Theophylline as a Green Catalyst for the Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones

Full text of DOI:10.1080/00304948.2019.1697611

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Theophylline as a Green Catalyst for the Synthesis
of 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones
Farzaneh Mohamadpour
To cite this article: Farzaneh Mohamadpour (2020): Theophylline as a Green Catalyst for the
Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones, Organic Preparations and Procedures
International, DOI: 10.1080/00304948.2019.1697611
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2019.1697611
OPPI BRIEF
Theophylline as a Green Catalyst for the Synthesis of
1H-Pyrazolo[1,2-b]phthalazine-5,10-diones
Farzaneh Mohamadpour
Young Researchers and Elite Club, Shiraz Branch, Islamic Azad University, Shiraz, Iran
ARTICLE HISTORY Received 8 August 2018; Accepted 31 August 2019
1H-Pyrazolo[1,2-b]phthalazine-5,10-diones are a significant class of heterocyclic com-
pounds and represent an interesting template in medicinal chemistry. Many of these
compounds are known for their biological and pharmacological activities. These include
1
2
3
4
5
anticancer, anti-inflammatory, vasorelaxant, cardiotonic, anticonvulsant and anti-
6
fungal properties.
For the preparation of these important materials, a number of methods have been
7
developed and include the use of such catalysts as Ce(SO ) ꢀ4H O, sulfonic acid func-
4
2
2
8
9
10
11
12
18
tionalized nanoporous silica, InCl , NiCl ꢀ6H O,
[Bmim] OH,
ultrasound,
3
2
2
1
3
14
15
16
17
PTSA, STA, CuI nanoparticles, PTSA/[Bmim]Br, TBBAD, Ni Zn . Fe O ,
0.5
0 5
2 4
1
9
20
K CO
2
and Zn(OAC) ꢀ2H O. Although each of these methods has its own value,
3
2
2
many also have disadvantages, such as cost or the use of environmentally unfriendly
reagents and solvents or lack of convenience. Therefore, it seemed desirable to seek a
convenient and eco-friendly protocol.
There are several advantages of using theophylline (Figure 1) as a green and
2
1–23
bio-based catalyst.
It is inexpensive, readily available, non-toxic and biodegradable.
We now report the theophylline-catalyzed preparation of the title compounds in a one-pot
four-component reaction of phthalimide, hydrazine monohydrate, aromatic aldehydes and
malononitrile. The reaction occurs under solvent-free conditions in high yields.
As a model reaction, we studied the one-pot reaction of phthalimide (1.0 mmol),
hydrazine monohydrate (1.0 mmol), benzaldehyde (1.0 mmol) and malononitrile
(1.0 mmol). We used varying amounts of theophylline as a catalyst and the results are
presented in Table 1. The best result (Entry 4, Table 1) was achieved by carrying out
ꢁ
the reaction with 15 mol% of catalyst at 70 C for 2.5 hours. The success of the reaction
appeared to be a balance among catalyst loading, reaction temperature and time. For
example, in the absence of catalyst no product was formed even at higher temperature
and prolonged reaction time (Entry 1). A high loading of catalyst and prolonged reac-
tion time were not enough to compensate for working at a lower temperature (Entry 5).
Use of a higher amount of catalyst did not improve the yield while a decrease in the
amount of catalyst decreased the yield. The effect of temperatures was studied under
CONTACT Farzaneh Mohamadpour
mohamadpour.f.7@gmail.com
Young Researchers and Elite Club, Shiraz
Branch, Islamic Azad University, Shiraz, Iran
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/uopp.
ß 2020 Taylor & Francis Group, LLC

2
F. MOHAMADPOUR
O
N
H
N
N
N
O
Figure 1. Structure of theophylline.
