Dodecylphosphonic acid (DPA): A highly efficient catalyst for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.01.095

A new green protocol has been developed for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones via one-pot, three-component condensation reaction of aromatic aldehydes with 1,3-dicarbonyl compounds and phthalhydrazide using reusable dodecylphosphonic

Full text of DOI:10.1016/j.tetlet.2012.01.095

Tetrahedron Letters 53 (2012) 1728–1731
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dodecylphosphonic acid (DPA): a highly efficient catalyst for the synthesis
of 2H-indazolo[2,1-b]phthalazine-triones under solvent-free conditions
Mazaahir Kidwai a, , Anwar Jahan a, Ritika Chauhan a, Neeraj Kumar Mishra a
⇑
a Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new green protocol has been developed for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones via
one-pot, three-component condensation reaction of aromatic aldehydes with 1,3-dicarbonyl compounds
and phthalhydrazide using reusable dodecylphosphonic acid (DPA) as heterogeneous solid acid catalyst
under solvent-free conditions. This protocol provides a novel and improved method for obtaining 2H-
indazolo[2,1-b]phthalazine-triones in terms of good yields with little catalyst loading.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 25 October 2011
Revised 16 January 2012
Accepted 22 January 2012
Available online 28 January 2012
Keywords:
Multicomponent reaction
Dodecylphosphonic acid (DPA)
Solvent-free conditions
Recyclability
2H-Indazolo[2,1-b]phthalazine-triones
The development of new methods for solvent-free organic syn-
thesis involving multicomponent reactions is an important and
attractive area of synthetic research.1,2 Organic reactions should
be fast and facile and the target products should be easily sepa-
rated and purified in high yields without the isolation of any inter-
mediate.3 From this point of view, solvent-free multicomponent
reactions4 find application as appealing methods to achieve these
goals. Multicomponent protocol emphasizes as one-pot reaction
in which three or more reactants are combined together to gener-
ate a single product with greater efficiency.5,6 Multicomponent
reactions (MCRs) enable multiple reactions leading to interesting
heterocyclic scaffolds which are useful for the construction of
poly-functionalized heterocyclic ‘drug like’ libraries.7,8
In the past few decades, the synthesis of nitrogen-containing
heterocyclic compounds has gained prominence as they are wide-
spread in nature.9 Also their applications to biologically active
pharmaceuticals, agrochemical and functional materials are
becoming increasingly important.10–12
Among a large variety of N-containing heterocyclic compounds,
heterocycles containing hydrazine moiety as ‘fusion site’ have re-
ceived considerable attention because of their pharmacological
properties and clinical applications.13 Moreover, fused phthala-
zines were found to possess multiple biological activities such as
antimicrobial,14 anticonvulsant,15 antifungal,16 anticancer,17 and
anti-inflammatory activities.18 Therefore, a number of methods
have been reported for the synthesis of phthalazine deriva-
tives.19,20 However, some of these methods suffered with several
drawbacks such as hazardous organic solvents, high cost, long
reaction time, use of stoichiometric, and excess amounts of acids
and harsh reaction conditions with non-recyclable catalyst. There-
fore, the development of a new, efficient, and environment friendly
procedure is necessary, which allow the ready synthesis of hetero-
cycles containing phthalazine ring fragment.
In recent years, solid acid catalysts have found several applica-
tions in organic synthesis, as they may be easily recovered and
recycled. In this connection, dodecylphosphonic acid (DPA) was
used as mild, harmless to the environment, recyclable, non-toxic,
and commercially available heterogeneous solid acid catalyst with
stability toward humidity.21,22 Despite its great importance, only a
few papers are reported on its catalytic application in organic
synthesis.21,22
In combination with the use of heterogeneous catalyst in organ-
ic transformations, solvent-free methodologies for the synthesis of
organic compounds have attracted much interest because of their
ease of experimental procedures as well as work-up, low cost,
clean, efficient, environmentally benign, and high yielding pro-
cesses.23,24 According to the principle of safe chemistry, synthetic
methods should be designed to use substances that exhibit little
or no toxicity to human health and the environment.25
As a part of our continuing studies in developing efficient syn-
thetic methodologies26,27 in organic preparations, we found that
the synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives
via a one-pot, three-component condensation reaction of aldehydes
⇑
Corresponding author at present address: Vice-chancellor, Jiwaji University,
Gwalior (M.P.), India (On Deputation from Department of Chemistry, University of
Delhi, Delhi 110 007, India). Tel./fax: +91 11 27666235.
E-mail address: kidwai.chemistry@gmail.com (M. Kidwai).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.095

