Phospho sulfonic acid: A novel and efficient solid acid catalyst for the one-pot preparation of indazolo[1,2-b]-phthalazinetriones

Article abstract of DOI:10.2298/JSC120508088K

An efficient one-pot condensation of aldehyde, dimedone and phthalhydrazide has been achieved in the presence of a catalytic amount of phospho sulfonic acid as a novel environmentally benign heterogeneous solid acid under solvent-free conditions. Diverse

Full text of DOI:10.2298/JSC120508088K

J. Serb. Chem. Soc. 78 (4) 469–476 (2013)
JSCS–4430
UDC 546.185–323+547.269.3+
547.387’592+544.478
Original scientific paper
Phospho sulfonic acid: a novel and efficient solid acid catalyst
for the one-pot preparation of indazolo[1,2-b]-
phthalazinetriones
*
ALI REZA KIASAT , ARASH MOURADZADEGUN
and SEYYED JAFAR SAGHANEZHAD
Chemistry Department, College of Science, Shahid Chamran University,
Ahvaz 61357-4-3169, Iran
(Received 8 May, revised 27 August 2012)
Abstract: An efficient one-pot condensation of aldehyde, dimedone and phthal-
hydrazide has been achieved in the presence of a catalytic amount of phospho
sulfonic acid as a novel environmentally benign heterogeneous solid acid under
solvent-free conditions. Diverse indazolo[1,2-b]phthalazinetrione derivatives
were prepared in good to excellent yields in short times. The economical
factors (time, cost, waste, etc.) for this three-component reaction hold promise
for the future of organic synthesis.
Keywords: indazolo[1,2-b]phthalazinetrione; multicomponent reaction; phthal-
hydrazide; dimedone; solvent-free; phospho sulfonic acid.
INTRODUCTION
Multicomponent reactions (MCRs) are defined as one-pot processes in
which three or more substrates combine either simultaneously (so-called tandem
or domino reactions), or through a sequential addition procedure that does not
require any change of solvent. MCRs are gaining more and more importance
especially in the total synthesis of natural products and medicinal heterocyclic
compounds because of their simplicity, high yield of the products and short
1,2
reaction times.
Solvent-free organic reactions have attracted much interest particularly from
the viewpoint of green chemistry. Solid-state reactions (or solvent-free reactions)
have many advantages, such as reduced pollution, low costs and simplicity in the
3
process and handling. The possibility of performing multicomponent reactions
under solvent-free conditions with a heterogeneous catalyst could enhance their
4
efficiency from economic and ecological points of view.
*Corresponding author. E-mail: akiasat@scu.ac.ir
doi: 10.2298/JSC120508088K
469
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KIASAT, MOURADEZADEGUN and SAGHANEZHAD
The synthesis of new heterocyclic compounds has always been a subject of
great interest due to their wide applicability. Among a large variety of hetero-
cyclic compounds, heterocycles containing phthalazine moiety are of interest
5–7
because they show several pharmacological and biological activities.
Phthala-
zine derivatives, which have two bridgehead nitrogen atoms in a fused ring sys-
8
9
10
11
tem, possess cytotoxic, antimicrobial, anticonvulsant, antifungal, antican-
12
13
cer and anti-inflammatory activities. Moreover, these compounds exhibited
good promise as new luminescent materials or fluorescence probes.
14
The first synthesis of indazolo[1,2-b]phthalazinetriones was reported by
15
Bazgir et al. using p-toluenesulfonic acid (p-TSA) as a catalyst . In recent years,
16
17
silica sulfuric acid, H SO in water–ethanol or an ionic liquid, silica-sup-
2
4
18
19
20
ported polyphosphoric acid, Mg(HSO )
amides, sulfonated poly(ethylene glycol), wet cyanuric chloride, molecular
iodine and nanosilica sulfuric acid, have been utilized for the three-com-
ponent condensation of 1,3-dicarbonyls, aromatic or aliphatic aldehydes and
phthalhydrazide/urazole. Moreover, there are a few reports about the four-com-
heteropoly acids, N-halosulfon-
4 2
22
21
23
24
25
ponent condensation of phthalic anhydride, hydrazinium hydroxide, aromatic
26
aldehydes and dimedone using Ce(SO ) ·4H O or 1-butyl-3-methylimidazo-
lium bromide ([Bmim]Br).
