Green one-pot synthesis of 2H-indazolo[2,1-b]phthalazine-triones: a comparative study of heterogeneous solid acid catalysts with magnetic core

Article abstract of DOI:10.1007/s13738-019-01601-w

The catalytic activity of four heterogeneous solid acid catalysts with magnetic core and sulfonic acid groups is evaluated and compared using one-pot three component synthesis of phthalazine-trione derivatives under solvent-free condition. The NiFe_2<

Full text of DOI:10.1007/s13738-019-01601-w

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01601-w
ORIGINAL PAPER
Green one-pot synthesis of 2H-indazolo[2,1-b]phthalazine-
triones: a comparative study of heterogeneous solid acid catalysts
with magnetic core
Mahdia Hamidinasab1,2 · Akbar Mobinikhaledi1,2
Received: 3 August 2018 / Accepted: 11 January 2019
©
Iranian Chemical Society 2019
Abstract
The catalytic activity of four heterogeneous solid acid catalysts with magnetic core and sulfonic acid groups is evaluated
and compared using one-pot three component synthesis of phthalazine-trione derivatives under solvent-free condition. The
NiFe O particles were selected as magnetic core, due to their enhanced chemical and magnetic stability. Furthermore, the
2
4
desired products were obtained in excellent yields at short reaction times and environmentally friendly condition using
the novel and reusable sulfonic acid grafted onto TiO -coated nickel ferrite nanoparticles. This protocol avoids the use of
2
expensive catalysts, toxic solvents and harsh reaction conditions.
Keywords Phthalazine-trione · Multicomponent reaction · Magnetic nanoparticles · Heterogeneous catalysis · Hybrid
materials · Green condition
Introduction
MCRs can be used as powerful approaches for synthesize
of these vital and pharmaceutical compounds.
Recently, considerable attention has been focused on syn-
thesis of phthalazine derivatives [1–4] as they possess dif-
ferent pharmaceutical and biological activities such as anti-
microbial [5], vasorelaxant [6], antifungal [7], anticancer
Nanocatalysis is a rapidly growing field in green chemis-
try, which involves the use of nanomaterials as catalysts for
various chemical reactions. By altering the size, morphol-
ogy, composition and chemical stability of nanomaterials,
a novel catalyst with modified properties can be achieved.
Nanocatalysts have both properties of homogenous and het-
erogeneous catalysts; therefore, they are more efficient than
normal homogeneous and heterogeneous catalysts for chemi-
cal reactions [10, 11]. In recent years, the use of magnetic
nanoparticles (MNPs) has found special interest due to their
super magnetic behaviors, easy separation from the reaction
media, large surface area, low toxicity, good stability and
possible functionalization [12–16].
[
8] and anti-inflammatory activities [9]. Several methods
have been reported for synthesis of phthalazine derivatives.
However, the traditional method of synthesis of these valu-
able compounds plays an important role in modern synthetic
methods.
Multicomponent reactions (MCRs) are important reac-
tions in modern organic synthesis in which three or more
different compounds react to give a single product (so-called
domino). These reactions are applicable for synthesis of dif-
ferent compounds, usually in a one-pot procedure and all of
the reagents are incorporated into the final product and cause
short reaction time and simplify purification. As a result,
In view of these reports and also due to development of
green procedures for synthesis of valuable heterocyclic com-
pounds, herein we wish to report an environmentally benign
protocol for synthesis of some phthalazine-trione derivatives
via three-component condensation of phthalhydrazide, dime-
done and aldehydes in the presence of sulfonic acid grafted
*
Mahdia Hamidinasab
mahdiahamidinasab@yahoo.com
TiO -coated nickel–ferrite nanoparticles under solvent-free
2
1
2
condition (Scheme 1).
Department of Chemistry, Faculty of Science, Arak
University, Arak 38156-88138, Iran
Institute of Nanosciences and Nanotechnology, Arak
University, Arak 38156-88138, Iran
Vol.:(0
1
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Journal of the Iranian Chemical Society
filtered and washed three times with deionized water and
ethanol and dried at 60 °C. The dried powder was annealed
at 400 °C for 3 h.
