Efficient One-Pot Solvent-Free Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones Catalyzed by Sulfonic Acid Functionalized Nanoporous Silica (SBA-Pr-SO3H)

Article abstract of DOI:10.1002/jccs.201300538

A green protocol has been developed for the 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 using sulfonic acid functionalized SBA

Full text of DOI:10.1002/jccs.201300538

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Efficient One-Pot Solvent-Free Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones
Catalyzed by Sulfonic Acid Functionalized Nanoporous Silica (SBA-Pr-SO3H)
Ghodsi Mohammadi Ziarani,a,* Nina Hosseini Mohtasham,a Alireza Badieib and Negar Lashgarib
aDepartment of Chemistry, Alzahra University, P.O. Box 1993891176, Tehran, Iran
bSchool of Chemistry, College of Science, University of Tehran, P.O Box 14155-6455, Tehran, Iran
(Received: Oct. 22, 2013; Accepted: Mar. 25, 2014; Published Online: ??; DOI: 10.1002/jccs.201300538)
A green protocol has been developed for the 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 using sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) as a heterogeneous solid acid
catalyst under solvent-free conditions.
Keywords: Multicomponent reaction; Phthalhydrazide; Functionalized SBA-15; One-pot synthesis;
Heterogeneous catalysis.
INTRODUCTION
Heterogeneous catalysts have attracted considerable
quinolines have been used as an alternative for aromatic al-
dehydes.12 Four-component synthesis of 1H-pyrazolo[1,2-
b]phthalazine-5,10-dione derivatives was also investi-
gated.18-19
attention in organic synthesis due to their unique catalytic
properties. These catalysts have advantages such as an ease
for removal, recyclability and reusability. In this regard, or-
ganic–inorganic hybrid mesoporous silica materials have
become a promising candidate for heterogeneous catalysts.
Ordered mesoporous silica such as SBA-15 with large pore
size and high surface area, hexagonal arrangement of uni-
form pores, thick walls, and high hydrothermal stability,
has been used in many fields including heterogeneous ca-
talysis,1 separation,2 electrochemistry,3 optics,4 biology
and medical practice.5-6 SBA-15 functionalized with or-
ganic and inorganic moieties exhibits efficient catalytic ac-
tivity in a variety of organic transformations.7-9
In continuation of our research on nanoporous heter-
ogeneous solid catalysts and their applications in organic
synthesis,20-23 herein we wish to report the synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives us-
ing SBA-Pr-SO3H as an efficient nano catalyst.
RESULTS AND DISCUSSION
In this paper, we want to report a simple, mild and ef-
fective method for the one-pot synthesis of 1H-pyrazolo-
[1,2-b]phthalazine-5,10-dione derivatives via a multicom-
ponent reaction of phthalhydrazide, aromatic aldehydes,
and malononitrile or ethyl cyanoacetate in the presence of
SBA-Pr-SO3H (Scheme 1).
Heterocyclic compounds containing phthalazine moi-
ety are important targets in synthetic and medicinal chemis-
try due to their pharmacological and biological activi-
ties.10-11 Pyrazolo[1,2-b]phthalazine-5,10-dione deriva-
tives were reported as antibacterial,12 anti-inflammatory,
analgesic, antipyretic, and antihypoxant compounds.13
Therefore, the development of simple methods for the syn-
thesis of titled compounds is very important.
Synthesis of 1H-pyrazolo[1,2-b]phthalaz-
ine-5,10-diones using SBA-Pr-SO3H as an
efficient nano acid catalyst
Scheme 1
To our knowledge, there are only several literatures
about the multicomponent synthesis of this class of com-
pounds which were synthesized by one-pot three-compo-
nent reactions of phthalhydrazide, malononitrile or ethyl
cyanoacetate, and aromatic aldehydes in the presence of
various catalysts.14-17 In another study, 2-chloro-3-formyl
In order to optimize the reaction condition, initially,
evaluation of various solvent systems was carried out. The
* Corresponding author. Tel: +982188041344; Fax: +982188041344;
Email: gmziarani@hotmail.com; gmohammadi@alzahra.ac.ir
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Article
Mohammadi Ziarani et al.