4 2
2
27
The aim of this presented protocol is to highlight the synergistic effects of
the combined use of MCRs and reactions under solvent-free conditions with a
heterogeneous catalyst for the development of a new eco-compatible strategy for
the synthesis of heterocyclics. Therefore, a straightforward convergent one-pot
synthesis of indazolo[1,2-b]phthalazinetrione derivatives using phospho sulfonic
acid as an efficient solid acid catalyst under solvent-free conditions through the
domino Knoevenagel condensation/Michael addition/intramolecular cyclodehyd-
ration sequence was examined (Scheme 1).
Scheme 1. Three-component reaction of dimedone, phthalhydrazide and aromatic aldehydes.
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PREPARATION OF PHTHALAZINE DERIVATIVES
471
RESULTS AND DISCUSSION
Phospho sulfonic acid, PSA, was easily prepared by the simple mixing of
diammonium hydrogen phosphate and chlorosulfonic acid in CH Cl at room
2
2
temperature (Scheme 2). This reaction is easy and clean because the by-products
of the reaction are HCl and NH gases, which are immediately evolved from the
3
reaction vessel.
Scheme 2. Preparation of the catalyst.
To evaluate the catalytic activity of PSA in the preparation of indazolo[1,2-
-b]phthalazine-1,6,11-trione derivatives, a model three-component coupling reac-
tion of phthalhydrazide (1 mmol), dimedone (1 mmol) and benzaldehyde (1.1
mmol) under solvent-free conditions at 100 °C in the absence and presence of
PSA were examined. It was found that in the absence of solid acid catalyst, only
trace amount of the desired product was observed on TLC plate even after 1 h of
heating (Table I). When the reaction was performed in the presence of PSA, it
proceeded rapidly to give the desired product.
TABLE I. Optimization of the conditions for the three-component condensation reaction of
phthalhydrazide (1 mmol), dimedone (1 mmol) and benzaldehyde (1.1 mmol) under thermal
(100 °C) solvent-free conditions
Entry
Catalyst amount, mol %
Temperature, °C
Time, min
Yield, %
1
2
3
4
5
6
–
3.5
7
9.5
7
100
100
100
100
25
60
45
10
8
60
60
–
85
91
90
–
7
60
40
In order to evaluate the appropriate catalyst loading, a model reaction was
performed using 3.5 to 9.5 mol % catalyst at different temperatures without
solvent (Table I). It was found that 7 mol % of the catalyst resulted in the maxi-
mum yield in the minimum time. A higher percentage of loading of the catalyst
(9.5 mol %) neither increased the yield nor shortened the conversion time. Next,
the effect of temperature was evaluated for the model reaction. It was observed
that the reaction did not proceed at room temperature. Elevating the reaction
temperature proved helpful, and the yield of desired product increased consi-
derably. It was gratifying to find that the reaction proceeded smoothly and almost
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KIASAT, MOURADEZADEGUN and SAGHANEZHAD
complete conversion to the product was observed at 100 °C, affording 2,3,4,13-
-tetrahydro-3,3-dimethyl-13-phenyl-1H-indazolo[1,2-b]phthalazine-1,6,11-trione
in 91 % yield within a short time.
Subsequently, with optimal conditions at hand, i.e., 1.1:1:1 molar ratios of
aldehyde, dimedone and phthalhydrazide and 7 mol % of PSA at 100 °C under
solvent-free conditions, the generality and synthetic scope of this coupling pro-
tocol were demonstrated by synthesizing a series of 1H-indazolo[1,2-b]phthala-
zine-1,6,11-triones (Table II). Gratifyingly, a wide range of aromatic aldehydes
was well tolerated under the optimized reaction conditions. The time taken for
complete conversion (monitored by TLC) and the isolated yields are presented in
Table II. All new compounds were characterized by their satisfactory spectral
1
13
(IR, H-NMR and C-NMR) studies, and the known compounds by comparison
of their physical and spectral data with those reported.