Preparation of titania‑coated nickel ferrite magnetic
nanoparticles
Scheme 1 The synthetic pathway of 2H-indazolo[2,1-b]phthalazine-
triones via three-component condensation reaction using functional-
ized magnetic nickel ferrite nanoparticles
0
.5 g of NiFe O MNPs was sonicated in 60 mL ethanol-ace-
2 4
tonitrile (2:1) for 1 h. Then aqueous ammonia 25% (1 mL)
and tetraethyl orthotitanate (TEOT, 0.5 mL) were added to
this suspension. The mixture was stirred at room temperature
for 24 h. The titania-modified nanoparticles were isolated by
external magnet and rinsed with ethanol and distilled water
three times and dried at 80 °C [18].
Experimental
Chemicals and apparatus
All chemicals were purchased from Merck or Fluka
chemical companies and used without further purifica-
tion. Melting points were measured using capillary tubes
on an electrothermal digital apparatus and all products
were identified by comparison of their melting points
and spectral data with those reported in the literature.
Thin layer chromatography (TLC) was performed on UV
active aluminum backed plates of silica gel. FT-IR spectra
were recorded on a Unicom Galaxy Series FT-IR 5000
Preparation of the nano‑NiFe O @TiO ‑SO H
2
4
2
3
0
.5 g of NiFe O @TiO MNPs was poured into a flask.
2 4 2
Then a solution of 0.3 mL of chlorosulfonic acid in 10 mL
CH Cl was added dropwise over a period of 30 min at room
2
2
temperature (Caution: a highly corrosive and water absor-
bent. Be careful when using this liquid. Protective gloves,
protective clothing and eye and face protection equipment’s
−
1
are needed). A powder of NiFe O @TiO MNP-supported
spectrophotometer in the region of 400–4000 cm using
2
4
2
1
13
sulfonic acid was obtained. The resulting nanoparticles were
then washed with ethanol and distilled water three times and
dried at 70 °C.
pressed KBr discs. The H and C-NMR spectra were
recorded on a Brucker Avance spectrometer operating
1
13
at 300 and 75 MHz for H and C-NMR, respectively.
Tetramethylsilane (TMS) was used as an internal stand-
ard. X-ray diffraction (XRD) was performed on Philips
PW1730 Cu-Ka radiation of wavelength 1.54 A. Thermal
gravimetric analysis (TGA) data for Thermal gravimetric
analysis (TGA) and differential thermal gravimetric (DTG)
data for NiFe O @TiO -SO H were recorded on a Met-
General procedure for synthesis
of 2H‑indazolo[2,1‑b]phthalazine‑trione derivatives
A mixture of dimedone (0.14 g, 1 mmol), phthalhydrazide
2
4
2
3
(
0.16 g, 1 mmol), aromatic aldehyde (1 mmol), and nano-
tler TGA/STTA351 System under an N atmosphere at a
2
−
1
catalyst (0.03 g) was heated at 80 °C for 10 min (TLC). After
cooling, the reaction mixture was poured in 10 mL of DMF
and the catalyst was separated easily by an external magnet.
The saturated sodium chloride solution was then added to
precipitate the pure product.
heating rate of 10 °C min . The scanning electron micros-
copy measurement was carried out on a tescan mira II field
emission-scanning electron magnetization (FE-SEM) and
hysteresis loop were measured at room temperature using
a Vibrating Sample Magnetometer (Model 7300 VSM sys-
tem, Lake Shore Cryotronic, Inc., Westerville, OH, USA).
Selected spectroscopic and physical data for prod‑
ucts
Preparation of nickel ferrite nanoparticles
3
,4-Dihydro-3,3-dimethyl-13-phenyl-2H-indazolo[2,1-b]
NiFe O nanoparticles were synthesized by co-precipita-
2
4
phthalazine-1,6,11(13H)-trione (4a)
tion method [17]. Aqueous solutions of Nickel chloride
and ferric chloride (1:2) were prepared in de-ionized water
−
1
Yellow powder, M.P.: 201–203 °C; IR (KBr) (ʋ , cm ):
(
25 mL) and the NaOH solution (3 M) was slowly added
max
3
018, 1668, 1601, 1556, 1493, 1294; δ (300 MHz, DMSO-
and stirred continuously using a stirrer to reach the pH 12.