Table 1. Solvent effect on the synthesis of compound 4a
results revealed when the reaction proceeded under sol-
vent-free conditions, the desired product was obtained in
high yield (Table 1). In the absence of any catalyst under
solvent-free conditions, this reaction afforded compound
4a after 4 h in low yield (50%). Different substituted alde-
hydes were subjected to this reaction to investigate the gen-
erality of this method and corresponding products were
successfully synthesized (Table 2). It was reported that this
reaction almost could not be observed when the aliphatic
aldehyde was used as a starting material.14 The progress of
the reaction was monitored by TLC. Upon completion of
the reaction, the mixture was dissolved in ethanol, filtered
for removing the unsolvable catalyst and then the filtrate
was cooled to afford the pure product as a solid. The cata-
lyst was washed subsequently with diluted acid solution,
distilled water and then acetone, dried under vacuum and
re-used for several times without loss of significant activ-
ity.
Entry
Solvent
Time (h)
Yield (%)[a]
1
2
3
4
EtOH
EtOH:H2O (1:1)
MeCN
4
4
3
70
60
65
90
Neat (80 °C)
20 min
[a] Isolated yield.
Scheme 2 Proposed mechanism
A reasonable mechanism was proposed for this reac-
tion (Scheme 2). Initially, the solid acid catalyst protonates
the carbonyl group of aldehyde 3 which then condenses
with CH-acidic group of malononitrile or ethyl cyanoace-
tate 2 through a fast Knoevenagel condensation to afford
benzylidenemalononitrile 8. Michael-type addition of
phthalhydrazide 1 to the C=C bond of this compound fol-
lowed by cyclization and tautomerism produces the desired
products 4a-i in high yields.
existing methods.
The SBA-15 as a new nanoporous silica can be pre-
pared by using commercially available triblock copolymer
Pluronic P126 as a structure directing agent.24 Integration
of acidic functional groups (e.g., -SO3H) into ordered
mesoporous SBA-15 has been explored to produce promis-
ing solid acids. The sulfonic acid functionalized SBA-15
was usually synthesized through direct synthesis or post-
grafting.1,25 The surface of the catalyst was analyzed by dif-
Literature surveys revealed that various conditions
have been employed in this reaction as demonstrated in Ta-
ble 3. The results illustrated that the present methodology,
using SBA-Pr-SO3H as the catalyst offers several advan-
tages such as simple procedure, short reaction times, sim-
ple work-up and greener conditions in contrast with other
Table 2. The SBA-Pr-SO3H catalyzed the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 4a-i under
solvent-free condition
Entry
Ar
X
Product
Time (min) Yield (%)[a]
M.p (°C)
M.p (Lit.)
1
2
3
4
5
6
7
8
9
C6H5
4-ClC6H4
CN
CN
CN
CN
CN
4a
4b
4c
4d
4e
4f
20
15
15
20
20
15
30
25
30
90
75
88
90
78
70
75
80
70
272-274
266-268
282-284
242-244
270 (dec.)
264-266
201-203
239-241
236-238
276-278 14
270-272 14
New
2,3-(Cl)2C6H3
2,4-(Cl)2C6H3
4-OMeC6H4
3-OMeC6H4
4-Me-C6H4
4-NO2C6H4
3-NO2C6H4
New
-
New
CN
CO2Et
CO2Et
CO2Et
4g
4h
4i
204-206 14
241-243 14
239-240 14
[a] Isolated yield.
2
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Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones
Table 3. Comparison of different conditions in the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones
Entry
Catalyst
Solvent
Condition Temp. (°C) Time (h)
Yield (%)
Ref.
1
2
3
4
5
p-TSA[a]
Et3N
[bmim]OH
Al-KIT-6[c]
SBA-Pr-SO3H
[bmim]Br[b]
Reflux
Sonication
MW
Reflux
Heating
100
50
45
60
80
3
1
94
92
94
93
90
2008 14
2010 15
EtOH
-
EtOH
-
4 min
4
20 min
2011 16
2012 17
This work
[a] p-Toluenesulfonic acid
[b] Ionic liquid 1-butyl-3-methylimidazolium bromide
[c] Cubic mesoporous aluminosilicate
1
ferent methods such as TGA, BET and other methods
which were demonstrated that the organic groups (propyl
sulfonic acid) were immobilized into the pores.26
mal 9200 apparatus. The H NMR (250 or 300 MHz) and 13C
NMR (300 or 75 MHz) were run on a Bruker DPX, using TMS as
an internal standard (CDCl3 or DMSO-d6 solution). GC-Mass
analysis was performed on a GC-Mass model: 5973 network mass
selective detector, GC 6890 Agilent. SEM analysis was per-
formed on a Philips XL-30 field-emission scanning electron mi-
croscope operated at 16 kV while TEM was carried out on a
Tecnai G2 F30 at 300 kV.
