One-pot and solvent-free synthesis of aliphatic and aromatic 1H-indazolo[2,1-b]phthalazinetriones catalyzed by boron sulfonic acid

Article abstract of DOI:10.1007/s00706-014-1194-9

An efficient and simple method for the synthesis of aliphatic and aromatic 1H-indazolo[2,1-b]phthalazinetrione derivatives through a one-pot three-component condensation of phthalhydrazide, aldehyde, and dimedone in the presence of boron sulfonic acid as

Full text of DOI:10.1007/s00706-014-1194-9

Monatsh Chem
DOI 10.1007/s00706-014-1194-9
ORIGINAL PAPER
One-pot and solvent-free synthesis of aliphatic and aromatic
1H-indazolo[2,1-b]phthalazinetriones catalyzed by boron sulfonic
acid
•
Mehdi Soheilizad Mehdi Adib Sami Sajjadifar
•
Received: 11 January 2014 / Accepted: 24 February 2014
Ó Springer-Verlag Wien 2014
Abstract An efficient and simple method for the syn-
thesis of aliphatic and aromatic 1H-indazolo[2,1-
b]phthalazinetrione derivatives through a one-pot three-
component condensation of phthalhydrazide, aldehyde, and
dimedone in the presence of boron sulfonic acid as a
reusable and efficient catalyst under solvent-free conditions
is described. The reusability of catalyst, good to excellent
yields, short reaction times, and the avoidance of harsh
reagents are the main advantages of this method.
In recent years, synthesis of nitrogen-containing het-
erocyclic compounds has received growing attention
because of their applications to biologically active phar-
maceuticals, agrochemicals, and functional materials [8–
11]. Among a large variety of heterocyclic compounds,
bridgehead nitrogen heterocycles containing a phthalazine
moiety are of interest because they exhibit pharmacological
and biological activities [12–14]. The phthalazine unit is an
important structural motif found in biologically active
organic compounds. Phthalazine derivatives, which have
two bridgehead nitrogen atoms in a fused ring system, were
reported to possess a multiplicity of pharmacological
properties including vasorelaxant cytotoxic [15], cardio-
tonic [16], antimicrobial [17], anticonvulsant [18], anti-
inflammatory [19], antifungal [20], and anticancer [21]
activities. Therefore, a number of methods have been
reported for the synthesis of phthalazine derivatives using
p-TSA [22], silica sulfuric acid [23], H2SO4 [24], silica-
supported polyphosphoric acid [25], Mg(HSO4)2 [26],
heteropoly acids [27], N-halosulfonamides [28], sulfonated
poly(ethylene glycol) [29], cyanuric chloride [30], nano-
silica sulfuric acid [31], and phosphosulfonic acid [32] as
catalysts.
Keywords Boron sulfonic acid Á
1H-Indazolo[2,1-b]phthalazinetrione Á
Multicomponent reactions Á Solvent-free
Introduction
Multicomponent reactions (MCRs) have become important
tools in synthetic chemistry because of efficient access to
complex molecules from readily available starting materi-
als, construction of interesting biologically active organic
compounds, and rapid generation of drug-like molecule
libraries [1–7].
Recently, more attention has been paid to the application
of inorganic acidic salts in organic synthesis [33, 34].
Simplicity in handling, decreased reactor and plant corro-
sion problems, more environmentally safe disposal in
different chemical processes, and minimized or avoided
wastes and by-products for the developing cleaner syn-
thesis routes are some of the main advantages of the
application of solid acids in organic synthesis. Boron sul-
fonic acid (BSA) is a novel solid acid catalyst that was
introduced by Kiasat and Fallah-Mehrjardi [35]
(Scheme 1) for the regioselective conversion of epoxides
to thiocyanohydrins under solvent-free reaction conditions.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-014-1194-9) contains supplementary
material, which is available to authorized users.
M. Soheilizad (&) Á M. Adib
School of Chemistry, College of Science, University of Tehran,
P.O. Box 14155-6455, Tehran, Iran
e-mail: m.soheilizad@yahoo.com
S. Sajjadifar
Department of Chemistry, Payame Noor University,
P.O. Box 19395-4697, Tehran, Iran
123