The mixture was heated at 80 °C for 4 h. The result was
H
d ) 1.09 (6H, s, 2Me), 2.24 (2H, s, CH C), 3.18 (2H, s,
6
2
CH CO), 6.26 (1H, s, CHN), 7.28–8.24 (9H, m, Ar-H).
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1
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Journal of the Iranian Chemical Society
3
,4-Dihydro-3,3-dime-
toxicity, albeit it can be said that TEOT is a little bit safer
than TEOS. The electronegativity deference (Δχ) of Ti–O
and Si–O bonds is 2.2 and 1.7, respectively. Therefore, we
think that the reactivity of TEOT, with hydroxyl groups on
nanoparticles surfaces, is higher than that of TEOS. The
vibrating sample magnetometer (VSM) technique was used
to prove this hypothesis (Fig. 2). The M of NiFe O @
thyl-13-(3-nitrophenyl)-2H-indazolo[2,1-b]phthala-
zine-1,6,11(13H)-trione (4b)
−
1
Yellow powder, M.P.: 265–267 °C; IR (KBr) (ʋ , cm ):
max
3
119, 1660, 1626, 1529, 1361, 1313; δ (300 MHz, DMSO-
6
H
d ) 1.11 and 1.13 (6H, s, 2Me), 2.26 (2H, s, CH C), 3.22
2
s
2
4
(
2H, m, CH CO), 6.48 (1H, s, CH), 7.59–8.37 (8H, m,
TiO was 27.1 while the M of NiFe O @SiO was 29.6,
2
2 s 2 4 2
Ar-H); δ (75 MHz, DMSO-d ) 28.2, 28.5, 34.7, 37.7, 50.6,
which represents the higher magnetic loss for titania coating
C
6
−
1
−1
6
1
4.1, 116.6, 122.9, 123.5, 127.2, 127.9, 128.8, 129.7, 130.2,
(8 emu g ) than silica (5.5 emu g ). The results confirm
that TEOT coated the nanoparticles with higher thickness.
For further investigation, different amounts of TEOT (5,
34.7, 134.9, 140.1, 148.1, 152.5, 154.4, 155.9, 192.3.
1
0 and 15 mmol) were reacted with NiFe O nanoparticle
2 4
Results and discussion
surfaces. Then, the magnetic properties of nanoparticles
were characterized using VSM (Fig. 3). The best result was
for 10 mmol of TEOT and there was no significant change
for 15 mmol.
Preparation and characterization of novel MNPs
catalyst
Finally, Sulfonic acid-grafted titania-coated nickel ferrite
nanoparticles were prepared using the procedure presented
in Scheme 2. In summary, NiFe O nanoparticles were easily
In recent years, many studies have reported the use of mag-
netite (Fe O ) as magnetic nanoparticles. In the present
3
4
2
4
work, nickel ferrite (NiFe O ) nanoparticles were used as a
2
4
catalyst instead of magnetite nanoparticles. The preparation
of NiFe O is easier than that of Fe O as it is not sensitive
2
4
3
4
to oxygen and the use of inert atmosphere such as N dur-
2
ing the reaction is not needed. Another important advantage
of NiFe O was proved by magnetic hysteresis loops. For
2
4
comparison of these two magnetic nanoparticles (Fe O and
3
4
NiFe O ) we have synthesized them under the same condi-
2
4
tions. The magnetic properties of nanoparticles were char-
acterized using a vibrating sample magnetometer (VSM). In
Fig. 1, the typical room temperature magnetization curves
of NiFe O and Fe O nanoparticles are shown. The satura-
2
4
3
4
tion magnetization (M ) of these nanoparticles changes from
s
−
1
−1
3
5.1 emu g for NiFe O to 32.2 emu g for Fe O core.
2 4 3 4
For the coating of nanoparticles, TEOT and TEOS were
used as coating reagents and the results were compared.