Figure 1 illustrates the SEM and TEM images of
SBA-Pr-SO3H. SEM image (Figure 1, a) shows uniform
particles about 1 µm. The same morphology was observed
for SBA-15. It can be concluded that morphology of solid
was saved without change during the surface modifica-
tions. On the other hand, the TEM image (Figure 1, b) re-
veals the parallel channels, which resemble the pores con-
figuration of SBA-15. This indicates that the pore of SBA-
Pr-SO3H was not collapsed during two-steps reactions.
In conclusion, a facile multi-component approach for
the synthesis of a series of 1H-pyrazolo[1,2-b]phthal-
azine-5,10-diones under solvent-free conditions utilizing
SBA-Pr-SO3H as an efficient nano catalyst has been de-
scribed. The process is simple, mild and efficient, gener-
ates a diverse range of the titled compounds in good yields.
Synthesis and functionalization of SBA-15: The nano-
porous compound SBA-15 was synthesized and functionalized
according to our previous report26 and the modified SBA-15-Pr-
SO3H was used as nanoporous solid acid catalyst in the following
reaction.
General procedure for the preparation of 1H-pyrazolo-
[1,2-b]phthalazine-5,10-diones: SBA-Pr-SO3H was activated in
vacuum at 100 °C, then, after cooling to room temperature,
phthalhydrazide (1 mmol), aromatic aldehydes (1 mmol), and
malononitrile or ethyl cyanoacetate (1 mmol) were added to it.
The mixture was heated in 80 °C for appropriate time as shown in
Table 2. After completion of the reaction, as monitored by TLC,
the crude product was dissolved in hot ethanol and then filtered to
remove the solid catalyst. Filtrate was cooled to give the pure
product. The solid acid catalyst was subsequently washed with di-
lute acid solution, distilled water, and acetone, and dried under
vacuum. It can be used for several times without significant loss
of activity. Spectroscopic data for selected examples are shown
below.
EXPERIMENTAL
All chemicals were obtained commercially and used with-
out further purification. IR spectra were recorded from KBr disks
using a FT-IR Bruker Tensor 27 instrument. Melting points were
measured by using the capillary tube method with an electro ther-
3-Amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyra-
zolo[1,2-b]phthalazine-2-carbonitrile 4a: M.p = 272-274 °C;
1
IR (KBr): 3359, 3190, 2197, 1690, 1658 cm-1; H NMR (300
MHz, DMSO-d6): d 6.13 (s, 1H), 7.29-7.47 (m, 5H), 7.93-8.26
(m, 4H), 8.09 (s, 2H); 13C NMR (75 MHz, DMSO-d6): d 62.4,
63.6, 116.1, 127.2, 127.3, 127.7, 128.7, 128.9, 129.2, 134.1,
135.1, 138.7, 151.2, 154.2, 157.1; MS: m/z: 316 (M+). 3-Amino-
1-(4-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo-
Fig. 1. SEM image (a) and TEM image (b) of SBA-Pr-
SO3H.
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Article
Mohammadi Ziarani et al.
[1,2-b]phthalazine-2-carbonitrile 4b: M.p = 266-268 °C; IR
(KBr): 3375, 3264, 2200, 1662, 1655 cm-1; 1H NMR (300 MHz,
DMSO-d6): d 6.15 (s, 1H), 7.41-7.53 (m, 4H), 7.93-8.26 (m, 4H),
8.13 (s, 2H); 13C NMR (75 MHz, DMSO-d6): d 61.3, 62.7, 116.4,
127.1, 127.7, 128.9, 129.3, 133.3, 134.2, 135.1, 137.9, 151.2,
154.1, 157.1; MS: m/z: 350 (M+). 3-Amino-1-(2,3-dichloro-
phenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthal-
azine-2-carbonitrile 4c: M.p = 282-284 °C; IR (KBr): 3162,
DMSO-d6): d 1.03 (t, J = 6.8 Hz, 3H), 3.95 (q, J = 6.7 Hz, 2H),
6.18 (s, 1H), 7.73-8.29 (m, 10H); 13C NMR (75 MHz, DMSO-d6):
d 14.6, 59.2, 63.0, 81.1, 123.5, 125.5, 127.1, 127.7, 129.0, 129.2,
133.0, 134.2, 135.1, 147.3, 147.7, 153.8, 157.3, 164.2; MS: m/z:
408 (M+). Ethyl 3-amino-1-(3-nitrophenyl)-5,10-dihydro-
5,10- dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carboxylate 4i:
M.p = 236-238 °C; IR (KBr): 3360, 3249, 1693, 1651, 1613 cm-1;
1H NMR (300 MHz, DMSO-d6): d 0.99 (t, J = 9.2 Hz, 3H), 3.94
(q, J = 7.8 Hz, 2H), 6.22 (s, 1H), 7.56-8.30 (m, 10H); 13C NMR
(75 MHz, DMSO-d6): d14.5, 59.1, 63.1, 81.1, 122.5, 123.1,
127.1, 127.6, 129.0, 129.4, 129.9, 134.1, 134.5, 135.0, 142.6,
147.9, 150.5, 153.9, 157.3, 164.3; MS: m/z: 408 (M+).
