] phthalazine-5,10-diones via three-
component coupling of phthalhydrazide, aldehydes and
malononitrile/ ethyl cyanoacetate in the presence of catalytic
amount (10 mol %) of InCl3 under solvent-free at 80 °C
(Scheme 1).
13
14
Solvent-free
Solvent-free
80
100
25
25
94
94
aReaction of 3-fluorobenzaldehyde (1 mmol), phthalhydrazide (1 mmol) and
malononitrile (1 mmol) catalyzed by InCl3 (mol 10 %) .
Because of the important role of catalyst in a reaction,
we investigated the effects of various catalysts by manipulating
the reaction conditions on the representative of model reaction
under solvent-free conditions. In the absence of the catalyst, the
reaction could be carried out but the product was obtained in very
low yield after prolonged reaction time. Therefore, our efforts
focused on the search for a suitable catalyst. Initially, GaCl3 was
chosen as the catalyst to carry out this reaction. As a result, long
reaction times were needed and low transformation rates were
observed. Attempts with different catalysts at 80 ºC, under
solvent-free conditions, and the results are listed in Table 2. It
was found that InCl3 showed better catalytic activity among these
catalysts. Most excitingly, when InCl3 was used, the reaction
proceeded very smoothly and gave the product in 94% yield
(Table 2, entry 8). Moreover, we found that the yields were
obviously affected by the amount of InCl3 loaded. When 2 mol
%, 5 mol %, 10 mol %, and 20 mol % of InCl3 were used, the
yields were 40, 70, 94, and 95%, respectively (Table 2, entries
8–11). Therefore, 10 mol % of InCl3 was sufficient and excessive
amount of catalyst did not increase the yields significantly
(Table 2, entries 8).
O
O
NH2
N
N
InCl3
NH
NH
X
NC
X
+ R CHO
(2a-y)
+
Solvent-Free
80 C
R
O
O
(1)
(4a-y)
(3)
Scheme-1 Solvent-free synthesis of 1H-pyrazolo [1,2-b] phthalazine-
5,10-diones.
.
2. Result and Discussions
In this letter, we have presented a new and efficient
method for the synthesis of 1H-pyrazolo [1,2-b] phthalazine-
5,10-diones using InCl3 (Schemes 1).49
In order to optimize the reaction conditions, firstly, we
investigated the effect of different solvents on the reaction rate
and as well as yields of the products. As a model reaction, the
reaction of phthalhydrazide (1, 1 mmol), 3-fluorobenzaldehyde
(2b, 1 mmol) and malononitrile (3,1 mmol) catalyzed by 10 %
InCl3 in various solvents including ethanol (EtOH), n-propanol
Table 2. Influence of the catalyst on the amino-1-(3-
fluorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-
b]phthalazine-2-carbonitrile (4b)a
(n-C3H7OH),
benzene
(C6H6),
chloroform
(CHCl3),
tetrahydrofuran (THF), acetonitrile (CH3CN) and water was
investigated at 80 °C (Table 1). In aprotic solvents such as
benzene, chloroform, THF and CH3CN, the reaction were very
slow and resulted in lower product yield (Table 1 entries 1-4).
Conducting the reactions in protic solvents improved both the
reaction rates as well as product yields (Table 1 entry 5-7).
Water has been identified as an ideal solvent because it is
inexpensive, non-flammable, abundant and environmentally
benign. However, when the same reaction was carried out in
water, the expected product was obtained only in low yield even
after 10 h (Table 1 entry 8). Furthermore, we also conducted this
InCl3 catalyzed condensation reaction under solvent-free
conditions at 80 °C. As shown in Table 1 entry 13, the yields of
the reaction under solvent-free conditions were higher and the
reaction times were shorter than under solvent conditions. The
better yield in solvent-free conditions could be explained by a
uniform distribution of the eutectic mixture of reactants, being in
closer proximity to react than in conditions using ethanol as the
solvent.
Entry
Catalyst
Catalyst (mol %)
Time
(min )
Yieldb
(%)
1
2
NO
GaCl3
AlCl3
GaBr3
FeCl3
InBr3
InF3
-
180
150
150
170
150
80
20
38
52
40
62
65
75
94
40
70
95
10
10
10
10
10
10
10
2
3
4
5
6
7
55
8
InCl3
InCl3
InCl3
InCl3
25
9
60
10
5
40
11
20
25
aReaction of 3-fluorobenzaldehyde (1 mmol), phthalhydrazide (1 mmol) and
malononitrile (1 mmol) under solvent-free conditions at 80 °C. bIsolated
yield
To optimize the reaction temperature, the mixture was
In order to extend the above reaction (Scheme 1) to a
library system, various kinds of aldehydes (2a-y), (Table 3) were
subjected to react with 1 and 3 to give the corresponding 1H-
pyrazolo [1,2-b] phthalazine-5,10-diones (4a-y) (Table 3). All of
2a-y gave the expected products at high yields, either bearing
electron-withdrawing groups or electron-donating groups under
the same reaction condition. The heterocyclic/aliphatic aldehydes
were also obtained in good yields. Comparatively with aromatic
aldehydes the aliphatic aldehydes showed significant yields even
though their inertness. It is noteworthy that there are no reports of
the synthesis of 1H-pyrazolo[1,2- b]phthalazine-5,10-diones
from aliphatic aldehydes. Now we are also tested the model
reaction with cinnamaldehyde and α,β-unsaturated butanal. But
we could not found significant amount of the title product from
these unsaturated aldehydes. Various functional groups were
found to be compatible under the reaction conditions. In addition,
malononitrile acts well in comparison with ethyl cyanoacetate in
the mentioned reaction. In general, the reactions were clean and
no side products were detected. In all cases, the reactions
proceeded efficiently at 80 °C under solvent-free and InCl3 (10
mol %) catalytic conditions. The simplicity, together with the use
of inexpensive, non-toxic, and environmentally benign nature of
InCl3 catalyst under solid state reaction condition is another
remarkable feature of the protocol. All of the structures were
heated at different temperatures ranging from 20 to 100 °C
(Table 1 entries 9-14). The yield of product 4b was increased
when the reaction was raised from 20 to 80 °C. However, no
more increments were found for product 4b when the reaction
temperature was raised from 80 to 100 °C. Therefore, 80 °C was
chosen as the reaction temperature for all further reactions.