TABLE II. The one-pot preparation of 1H-indazolo[1,2-b]phthalazine-1,6,11-trione deriva-
tives promoted by PSA under solvent-free conditions at 100 °C
Melting point, °C
Product
R
R′
Time, min
Yield, %
Found
Lit.
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
10
4
5
11
10
5
10
15
8
91
89
98
88
94
92
95
86
98
91
75
208–210
220–222
269–272
265–267
227–228
262–264
218–220
220
207–20915
223–22515
270–27215
264–26615
227–22915
262–26415
218–22017
219–22118
213–21520
232–23320
–
4-NO2
3-NO2
2-Cl
4-CH3
4-Cl
4-OCH3
2,4-Cl2
3-CF3
3-CH3
4-CF3
214
232
265
4j
4k
10
15
As shown in Table II, aromatic aldehydes having electron-releasing, as well
as electron-withdrawing, groups were uniformly transformed into the corres-
ponding indazolo[1,2-b]phthalazinetriones in high to excellent yields within 4–15
min. Substituents on the aromatic ring had no obvious effect on yield or reaction
time under the above optimal conditions.
A plausible mechanistic rationale portraying a sequence of events for this
coupling reaction is postulated in Scheme 3. The first step is believed to be the
acid-catalyzed Knoevenagel condensation between the aldehyde and dimedone to
generate adduct A, which acts as a Michael acceptor. The phthalhydrazide
attacks adduct A in a Michael-type fashion to produce an open chain intermediate
B. Intermediate B undergoes intramolecular cyclization by the reaction of nuc-
leophilic amino function to carbonyl group followed by dehydration to form
indazolo[1,2-b]phthalazinetriones.
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PREPARATION OF PHTHALAZINE DERIVATIVES
473
Scheme 3. A plausible reaction mechanism.
The reusability of the catalyst in the reaction of dimedone, phthalhydrazide,
and benzaldehyde, under solvent-free conditions at 100 °C was evaluated. In this
procedure, after completion of each reaction, hot ethanol was added and the
catalyst was filtered. The recovered catalyst was washed with ethanol, dried and
reused five times. A mild depression in the catalytic activity of the catalyst was
th
observed after the 5 time of reuse (Table III).
To compare the advantages of the employment of PSA over other reported
catalysts, the model reaction of dimedone, phthalhydrazide and benzaldehyde
was considered as a representative example (Table IV). While in most of these
cases, comparative yields of the desired product were obtained as when the PSA-
-catalyzed procedure was followed, the reported procedures required high catal-
yst loading (entries 1, 2 and 4), or long reaction times (entries 3 and 5). These
results clearly demonstrate that PSA is an equally or more efficient catalyst for
this three-component reaction.
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KIASAT, MOURADEZADEGUN and SAGHANEZHAD
TABLE III. The reusability of the catalyst in five cycles for the reaction of dimedone, phthal-
hydrazide and benzaldehyde, under solvent-free conditions at 100 °C
Run
Time, min
Yield, %
1
2
3
4
5
10
10
11
12
13
91
90
88
85
82
TABLE IV. Comparison of PSA with reported catalysts in the reaction of dimedone, phthal-
hydrazide and benzaldehyde, under solvent-free conditions
Catalyst loading
Entry
Catalyst/temperature, °C
Time, min Yield, %
Ref.
mol %
1
2
3
4
5
6
p-Toluenesulfonic acid/80
Silica-supported PPA/80
Cyanuric chloride/100
Mg(HSO4)2/100
30
0.1 g
3
11.5
1
10
7
15
10
16
10
86
91
96
85
92
91
15
18
23
19
20
H4SiW12O40/100
PSA/100
7
This work
EXPERIMENTAL
All commercially available chemicals were purchased from Fluka or Merck and used
without further purification. The IR spectra were recorded on a BOMEM MB-Series 1998 FT-
1
IR spectrophotometer. The H- and 13C-NMR spectra were recorded in CDCl3 on a Bruker
Advanced DPX 400 MHz spectrometer using TMS as an internal standard. The obtained
spectral data are given in the Supplementary material to this paper. Reaction monitoring was
accomplished by TLC on silica gel polygram SILG/UV 254 plates.