1
3017, 2895, 2581, 2226, 1660, 1580, 1492, 822 cm-1; H NMR
(250 MHz, CDCl3): d 6.52 (s, 1H), 6.75 (s, 2H), 7.30-7.61 (m,
3H), 8.16-8.28 (m, 4H); 13C NMR (300 MHz, DMSO-d6): d 59.2,
60.9, 115.5, 125.1, 126.7, 127.3, 128.2, 128.8, 129.3, 130.3,
132.0, 132.5, 133.9, 134.7, 138.0, 151.2, 153.6, 156.6; MS: m/z:
384 (M+). 3-Amino-1-(2,4-dichlorophenyl)-5,10-dihydro-5,10-
dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile 4d: M.p
= 242-244 °C; IR (KBr): 3370, 3232, 3172, 2896, 2209, 1660,
1562, 1493, 824 cm-1; 1H NMR (250 MHz, CDCl3): d 6.53 (s, 1H),
6.74 (s, 2H), 7.29-7.61 (m, 3H), 8.16-8.28 (m, 4H); 13C NMR
(300 MHz, DMSO-d6): d 56.0, 59.2, 115.5, 126.7, 127.3, 128.0,
128.2, 128.8, 129.1, 130.4, 132.3, 133.6, 133.9, 134.4, 134.7,
151.1, 153.5, 156.6; MS: m/z: 384 (M+). 3-Amino-1-(4-methoxy-
phenyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthal-
azine-2-carbonitrile 4e: M.p = 270 °C (dec.); IR (KBr): 3016,
2895, 2220, 1660, 1555, 825 cm-1; 1H NMR (250 MHz, CDCl3): d
3.94 (s, 3H), 6.23 (s, 1H), 7.03-7.29 (m, 4H), 7.68-7.95 (m, 5H);
13C NMR (300 MHz, DMSO-d6): d 55.8, 61.8, 76.8, 113.8, 114.8,
115.1, 124.0, 125.1, 125.4, 127.1, 132.5, 133.3, 154.6, 160.3,
164.3; MS: m/z: 346 (M+). 3-Amino-1-(3-methoxyphenyl)-
5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-
carbonitrile 4f: M.p = 264-266 °C; IR (KBr): 3011, 2897, 2227,
1661, 1598, 1571, 1493, 952 cm-1; 1H NMR (250 MHz, CDCl3): d
3.84 (s, 3H), 6.10 (s, 1H), 6.22-7.06 (m, 4H), 7.29-7.55 (m, 4H),
8.30 (s, 2H); 13C NMR (300 MHz, DMSO-d6): d 56.2, 58.8, 59.0,
111.5, 121.4, 121.6, 122.0, 122.2, 123.8, 124.3, 124.6, 127.2,
132.6, 154.6, 158.2, 160.9; MS: m/z: 346 (M+). Ethyl 3-amino-
1-(p-tolyl)-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]phth-
alazine-2-carboxylate 4g: M.p = 201-203 °C; IR (KBr): 3447,
3333, 1706, 1658, 1624 cm-1; 1H NMR (300 MHz, DMSO-d6): d
1.04 (t, J = 8.9 Hz, 3H), 2.25 (s, 3H), 3.96 (q, J = 9.0 Hz, 2H), 6.04
ACKNOWLEDGEMENTS
We gratefully acknowledge for the financial support
from the Research Council of Alzahra University and the
University of Tehran.
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