TEOT and TEOS are not significantly different in terms of
Fig. 2 The comparison of magnetic hysteresis loops of NiFe O @
2
4
TiO and NiFe O @SiO nanoparticles
2
2
4
2
Fig. 1 The comparison of magnetic hysteresis loops of NiFe O and
2
4
Fig. 3 The comparison of magnetic hysteresis loops of NiFe O @
2 4
Fe O nanoparticles
3
4
TiO nanoparticles with different shell thickness
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Journal of the Iranian Chemical Society
O=S=O asymmetric and symmetric stretching vibration and
S–O stretching vibration of sulfonic groups, respectively,
−
1
−1
−1
at 1242 cm , 1145 cm , 974 cm [11, 25], respectively.
The morphology of NiFe O @TiO -SO H was charac-
2
4
2
3
terized by FE-SEM. Figure 5 indicates that these modified
titania-coated MNPs are almost spherical with regular shape
and the average particle size is about 37.1 nm, as indicated
by the size histogram in Fig. 6B. Figure 6A shows the X-ray
diffraction patterns of the synthesized NiFe O nanoparticle
Scheme 2 Preparation of nano- NiFe O @TiO -SO H
2
4
2
3
prepared via the chemical co-precipitation of Ni2+ and Fe3+
ions in basic solution [17]. The prepared NiFe O nanopar-
2
4
2
4
ticles were subsequently coated with titania through the easy
and modified nano-NiFe O @TiO -SO H particles. Several
2 4 2 3
protocol [11, 19–21]. The free OH groups on TiO -coated
peaks appeared at values of (111), (220), (311), (222), (400),
(422), (511), (440) and (533) indicating a cubic crystal sys-
tem for NiFe O nanoparticles (Fig. 6A curve (a)), [26, 27],
2
nickel ferrite nanoparticles were reacted with chlorosulfonic
acid to give the sulfonic acid-grafted TiO -coated nickel fer-
2
2
4
rite nanoparticles (NiFe O @TiO -SO H). For comparison
which conforms with JCPDS file (no. 44-1485) standard
2
4
2
3
study of catalytic activity, the nano-NiFe O @SiO -SO H
[24]. The peak at 2θ=26.6° confirms the formation of TiO
2
4
2
3
2
[
22], nano-Fe O @SiO -SO H [23] and nano-Fe O @
shell (Fig. 6A curve (a)) [27].
3
4
2
3
3
4
TiO -SO H [11] were prepared according to the reported
The average size of the crystallites was calculated by
applying Scherer’s equation: D=0.9λ/β Cos θ, where h is the
diffraction angle, λ is the wavelength of the incident X-rays,
β is full width at half maximum height in radians, θ is the
Bragg diffraction angle and D is the average diameter in Å.
The peak at 2θ=35.7° is selected to calculate the crystallite
size, according to the result calculated by Scherer’s equation;
it is found that the diameter of nano-NiFe O @TiO -SO H
2
3
procedures.
The prepared acidic magnetic nanoparticles were charac-
terized by the various standard techniques, including Fou-
rier transform infrared (FT-IR) spectroscopy, field emission
scanning electron microscopy (FE-SEM), energy dispersive
X-ray spectroscopy (EDS), vibrating sample magnetometer
(
VSM), X-ray diffraction (XRD) and thermogravimetric
2
4
2
3
analysis (TGA).
particles is about 43.1 nm, which is in the range determined
The FT-IR Spectra of NiFe O MNPs, NiFe O @TiO
using size histogram analysis (Fig. 6B).
2
4
2
4
2
core–shell MNPs, NiFe O @TiO -SO H, are presented in
The energy-dispersive X-ray spectroscopy (EDS) of
NiFe O @TiO -SO H is shown in Fig. 7. The presence of
2
4
2
3
Fig. 4. In curve (a), the spectrum of NiFe O nanoparti-
2
4
2
4
2
3
−
1
cles shows strong absorption bands around 401 cm and
Fe, Ni, O, S and Ti atoms was observed in the EDX spec-
trum. The presence of Ti, O and Ni signals confirms the
existence of titania shell on the nickel ferrite nanoparticles.