M. Kidwai et al. / Tetrahedron Letters 53 (2012) 1728–1731
1729
R1
O
R1
H
R1
O
O
R1
N
NH
N
DPA (10 mol%)
+
Solvent-free, 80 oC
+
O
NH
O
O
O
R
(3)
O
(2)
(1)
R
(4a-p)
Scheme 1. DPA catalyzed synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives.
O
H
O
O
O
N
NH
NH
N
DPA (10 mol%)
+
O
+
Solvent-free, 80 oC
O
O
(4a)
O
(2)
(3)
(1)
Scheme 2. DPA catalyzed model reaction.
(1) with 1,3-dicarbonyl compounds (2) and phthalhydrazide (3) can
be efficiently achieved without any solvent with the use of dodecyl-
phosphonic acid under mild conditions at 80 °C (Scheme 1).
To optimize the reaction conditions, we first examined the reac-
tion of benzaldehyde (1 mmol), dimedone (1 mmol), and
phthalhydrazide (1.5 mmol) at 80 °C without catalyst under sol-
vent-free conditions in order to recognize the capability of the cat-
alyst. The reaction did not proceed even after prolonged reaction
time and no desired product was formed which supported the cat-
alytic activity of DPA. When the reaction was performed in the
presence dodecylphosphonic acid, it proceeded effectively to pro-
duce the desired product (4a) in high yields (Scheme 2).
Table 1
Influence of different catalysts on the reaction of benzaldehyde, dimedone and
phthalhydrazidea
Entry Catalyst
Amount (mol %) Time (min) Yieldb (%)
1
2
No
-Proline
—
10
3600
600
Trace
Nil
L
3
4
5
6
7
8
9
10
11
Montmorillonite K-10 10
30
12
10
30
7
12
20
10
10
65
83
86
85
91
86
82
92
96
Amberlyst-15
p-TSA
PMA-SiO2
Silica sulfuric acid
HClO4–SiO2
DPA
10
30
10
6.5
10
2
Some other solid acid catalysts such as L-proline, montmorillon-
DPA
DPA
5
10
ite K-10, Amberlyst-15, p-TSA, PMA-SiO2, silica sulfuric acid, and
HClO4–SiO2 exhibited moderate to good catalytic properties. In
most of these cases comparative yields of the desired product were
obtained. Following the DPA-catalyzed procedure, the reported
methods required expensive catalyst, toxic or organic solvents,
strong acidic conditions, high catalyst loading, and long reaction
times. These results clearly demonstrated that DPA is a more effi-
cient catalyst for the synthesis of 2H-indazolo[2,1-b]phthalazine-
triones. The results are summarized in Table 1.
a
Reaction conditions: Benzaldehyde (1 mmol), dimedone (1 mmol) and
phthalhydrazide (1.5 mmol); temperature: 80 °C.
b
Isolated yields.
Table 2
Effect of temperaturea
Entry
Temperature (°C)
Time (min)
Yieldb (%)
Besides this, we observed that the concentration of the catalyst
played a major role in catalyzing the condensation reaction for the
synthesis of 2H-indazolo[2,1-b]phthalazine-triones. Using a model
reaction as described above and varying just the concentration of
DPA from 2 mol % to 10 mol %, the yield of product was increased
from 82% to 96%. This shows that 10 mol % of DPA is the suitable
choice for the optimum reaction rate and yield of 2H-indazol-
o[2,1-b]phthalazine-triones (Table 1, entries 9–11).
1
2
3
4
20
40
60
80
60
35
20
10
25
65
90
96
a
Reaction conditions: Benzaldehyde (1 mmol), dimedone (1 mmol), and
phthalhydrazide (1.5 mmol); catalyst: DPA (10 mol %); at different temperatures.
b
Isolated yields.
Next, the effect of temperature was also evaluated for the model
reaction. It was observed that fast reaction occurred on raising the
temperature from 20 °C to 80 °C and the yield of desired product in-
creased considerably. We were pleased to find that the reaction
proceeded smoothly and almost complete conversion of reactants
was observed at 80 °C to afford the desired product (4a) in 96% yield
within 10 min (Table 2). However, at room temperature a lower
yield of product was obtained even after longer reaction times.
With the optimistic results in hand, we chose a variety of struc-
turally diverse aromatic aldehydes and 1,3-dicarbonyl compounds
to understand the scope and efficiency of the dodecylphosphonic
acid promoted synthesis of 2H-indazolo[2,1-b]phthalazine-triones.
It was observed that aromatic aldehydes having electron-with-
drawing groups (Table 3, entries 2 and 3) afforded high yield of
products as compared to aromatic aldehydes substituted with elec-
tron-donating groups (Table 3, entries 4 and 5). Heterocyclic alde-
hydes also displayed good reactivity (Table 3, entry 7). Besides this,
our methodology has been used successfully with cyclohexane-
1,3-dione in place of dimedone and corresponding products were