Table 1. Influence of the solvent and temperature on the 3-
amino-1-(3-fuorophenyl)-5,10-dihydro-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4b)a
Entry
Solvent
Temperature °C
Time
(min)
180
180
180
Yieldb
(%)
42
55
51
1
2
3
4
5
THF
80
80
80
80
80
CH3CN
CHCl3
C6H6
180
180
62
85
Ethanol
6
7
n-Propanol
n-Propanol
80
180
160
86
82
100
8
9
H2O
80
20
40
60
70
600
180
150
90
40
30
40
70
85
Solvent-free
Solvent-free
Solvent-free
Solvent-free
10
11
12
1
characterized by H NMR, 13C NMR and HRMS. 4n and 4y
45
compounds data coincide with reported compounds.

4
Tetrahedron Letters
addition of phthalhydrazide, 1 to the C=C bond of 5 forms
iminomethylene derivative intermediate 6. Finally the titled
compounds (4a-y) were formed by intramolecular concerted
cyclisation by tautomerization of Michael adduct, 6. The role of
InCl3 probably would be Lewis acid for the activation of the
nitrile to transform into amine.
Table 3. InCl3 catalyzed multi-component synthesis of 1H-
pyrazolo [1,2-b] phthalazine-5,10-diones
Entry
Aldehyde R
X
Yielda
(%)
92
94
90
90
91
90
92
Time
(min)
25
25
30
26
28
29
26
mp (°C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
2-F-C6H4
3-F-C6H4
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
268-270
264-266
258-260
261-263
232-234
258-260
270-272
264-266
253-255
251-253
3-NO2-4-F-C6H3
3-F-4-Me-C6H3
2-F-4-OMe-C6H3
4-OEt-C6H4
4-OH-C6H4
4-IsoPropyl-C6H4
3,4-5-OMe-C6H2
6-
93
89
85
24
28
35
4j
nitrobenzo[d][1,3]dio
xole
(C7H5NO4)
4k
C2H5
CN
85
32
238-240
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
C3H7
CH(CH3)2
2-thiophene (C4H3S)
2-F-C6H4
3-F-C6H4
2-Br-4-F-C6H3
3-F-4-Me-C6H3
2-F-4-OMe-C6H3
4-OEt-C6H4
CN
CN
CN
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
88
88
90
90
89
88
87
89
90
89
30
30
31
28
27
30
35
32
28
35
220-222
228-230
244-246
235-237
228-230
238-240
222-224
227-229
210-212
231-233
Scheme 2: Schematic mechanism for the catalytic activity ofInCl3
in the synthesis of titled compounds (4a-y)
3. Conclusion
In conclusion, an efficient, environmentally benign,
atom economical, and simple methodology for the preparation of
1H-pyrazolo[1,2-b]phthalazine-5,10-diones in a three-component
reaction in the presence of InCl3 under solvent-free condition is
reported. The procedure offers several advantages including
cleaner reaction profiles, use of easily available, cheap, high
yields, and simple experimental and work-up procedures. These
InCl3 catalyzed one-pot, multi-component reactions provide a
rapid and efficient route to the preparation of a variety of unusual
heterocycles.
4-IsoPropyl-C6H4
4v
4w
4x
4y
C2H5
C3H7
COOEt
COOEt
COOEt
COOEt
83
85
84
88
35
33
40
35
165-167
150-152
160-162
228-230
CH(CH3)2
2-thiophene (C4H3S)
aIsolated yield
A schematic mechanism for the catalytic activity of
InCl3 in the synthesis of titled compounds (4a-y) should be
postulated as shown in Scheme 2. The reaction is thought to
proceed in a stepwise manner. Firstly, we assumed that the
reaction occurs via
malononitrile, 3 and aldehyde, 2 to form the intermediate 5 on
Supplementary data
All Compounds NMR spectra were provided as Supplementary
data.
a Knoevenagel condensation between
the acidic activity of InCl3, which suffers immediate Michael
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Acknowledgments
This research work was supported by the grant from second of
BK21 Program.
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General procedure for the synthesis of 3-amino-1-(3-
fluorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-
b]phthalazine-2-carbonitrile 4b. A mixture of phthalhydrazide (1, 1
mmol), 3-fluorobenzaldehyde (2b, 1 mmol), malononitrile (3, 1
mmol) and InCl3 (10 mol %) was stirred at 80 °C under solvent-free
condition for 25 min (Table 3, entry 2). The progress of the reaction
was monitored by TLC. After completion of reaction, the reaction
mixture was washed with water and ethanol and residue recrystallized
from ethanol to afford the pure product 4b (94%).