Furthermore, the EDX maps of NiFe O @TiO -SO H nano-
−
1
6
01 cm , corresponding to stretching vibration of metal-O
at octahedral site and metal-O of tetrahedral site [24]. The
−
1
low-frequency absorption band at 1400 cm in curve (b) is
assigned to the stretching vibration of Ti–O–Ti. The broad
2
4
2
3
particles are presented in Fig. 8. According to the results,
there is a good dispersion of Fe, Ni, O, S and Ti elements on
the surface of NiFe O @TiO -SO H nanoparticles.
−
1
peaks in the range of 3000–3600 cm and the weak peak
at 1631 cm− are due to the O–H stretching vibration mode
1
2
4
2
3
The stability of the NiFe O @TiO -SO H catalyst was
2
4
2
3
determined by thermogravimetric analysis (TGA) and deriv-
ative thermogravimetry (DTG) (Fig. 9). The TGA curve of
magnetic catalyst shows an initial 2% weight loss from r.t
to about 250 °C, which is due to the removal of physically
adsorbed solvent and surface hydroxyl groups (Fig. 9). The
major weight loss beyond 200 °C to nearly 650 °C is attrib-
uted to the decomposition of the sulfonic acid groups in the
nanocomposite. Therefore, the catalyst is reasonably stable
up to 250 °C and it is safe to use under thermal reaction con-
dition. The grafted sulfonic acid content on the NiFe O @
2
4
TiO is approximately 8 wt%. Moreover, the DTG curve
2
indicates that the deformation of the inorganic structure
mainly occurred at 710 °C. Therefore, the NiFe O @TiO -
2
4
2
Fig. 4 The FT-IR spectra of (a) nano-NiFe O (b) nano-NiFe O @
2
4
2
4
SO H is stable around or below 300 °C (Fig. 9).
3
TiO and (c) nano-NiFe O @TiO -SO H catalyst
2
2
4
2
3
The magnetic properties of nanoparticles were character-
ized using a vibrating sample magnetometer (VSM). Fig-
ure 10 shows the typical room temperature magnetization
(
Ti–O) and twisting vibration mode of H–O–H adsorbed in
the titania shell, respectively. In curve (c) we can find the
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Journal of the Iranian Chemical Society
Fig. 5 The FE-SEM image of
NiFe O @TiO -SO H nanopar-
2
4
2
3
ticles (200, 500 nm)
Fig. 7 The EDS spectrum of modified nano-NiFe O @TiO -SO H
2
4
2
3
particles
up to ± 8000.0 Oe and, Ms of samples changes from 35.1 to
−
1
2
1.1 emu g due to the formation of a titania shell and inor-
ganic layer around the NiFe O core. The hysteresis loops
2
4
show the superparamagnetic behaviour of the NiFe O and
2
4
NiFe O @TiO -SO H particles in which M and H are close
2
4
2
3
r
c
−
1
to zero (M =119 and 154 emu g and H =4.1 and 6.1 Oe,
r
c
respectively) [28].
Fig. 6 A The XRD patterns of (a) NiFe O nanoparticle and (b)
2
4
nano-NiFe O @TiO -SO H. B The particle size distribution histo-
2
4
2
3
gram of spherical acidic modified nano- NiFe O @TiO -SO H
Acidity of NiFe O @TiO ‑SO H
2
4
2
3
2
4
2
3
The concentration of grafted sulfonic acid on the NiFe O @
2
4
curves of NiFe O MNPs (Fig. 10, curve a), and NiFe O @
2
4
2
4
TiO -SO H, NiFe O @SiO -SO H, Fe O @TiO -SO H and
2
3
2
4
2
3
3
4
2
3
TiO -SO H (Fig. 10, curve b). The hysteresis curve allows
2
3
Fe O @SiO -SO H nanomaterials was determined via a back
3
4
2
3
determination of the coercivity (H ), remanent magnetiza-
c
titration with HCl (0.01 N). A solution of KOH (2 mL, 0.01 N)
was added to 0.02 g of the magnetic nanoparticles and the mix-
ture was stirred at room temperature for 30 min. The catalyst
tion (M ) and saturation magnetization (M ). The magnetiza-
r
s
tion of sample could be completely saturated at high fields of
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Journal of the Iranian Chemical Society
Fig. 8 The FE-SEM image and EDX maps of NiFe O @TiO -SO H nanoparticles
2
4
2
3
was magnetically separated and washed with deionized water.