Table 1. Optimization of the reaction conditions.
a
O
O
NH2
O
O
H
N
N
NH2
NH2
CN
NH
+
+
+
NC
CN
O
Entry
Theophylline (mol %)
Temperature (0C)
Time (h)
Isolated Yields (%)
1
2
3
4
5
6
7
8
9
Catalyst free
70
70
70
70
rt
40
50
60
80
70
8
6.5
4
2.5
8
7
5
3.5
2.5
2.5
No product
5
47
65
88
10
15
15
15
15
15
15
20
No product
39
55
70
88
89
1
0
a
Reaction times determined by tlc (see experimental section).
ꢁ
solvent-free conditions (rt, 40, 50, 60, 70 and 80 C) and the best results were obtained
ꢁ
at 70 C (Entry 4, Table 1).
To study the generality of this process, it was carried out using a good range of alde-
hydes. The related 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives were obtained
without observation of any by-products in high to excellent yields (Table 2).
A comparison of catalysts reported in the literature for the synthesis of the title com-
pounds is shown in Table 3. As can be seen, theophylline catalysis offers yields compar-
able to other methods, but has the advantage of being green, readily available, and
inexpensive. Our study suggests that theophylline has shown significant potential to be
an alternative green catalyst for the synthesis of these valuable heterocyclic compounds.
Its use permits solvent-free conditions with very good yields. We hope that our results
will lead to increased research into this worthwhile catalyst.
Experimental section
Melting points of all compounds were determined using an Electro thermal 9100 appar-
1
atus and are uncorrected. H NMR spectra were recorded on a Bruker DRX-400
Avance instrument with DMSO-d as solvents. All reagents and solvents were purchased
6
from Merck, Fluka and Acros chemical companies and were used without further
purification.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Table 2. Theophylline catalyzed synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
under solvent-free conditions.
O
H
O
NH2
O
N
N
Theophylline (15 mol%)
Solvent free, 70 °C
NH2
NH2
CN
NC
CN
NH
+
+
+
X
O
O
1
2
3
4
5a-w
X
ꢁ
ꢁ
References
Entry
Ar
4-F-C
3-Cl-C
2-O N-C
3-Br-C
2,4-Cl -C
3-OMe-C
4-OH-C
3,4,5-(OMe)
2-F-C
4-OMe-C
4-Br-C
2-Cl-C
Product
Time (h)
Isolated Yields (%)
m.p. C
Lit. m.p. C
1
1
1
1
1
2
1
2
2
2
2
1
0
5
1
2
3
4
5
6
7
8
9
6
H
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
2
3.5
2
3.5
4
3
4
3.5
2
3
4
3
2
4
2.5
2
2.5
3.5
3
3
2
91
80
88
78
75
86
79
82
93
88
76
83
90
78
88
92
87
82
90
85
84
89
90
264-266
265-267
263-265
272-274
255-257
249-251
272-274
251-253
267-268
265-267
263-265
259-261
263-265
271-273
268-270
249-251
255-257
269-271
242-244
272-274
257-259
155-157
249-251
263-265
266-267
265-266
270-272
257-258
248-251
270-272
6
H
4
2
6
H
4
6
H
4
2
6 3
H
6
H
4
6
H
4
9
3
-C
6
H
2
253-255
268-270
9
6 4
H
6
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
H
4
4
264-266
265-267
261-262
263-265
270-272
265-268
248-250
253-255
270-272
244-246
272-274
258-260
153-155
250-252
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
4
5
9
5
5
8
5
1
8
8
5
6
H
6
H
4
3-F-C
6
H
4
4-Cl-C
6
H
4
C
6
H
5
2-Me-C
4-Me-C
3-OH-C
6 4
H
6
H
H
4
6
4
C
4
H
N-C
N-C
3
S
6
5s
5t
5u
5v
5w
4-O
3-O
2
H
H
6
H
4
2
6
4
2-OMe-C
3-Me-C
H
4
2
2.5
6
4
Table 3. Comparison of catalytic ability some of catalysts reported in the literature for synthesis of
a
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives.
