Application of citric acid as highly efficient and green organocatalyst for multi-component synthesis of indazolo[2,1-b]phthalazine-triones

Article abstract of DOI:10.1007/s13738-012-0193-1

The condensation of aryl aldehydes with dimedone and phthalhydrazide efficiently catalyzed using citric acid as highly efficient and green organocatalyst in excellent yields and short times.

Full text of DOI:10.1007/s13738-012-0193-1

J IRAN CHEM SOC (2013) 10:577–581
DOI 10.1007/s13738-012-0193-1
ORIGINAL PAPER
Application of citric acid as highly efficient and green
organocatalyst for multi-component synthesis
of indazolo[2,1-b]phthalazine-triones
•
Mohammad Ali Zolfigol Mohammad Mokhlesi
•
Shohreh Farahmand
Received: 17 July 2012 / Accepted: 22 November 2012 / Published online: 20 December 2012
Ó Iranian Chemical Society 2012
Abstract The condensation of aryl aldehydes with
dimedone and phthalhydrazide efficiently catalyzed using
citric acid as highly efficient and green organocatalyst in
excellent yields and short times.
carbohydrate synthesis [18], has benefited from the devel-
opments in this area [19–21].
Both five- and six-membered nitrogenous heterocyclic
structural skeletons are prevalent in biologically active
natural products and some of those constitute key inter-
mediates with widespread application in organic synthesis.
Moreover, a large number of artificial molecules based on
these structures hold great potential in pharmaceutical and
medicinal research. Amongst a large variety of heterocy-
clic compounds, heterocycles containing a phthalhydrazide
moiety are very interesting compounds. It was found that
they possess cytotoxic, antimicrobial, anticonvulsant,
antifungal, anticancer, and anti-inflammatory activities.
Phthalazine-containing compounds are also highly potent
inhibitors of vascular endothelial growth factor receptor II
(VEGFR-2). Moreover, these compounds exhibited good
promise as new luminescence materials or fluorescence
probes [22–26]. Various catalysts have been reported for
the synthesis of indazolo[2,1-b]phthalazine-triones. For
instead, Ce(SO4)2ꢀ4H2O [27], p-TSA [28], H2SO4 [29],
Dodecylphosphonic acid (DPA) [30], silica supported poly
phosphoric [31], wet cyanuric chloride [32], CAN [33],
Phosphomolybdic acid (PMA)–SiO2 [34]. However, most
of the reported methods for the synthesis of them are
associated with one or more drawbacks such as the use of
large amount of catalyst [29], toxic or expensive catalysts
[28, 33, 34], toxic solvent and long reaction time [27], and
harsh reaction conditions [28, 31, 32].
Keywords Citric acid ꢀ Organocatalyst ꢀ Multicomponent
reaction ꢀ Indazolo[2,1-b]phthalazine-triones
Introduction
The quest for multicomponent reactions (MCRs) with
organic molecules as catalysts is a continuing challenge at the
forefront of synthetic chemistry. Organocatalytic reactions
are currently very much en vogue, as the term implies a
connotation of environmentally benign. Therefore, in the few
years research in academia and industry has increasingly
emphasized the use of organocatalytic reactions for a broad
range of products [1–4]. A diverse set of organocatalytic
reactions, including C–C, C–N, and C–O bond formation
such as Hantzsch reaction [5], Diels–Alder [6, 7], Baylis–
Hillman [8–10], Mannich [8, 11, 12], Michael [8, 13, 14],
Friedel–Crafts alkylation [15], oxidation [16, 17], and
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-012-0193-1) contains supplementary
material, which is available to authorized users.
M. A. Zolfigol (&) ꢀ S. Farahmand
Faculty of Chemistry, Bu-Ali Sina University,
Hamedan 6517838683, Iran
Citric acid is an organic acid of huge industrial impor-
tance. This acid is a nearly universal intermediate product of
metabolism and its traces are found in virtually all plants and
animals. It was known as harmless to the environment and
commercially available with stability toward humidity [35].
Despite its great importance, only a few papers are reported
on its catalytic application in organic synthesis [36, 37].
e-mail: mzolfigol1345@gmail.com
M. Mokhlesi (&)
Fateh sanat group company, Nitelpars Co.,
Fateh Bldg., No. 32, Aftab St., Khodami St., Vanak Sq.,
Tehran 1994964743, Iran
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J IRAN CHEM SOC (2013) 10:577–581
Scheme 1 Citric acid catalyzed
synthesis of indazolo[2,1-
b]phthalazine-trione derivatives
R
R
COOH
O
R
O
O
COOH
COOH
HO
R
O
O
N
N
HN
HN
Solvent-free, 80oC
+
Ar-CHO
O
Ar
O
1a-l
Table 1 Influence of different
organocatalysts on the reaction
of 4-chloro benzaldehyde,
Entry
Catalyst
Free
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
2.5
–
dimedone and phthalhydrazide
1-Phenylthio acetic acid
Benzoic acid
2.5
30
70
25
30
55
92
25
70
2.5
4-Methoxy-benzoic acid
4-Chloro-benzoic acid
4-Nitro-benzoic acid
Citric acid
2.5
2.5
Reaction conditions: 4-Chloro
benzaldehyde (1.1 mmol),
dimedone (1 mmol) and
phthalhydrazide (1 mmol);