The excess amount of KOH was titrated with HCl (0.01 N) in
the presence of phenolphthalein as an indicator. The results
revealed that the NiFe O @TiO -SO H, NiFe O @SiO -
2
4
2
3
2
4
2
SO H, Fe O @TiO -SO H and Fe O @SiO -SO H have 2.9,
3
3
4
2
3
3
4
2
3
−
1
2
.3, 2.8 and 2.1 mmol g acid content, respectively. These
results confirm the greater porosity of silica layer.
Synthesis of 2H‑indazolo[2,1‑b]phthalazine‑triones
derivatives
Fig. 9 TG-DTG curves of NiFe O @TiO -SO H nanoparticles
2
4
2
3
After the characterization of the NiFe O @TiO -SO H
2
4
2
3
nanoparticles, its role as a catalyst was evaluated for syn-
thesis of 2H-indazolo[2,1-b]phthalazine-triones 4a–m
is sufficient to complete the reaction after 5 min in 92%
(Table 1, entry 10). To define the role of NiFe O @TiO -
(
Scheme 1). For optimization of reaction conditions, a one-
2
4
2
pot three-component condensation reaction of dimedone 1
1 mmol), benzaldehyde 2a (1 mmol) and phthalhydrazide
SO H as a catalyst for the preparation of 2H-indazolo[2,1-b]
3
(
phthalazine-trione derivatives, the model reaction was car-
3
(1 mmol) was used as a model reaction. At first, to inves-
ried out with NiFe O , NiFe O @TiO -SO H and without
2
4
2
4
2
3
tigate the efficiency of the catalyst the model reaction was
the catalyst (Table 1, entries 12–14). With respect to yield of
product and reaction time, the best results are attained using
NiFe O @TiO -SO H as the catalyst. To compare the cata-
carried out in several solvents such as CH CN, EtOH, THF,
3
toluene and H O under reflux as well as under solvent-free
2
2
4
2
3
conditions (Table 1). As shown in Table 1, it was found
that conventional heating at 80 °C under solvent-free con-
ditions is more efficient than using organic solvents, with
respect to reaction time and yield of the desired product
lytic activity, the same reactions were carried out in the pres-
ence of as-prepared solid acids: nano-Fe O @TiO -SO H,
3
4
2
3
nano-NiFe O @SiO -SO H and nano-Fe O @SiO -SO H.
2
4
2
3
3
4
2
3
As presented in Table 1 (entry 10, 15, 17 and 18), the yield
and activity of them are almost the same. The magnetic core
of NiFe O @TiO particles is more stable than others and
(
Table 1, entry 9). The effect of catalyst amount on reaction
yield was studied using various amounts of NiFe O @TiO -
2
4
2
2
4
2
SO H. The results displayed that 30 mg of the nanocatalyst
so is the best choice for this reaction [29, 30].
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Journal of the Iranian Chemical Society
Table 1 Optimization of
reaction conditions for
synthesis of 2H-indazolo[2,1-b]
phthalazine-trione
Yield (%)a
Entry
Catalyst (mg)
Solvent
Temp. (°C)
Time
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
NiFe O @TiO -SO H (10)
CH CN
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
50
80
80
80
80
80
80
80
80
80
80
6 h
3 h
3.5 h
4 h
4 h
8 h
10 h
3 h
5 min
5 min
5 min
1 h
30 min
30 min
5 min
45 min
5 min
5 min
75
86
78
71
81
73
39
89
85
92
92
51
78
67
93
59
91
90
2
4
2
3
3
NiFe O @TiO -SO H (10)
EtOH
THF
2
4
2
3
NiFe O @TiO -SO H (10)
2
4
2
3
NiFe O @TiO -SO H (10)
H O
2
4
2
3
2
NiFe O @TiO -SO H (10)
CHCl3
Toluene
2
4
2
3
NiFe O @TiO -SO H (10)
2
4
2
3
NiFe O @TiO -SO H (10)
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
2
4
2
3
NiFe O @TiO -SO H (10)
2
4
2
3
NiFe O @TiO -SO H (10)
2
4
2
3
1
1
1
1
1
1
1
1
1
NiFe O @TiO -SO H (30)
2
4
2
3
NiFe O @TiO -SO H (50)
2
4
2
3
–
NiFe O (30)
2
4
NiFe O @TiO (30)
2
4
2
NiFe O @SiO -SO H (30)
2
4
2
3
Fe O (30)
3
4
Fe O @SiO -SO H (30)
3
4
2
3
Fe O @TiO -SO H (30)
3
4
2
3
Reaction conditions: dimedone (1 mmol), phthalhydrazide (1 mmol), benzaldehyde (1 mmol) and nano-
catalyst
Bold rows are optimum conditions
a
Isolated yield
the results were compared with other used catalysts in this
reaction (Table 3). As can be seen, the catalytic system
reported in this paper has benefits in terms of simple con-
dition, reaction time and yield.