References
9
Entry
Catalyst
InCl
NiCl
p-TSA
STA
Conditions
Time/Yield (%)
1.5h/85
1
2
3
4
5
6
7
a
3
ꢀ6H
Water, Reflux
EtOH, Reflux
[Bmim]Br, 100 C
Solvent-free, 70 C
MeCN, Reflux
Solvent-free, 80-100 C
Solvent-free, 70 C
1
0
2
2
O
3h/87
3h/94
ꢁ
13
ꢁ
14
20 min/94
27 min/91
15 min/89
1
5
CuI nanoparticles
TBBAD
Theophylline
ꢁ
17
ꢁ
This work
2.5h/88
Based on the four-component reaction of benzaldehyde, phthalimide, hydrazine monohydrate and malononitrile.
General procedure for preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives (5a-w)
A mixture of phthalimide (1, 1.0 mmol), hydrazine monohydrate (Caution! Hydrazine
hydrate is corrosive. All workers should be thoroughly trained in its use prior to undertaking
experiments, to include eye protection, gloves and ventilation) (2, 1.0 mmol) and theophyl-
ꢁ
line (15 mol%) was heated for 2h at 70 C. Then an aromatic aldehyde (3, 1.0 mmol) and
malononitrile (4, 1.0 mmol) were added and the mixture was heated for the time specified
to complete the reaction as determined by TLC (n-hexane:ethyl acetate (8:3)). After

4
F. MOHAMADPOUR
completion of the reaction the mixture was cooled to ambient temperature, the solid prod-
ucts were filtered and were recrystallized from ethanol to give pure compounds (5a-w). All
of the compounds are known, and their melting points matched those in the literature
1
references cited in Table 2. For the sake of completeness, some representative H-NMR
data are given below along with the appropriate references.
3
-Amino-1-(3,4,5-trimethoxyphenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]
9
phthalazine-2-carbonitrile (5h)
1
H NMR (400 MHz, DMSO-d ): 3.66 (3H, s, OCH ), 3.76 (6H, s, 2 ꢂ OCH ), 6.07 (1H,
6
3
3
s, H
), 6.78 (2H, s, H ), 7.89- 8.29 (6H, m, NH and H ).
Ar 2 Ar
benzylic
3
-Amino-1-(2-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-
11
2-carbonitrile (5l)
1
H NMR (400 MHz, DMSO-d ): 6.47 (1H, s, Hbenzylic), 7.39-7.65 (4H, m, H ), 7.91-
6
Ar
8
.31 (6H, m, NH and H ).
2 Ar
3
-Amino-1-(4-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-
15
2-carbonitrile (5n)
1
H NMR (400 MHz, DMSO-d ): 6.15 (1H, s, Hbenzylic), 7.43 (2H, d, J ¼ 11.2 Hz, H ),
6
Ar
7
.54 (2H, d, J ¼ 11.2 Hz, H ), 7.88-8.28 (6H, m, NH and H ).
Ar
2
Ar
3
-Amino-1-(phenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-
1
9
carbonitrile (5o)
1
H NMR (400 MHz, DMSO-d ): 6.14 (1H, s, Hbenzylic), 7.33-7.48 (5H, m, H ), 7.97-
6
Ar
8
.29 (6H, m, NH and H ).
2 Ar
3
-Amino-1-(4-methylphenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-
15
2-carbonitrile (5q)
1
H NMR (400 MHz, DMSO-d ): 2.30 (3H, s, CH ), 6.10 (1H, s, Hbenzylic), 7.18 (2H, d,
6
3
J ¼ 8.0 Hz, H ), 7.34 (2H, d, J ¼ 8.0 Hz, H ), 7.97-8.28 (6H, m, NH and H ).
Ar
Ar
2
Ar
3
-Amino-1-(3-methylphenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-
15
2-carbonitrile (5w)
1
H NMR (400 MHz, DMSO-d ): 2.30 (3H, s, CH ), 6.08 (1H, s, Hbenzylic), 7.14-7.26 (4H,
6
3
m, H ), 7.97-8.29 (6H, m, NH and H ).
Ar
2
Ar
Acknowledgment
I gratefully acknowledge financial support from the Young Researchers and Elite Club, Islamic
Azad University, Shiraz Branch, Shiraz, Iran.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
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