catalyst 3 mol%; temperature:
80 °C, solvent free
2.5
20 (min)
2.5
Sodium citrate
Acetic Acid
1.25
Scheme 2 Synthesis of 2H-
indazolo[1,2-b]phthalazine-
triones by sodium citrate
O
O
CHO
Cl
O
N
N
Sodium Citrate
HN
+
+
HN
O
O
O
O
Cl
Sluggish
Table 2 The reaction of
dimedone, 4-chloro
benzaldehyde and
phthalhydrazide using different
amounts of citric acid
Entry
Amount of catalysta
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
1
3
80
80
2.5
30
92
92
91
–
20 (min)
20 (min)
20 (min)
2.5
5
80
10
3
80
25
3
50
2.5
30
55
90
91
93
3
60
2.5
3
70
2.5
3
90
20 (min)
20 (min)
a
3
100
mol% of catalyst
Keeping these aspects in mind and in the continue of
pervious report [38], we report a rapid and green synthetic
approach for the synthesis of indazolo[2,1-b]phthalazine-
trione derivatives from aryl aldehydes with dimedone and
phthalhydrazide in the presence of nontoxic, cheap, and
edible citric acid as a catalyst in the absence of solvent
(Scheme 1).
Results and discussion
In an initial experiment, to optimize the reaction conditions
for the synthesis of indazolo[2,1-b]phthalazine-trione
derivatives, the condensation of dimedone, 4-chloro benz-
aldehyde, and phthalhydrazide as a model reaction to
provide compound 1f. The reaction was examined in the
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J IRAN CHEM SOC (2013) 10:577–581
579
Table 3 The Preparation of Indazolo[2,1-b]phthalazine-triones using citric acid in the absence of solvent
Aldehyde
Product
Time (min)
25
Yield (%)a
M. p. (°C) (lit.)Ref
85
219–220 (222–224) [30]
10
25
90
88
205–207(204–206) [29]
245–246(244–246) [30]
228–230(233–235) [29]
265–266b
20
15
20
92
81
92
262–264(262–264) [29]
15
30
81
84
268–270(264–266) [29]
267–269(268–270) [28]
25
86
178–180b
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J IRAN CHEM SOC (2013) 10:577–581
Table 3 continued
Aldehyde
Product
Time (min)
20
Yield (%)a
84
M. p. (°C) (lit.)Ref
175–177b
10
25
83
86
274–277b
219–221(219–221) [28]
a
Isolated yield
b
This compound is new
presence of some various organocatalysts such as benzene
sulfonic acid, 1-phenylthio acetic acid, 4-nitro-benzoic
acid, 4-chloro benzoic acid, benzoic acid, 4-methoxy
benzoic acid, sodium citrate, acetic acid, and citric acid.
The results are summarized in Table 1. As Table 1 indi-
cates, in the absence of catalyst, when dimedone was
treated with 4-chloro benzaldehyde and phthalhydrazide no
product was obtained. Brønsted acidic organocatalyst such
as benzene sulfonic acid, 1-phenylthio acetic acid, acetic
acid, and benzoic acid with different substitution (electron
releasing and withdrawing) gave low yields of the corre-
sponding product. Then, citric acid was tested in the model
reaction, and efficiently gave an excellent yield of the
product 1f in a shorter reaction time (Table 1, entry 7).
Also, to recognize efficiency and importance of the
acidic portion of catalyst in the synthesis of indazolo[2,1-
b]phthalazine-trione compounds, the model reaction was
also examined using sodium citrate(sodium salt of citric
acid), separately (Scheme 2). As seen in Scheme, the
reaction was sluggish. In these conditions, large amounts of
the starting materials remained.
Table 4 Comparison of the synthesis of 2H-indazolo[1,2-b]phthal-
azine-triones using the reported catalysts versus citric acid
Entry Catalyst/
temperature
Time
(min) (%)
Yield TOF (h)-1 Ref.
1
2
3
4
5
6
Citric acid/80
p-TSA/80
H2SO4/80
DPA/80
20
15
92
80
94
96
97
90
93
0.2
This work
[28]
30
12.5
60
[29]
10
[30]
TCT/100
CAN/50
15
72.5
9
[32]
120
[33]
model reaction. The reaction proceeded poorly at room
temperature (Table 2, entry 5). Elevating the reaction
temperature proved helpful, and the yield of the desired
product 1f increased considerably. We were pleased to find
that the reaction proceeded smoothly, and to almost com-
plete conversion at 80 °C (Table 2, entry 2). Increasing the
temperature did not improve the results (Table 2, entries 9,
10).
Consequently, 3 mol% of citric acid was used in sub-
sequent experiments. Under the optimal reaction condition,
the generality of the reaction was examined using various
aryl aldehydes with different substituted (electron releasing
and withdrawing) as shown in Table 3. As the results show,
the catalyst was general, all reactions proceeded efficiently,
and the desired products were obtained in high to excellent
yields and in short reaction times.
In the next step, the reaction of dimedone, 4-chloro
benzaldehyde, and phthalhydrazide was tested using dif-
ferent amounts of citric acid at 80 °C. Interestingly, when
the amount of catalyst is less than 3 mol%, the yield of
product is reduced strongly (Table 2, entry 1). Otherwise,
increasing the catalyst loading from 3 to 5 and 10 mol%
does not significantly change the yield (Table 2, entries 3,
4). The effect of temperature was also evaluated for the
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581
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