1730
M. Kidwai et al. / Tetrahedron Letters 53 (2012) 1728–1731
Table 3
Dodecylphosphonic acid (DPA) catalyzed synthesis of 2H-indazolo[2,1-b]phthalazine-triones (4a–p)a
Entry
R
R1
Product
Time (min)
Yieldb (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
4-Cl
4-NO2
4-OCH3
4-CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
10
5
96
90
94
88
85
83
79
82
94
92
84
80
87
91
86
80
203–20520a
263–26520a
224–22620a
217–21928a
226–22820a
185–187
10
10
10
10
10
15
10
5
10
10
10
10
10
15
2-OH
Piperonyl
1-Naphthyl
H
3-NO2
4-CH3
3-OH
4-Br
4-HO-3-MeO
4-(CH3)2N
1-Naphthyl
196–198
263–26529
222–22528b
228–23128a
245–24628a
266–26828b
279–28228b
203–205
H
H
H
255–25728a
259–26128b
a
Reaction conditions: Aromatic aldehydes (1 mmol), 1,3-dicarbonyl compounds (1 mmol), and phthalhydrazide (1.5 mmol); catalyst: DPA
(10 mol %); temperature: 80 °C.
b
Isolated yields.
R1
R1
O
O
R
R
H
H
O
[DPA]
HC
H
O
(2)
R
O
O
H
(1)
[DPA]
(5)
R
O
R1
R1
H
N
[DPA]
O
HN
H2O
O
O
(3)
R1
R1
N
R1
O
HN
O
R1
[DPA]
N
N
(6)
O
[DPA]
O
O
(4a-p)
R
Scheme 3. Plausible mechanism for the synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives.
Table 4
obtained in excellent yields under similar reaction conditions
(Table 3, entries 9–16). The scope of the reaction was also investi-
Recycling yieldsa
No of Cyclesa
gated with aliphatic and
a,b-unsaturated aldehydes as substrates
Fresh
Run 1
Run 2
Run 3
Run 4
Run 5
and incomplete conversion of the starting materials to the product
was observed.
Yieldb
Time (min)
96
10
96
10
95
10
92
10
90
10
86
10
A plausible mechanism29 for the formation of 2H-indazolo[2,1-
b]phthalazine-triones30 is shown in Scheme 3. The reaction is
thought to proceed in a stepwise manner. Firstly, we assumed that
the reaction occurs via a Knoevenagel condensation between 1,3-
dicarbonyl compounds 2 and aromatic aldehydes 1 to form the
intermediate 5 in the presence of DPA, which suffers immediate
Michael addition of phthalhydrazide 3 to the C@C bond of 5. The
concerted cyclocondensation of amino and carbonyl of the Michael
adduct 6 was performed to afford the corresponding products (4a–
p). During the reaction process, the hydrogen ion is donated by the
dodecylphosphonic acid. The hydrogen ion helps in the enolization
of 1,3-dicarbonyl compounds to form the enolate intermediate.
a
Reaction conditions: Benzaldehyde (1 mmol), dimedone (1 mmol), and
phthalhydrazide (1.5 mmol); catalyst: DPA (10 mol %), temperature: 80 °C.
b
Isolated yields.
The recyclability of DPA was also examined. When the reaction
was completed, water was added and the product was filtered. The
aqueous solution was evaporated under reduced pressure and the
powder obtained (catalyst) was washed with diethyl ether, dried,
and reused for the same reaction again. It was observed that, with
an increase in reusability runs, the catalytic activity of DPA de-
creased slightly (Table 4).

M. Kidwai et al. / Tetrahedron Letters 53 (2012) 1728–1731
1731
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In conclusion, we have developed a solvent-free reaction for the
synthesis of 2H-indazolo[1,2-b]phthalazine-triones via one-pot,
three-component condensation reaction of aromatic aldehydes
with 1,3-dicarbonyl compounds and phthalhydrazide using dode-
cylphosphonic acid (DPA) as a novel, efficient, and recyclable cata-
lyst . The salient features of this protocol are high product yields,
shorter reaction time, solvent-free condition, low catalyst loading,
and relatively mild acid catalyst with easy work-up procedure,
which make this procedure quite simple, more convenient, and
environmentally benign. Hopefully, our methodology could be a
valid contribution to the existing processes in the field of 2H-
indazolo[2,1-b]phthalazine-triones synthesis.
Acknowledgments
Authors (A.J. and R.C.) are thankful to University Grants Com-
mission (UGC) for the Grant of Junior Research Fellowships. The
author N.K.M. thanks CSIR, New Delhi, India for providing Research
Associateship. Authors would also like to acknowledge the USIC,
University of Delhi for providing the instrumentational facilities
to characterize the compounds.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.095.
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References and notes
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aldehydes
dodecylphosphonic acid (DPA) (10 mol %) were added and the mixture was
stirred over magnetic stirrer. After 5 min, to this stirred mixture,
(1 mmol),
1,3-dicarbonyl
compounds
(1 mmol),
and
a
phthalhydrazide (1.5 mmol) was added and the contents were stirred at
80 °C for an appropriate time. The progress of reaction was monitored by TLC.
After completion of the reaction, the reaction mixture was allowed to cool at
room temperature and washed with water. The crude product was crystallized
with ethanol, which was further purified by silica gel column chromatography
(hexane/ethylacetate 70:30) to give the desired products. All the products were
characterized by comparing their physical (MPs) and spectral data with those
reported earlier. After the evaporation of aqueous layer, the catalyst was
recovered and reused for next reaction.
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