Preparation of phospho sulfonic acid
A 50 mL suction flask was equipped with a constant-pressure dropping funnel. The gas
outlet was connected to a vacuum system through an alkali solution trap. Diammonium
hydrogen phosphate (2 g, 15 mmol) was charged into the flask and chlorosulfonic acid (5.24
g, ca. 3 mL, 45 mmol) in CH2Cl2 (10 mL) was added dropwise over a period of 30 min at
room temperature. After completion of the addition, the mixture was shaken for 2 h, while the
residual HCl was eliminated by suction. Then the mixture was washed with excess dried
CH2Cl2. Finally, a solid white powder (4.2 g) was obtained. The FT-IR spectrum of the catal-
yst (KBr disk), showed O=S=O asymmetric and symmetric stretching peaks at 1124 and 1075
cm-1, respectively, and the S–O stretching peak at 678 cm-1, which strictly confirmed the
sulfonic group linkage.
Typical procedure for the preparation of indazolo[1,2-b]phthalazinetriones
A mixture of dimedone (0.14 g, 1.0 mmol), phthalhydrazide (0.16 g, 1.0 mmol), an
aromatic aldehyde (1.1 mmol) and PSA (0.05 g) was heated at 100 °C for 10 min. Completion
of the reaction was indicated by TLC [TLC acetone/n-hexane (3:10)]. After completion of the
reaction, the insoluble crude product was dissolved in hot ethanol and phospho sulfuric acid
was filtered off. The crude product was purified by recrystallization from ethanol to afford the
pure product.
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PREPARATION OF PHTHALAZINE DERIVATIVES
475
CONCLUSIONS
In summary, a simple and facile protocol has been described for the synthe-
sis of indazolo[1,2-b]phthalazinetrione derivatives from a one-pot, three-compo-
nent condensation reaction of aromatic aldehydes, phthalhydrazide and dimedone
under solvent-free conditions using phospho sulfonic acid as a novel environ-
mentally safe heterogeneous solid acid catalyst. The method offers several ad-
vantages, including high yields, application of an inexpensive catalyst, short re-
action times, easy workup and performing a multicomponent reaction under sol-
vent-free conditions that is considered relatively environmentally benign.
SUPPLEMENTARY MATERIAL
Spectral data for obtained compounds are available electronically from http://
//www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgement. We gratefully acknowledge the support of this work by Shahid
Chamran University Research Council, Iran.
И З В О Д
ФОСФО-СУЛФОНСКА КИСЕЛИНА: НОВ И ЕФИКАСАН КИСЕЛИ КАТАЛИЗАТОР У
ЧВРСТОЈ ФАЗИ ЗА СИНТЕЗУ ИНДАЗОЛО[1,2-b]ФТАЛАЗИН-ТРИОНА У ЈЕДНОМ
РЕАКЦИОНОМ КОРАКУ
ALI REZA KIASAT, ARASH MOURADZADEGUN и SEYYED JAFAR SAGHANEZHAD
Chemistry Department, College of Science, Shahid Chamran University, Ahvaz 61357-4-3169, Iran
Постигнута је ефикасна кондензација, у једном реакционом кораку, алдехида, ди-
медона и фталхидразида, у присуству каталитичких количина фосфо-сулфонске кисе-
лине као новог, еколошки прихватљивог хетерогеног катализатора у одсуству органских
растварача. Добијена је серија деривата индазоло[1,2-b]фталазин-триона у добром до
одличном приносу за кратко реакционо време. Економски показатељи (време, цена и гу-
бици) за ову трокомпонентну реакцију пружају основ за даљи развој поступка.
(Примљено 8. маја, ревидирано 27. августа 2012)
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