M. Soheilizad et al.
BSA as a trifunctional inorganocatalyst is a strong acid that
efficiently catalyzes many reactions.
for preparation of compound 4l is the use of 5 mol% of BSA
at 100 °C (Table 1, entry 3). The results are summarized in
Table 1.
Based on the optimized reaction conditions, the reactions
of phthalhydrazide, dimedone, and various aromatic and
aliphatic aldehydes were investigated. As shown in Table 2,
aromatic aldehydes carrying either electron-withdrawing or
electron-donating substituents afforded excellent yields of
products with high purity at 100 °C under solvent-free
conditions (Table 2, entries 4a–4g). Also, aliphatic alde-
hydes afforded the desired product with lower yields than
aromatic aldehydes (Table 2, entries 4h–4l).
Results and discussion
As part of our continuing studies in the use of BSA as a
solid acid in organic synthesis [36–41], herein we report
one-pot, three-component condensation of phthalhydrazide
1, aldehydes 2a–2l, and dimedone 3 for the synthesis of
aliphatic and aromatic 1H-indazolo[2,1-b]phthalazinetri-
ones 4a–4l using BSA as a valuable catalyst under solvent-
free conditions in good to excellent yields and short reac-
tion times (Scheme 2).
A suggested mechanism for the formation of the 1H-in-
dazolo[2,1-b]phthalazinetriones is shown in Scheme 3. BSA
as an acid catalyst in situ generates H?; thus, it is reasonable
to assume that aldehyde 2 and dimedone 3 through a Knoe-
venagel condensation are converted to intermediate 5. Then,
the subsequent Michael-type addition of phthalhydrazide 1
to this intermediate followed by cyclization affords 1H-in-
dazolo[2,1-b]phthalazine-triones 4.
In order to optimize the reaction conditions, phthalhyd-
razide (1.0 mmol), benzaldehyde (1.2 mmol) as an aromatic
aldehyde, and dimedone (1.0 mmol) were used as model
substrates (Table 2, entry 4a). To evaluate the catalyst
effect, first, the reaction was examined in the absence and
presence of BSA under solvent-free conditions. In the
absence of BSA, no product was formed after 60 min at
100 °C (Table 1, entry 1), but in the presence of BSA, the
reaction took place with the best result. Next, to optimize the
amount of BSA, the reaction was carried out using various
amounts of the catalyst. As shown in Table 1, the best yield
(94 %) was obtained with 5 mol% (0.05 g, 0.15 mmol H?)
of the BSA at 100 °C (Table 1, entry 3). The use of more
than 5 mol% BSA did not enhance chemical yield (Table 1,
entry 4). Finally, to evaluate the temperature effect, the
model reaction was examined at 80 and 120 °C (Table 1,
entries 5 and 6). It was observed that the reaction at 100 and
120 °C proceeded in the highest yield; thus, 100 °C was
chosen as the reaction temperature (Table 1, entry 7). Also,
a similar optimization was performed using phthalhydrazide
(1.0 mmol), 3-phenylpropanal (1.2 mmol) as an aliphatic
aldehyde and dimedone (1.0 mmol) as a model substrate
(Table 2, entry 4l). As shown in Table 1, the best condition
The reusability of BSA as catalyst was investigated for
the synthesis of compounds 4a and 4l as two aromatic and
aliphatic models, respectively. After each run, ethanol was
added, and the catalyst was filtered. The recycled BSA was
dried and reused for further runs. A mild depression in the
Table 1 Optimization of the reaction conditions for the synthesis of
4a and 4l under solvent-free conditions
Entry
BSA/mol%
Temp./°C
Time/min
Yield/%a
4a
4l
1
2
3
4
5
6
7
8
a
0
100
100
100
100
120
80
60
15
15
15
15
15
10
5
0
74
94
92
94
82
94
90
0
2.5
5
52
78
78
77
64
72
70
10
5
5
5
100
100
5
Scheme 1
Yield of isolated product
Scheme 2
123

One-pot and solvent-free synthesis
catalytic activity of the catalyst was observed after four
runs (Fig. 1). This shows that the BSA is an effective and
recyclable catalyst for the synthesis of 1H-indazolo[2,1-
b]phthalazinetriones.
condensation of phthalhydrazide, aldehyde, and dimedone
under solvent-free conditions. The simplicity of the starting
materials, good to excellent yields, short reaction times,
easy workup, reusability of the catalyst, and use of solvent-
free conditions are main advantages of this method.
Conclusion
Experimental
BSA is an extremely efficient acidic catalyst for the
preparation of aliphatic and aromatic 1H-indazolo[2,1-b]
phthalazinetriones using one-pot, three-component
All chemicals were purchased from Merck and Fluka
companies. All yields refer to isolated products. IR spectra
of the compounds were obtained on a Perkin-Elmer GX
FT-IR spectrometer. 1H and 13C NMR spectra were
recorded on a Bruker Avance 300 MHz NMR spectrometer
using tetramethylsilane (TMS) as internal standard. Melt-
ing points were determined in a capillary tube. The
progress of reaction was followed with TLC using silica
gel SILG/UV 254 and 365 plates. All products are known
compounds and were characterized by comparing the IR,
1H, and 13C NMR spectroscopic data and their melting
points with the literature values.
Table 2 Synthesis of 1H-indazolo[2,1-b]phthalazinetrione deriva-
tives using BSA as a catalyst (Scheme 2)
Entry
R
Time/ Yield/ M.p./°C
a
min
%
Found
Reported
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5-
10
10
94
90
86
96
92
91
89
65
71
65
68
78
201–203 204–206 [22]
223–225 227–228 [32]
216–218 218–220 [32]
224–225 223–225 [22]
260–261 262–264 [22]
218–220 219–221 [28]
252–254 251–253 [28]
145–147 145–147 [28]
133–135 136–138 [28]
135–137 138–140 [28]
133–135 132–134 [28]
170–172 171–173 [28]
4-CH3-C6H4-
4-CH3O-C6H4- 12
4-NO2-C6H4-
4-Cl-C6H4-
2,4-Cl2-C6H3-
2-Naphthyl
CH3CH2-
8
8
General procedure for the preparation
10
10
15
18
20
20
15
of 1H-indazolo[2,1-b]phthalazinetriones 4a–4l
A mixture of 0.16 g phthalhydrazide (1.0 mmol), aldehyde
(1.2 mmol), 0.14 g dimedone (1.0 mmol), and 0.05 g BSA
(5 mol%) was heated at 100 °C for the time indicated in
Table 2. After completion of the reaction as indicated
by TLC, the reaction mixture was cooled, quenched by
CH3(CH2)2-
CH3(CH2)4-
(CH3)2CH-
C6H5(CH2)2-
4j
4k
4l
a
Isolated yields
Scheme 3
Scheme 3 .
123

M. Soheilizad et al.
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Fig. 1 The reusability of the BSA for the synthesis of 4a and 4l in
four cycles
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