The formation of products 4a–m can be rationalized by
initial formation of intermediate 1′ by standard Knoevenagel
condensation of dimedone 1 and aldehyde 2 in the presence
of acidic nanocatalyst. Then, the subsequent Michael-type
addition of the phthalhydrazide 3 to the intermediate 1′,
produces intermediate 2′ that followed by cyclization and
tautomerization and affords the corresponding product 4
(
Scheme 3).
Fig. 10 Magnetic hysteresis loops of (a) NiFe O MNPs and (b)
2
4
NiFe O @TiO -SO H nanoparticles
2
4
2
3
Catalyst recovery and reusability
As shown in Table 2, various aldehydes (2a–m) reacted
with phthalhydrazide (1) and dimedone (2) to give the cor-
responding 2H-indazolo[2,1-b]phthalazine-triones (4a–m)
with good to excellent yields under optimized conditions.
Arylaldehydes with electron-donating or electron-withdraw-
ing groups could lead to the favourite products. Aliphatic
aldehydes were also used, but did not afford desired products.
To demonstrate the applicability of our catalyst, the
condensation reaction of benzaldehyde, dimedone and
phthalhydrazide under optimized conditions for synthesis
of 2H-indazolo[2,1-b]phthalazine-trione in the presence of
NiFe O @TiO -SO H nanoparticles was carried out and
The recovery and recyclability of the catalyst are important
features for industrial and commercial applications. Thus
reusability of the nano-NiFe O @TiO -SO H particles
2
4
2
3
was investigated by three-component reaction of dimedone
(
(
1 mmol), phthalhydrazide (1 mmol) and benzaldehyde
1 mmol) in the presence of catalyst (0.03 g).
After completion of the reaction, the nanocatalyst was
easily separated using an external magnet, washed with
EtOH, double distilled water and then dried. The catalyst
could be used at least six times without significant loss of
activity as seen in Fig. 11. The FT-IR spectrum of the cata-
lyst after six runs confirmed its stability (Fig. 11).
2
4
2
3
1
3

Journal of the Iranian Chemical Society
Table 2 The synthesis of
H-indazolo[2,1-b]phthalazine-
Entry
Aldehyde
Product
Time (min)
Yield (%)
M.p (°C) [lit] Refs.
2
triones using NiFe O @TiO -
2
4
2
1
2
3
4
5
6
7
8
9
Benzaldehyde
3-Nitrobenzaldehyde
4a
4b
4c
4d
4e
4f
4g
4h
4i
5
10
10
30
20
10
10
10
5
10
20
35
20
92
95
89
88
89
91
90
93
94
92
91
87
88
205 [31]
268 [31]
260 [31]
257 [32]
266 [32]
262 [31]
265 [31]
215 [31]
226 [31]
207 [33]
185 [34]
206 [32]
257 [32]
SO H nanoparticles as a catalyst
3
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
4-Hydroxybenzaldehyde
4-Bromobenzaldehyde
2-Chlorobenzaldehyde
4-Flurobenzaldehyde
4-Nitrobenzaldehyde
1
1
1
1
0
1
2
3
2,4-Dichlorobenzaldehyde
2-Hydroxybenzaldehyde
3,4-Dimethoxybenzaldehyde
4-(Dimethylamino)benzaldehyde
4j
4 k
4l
4m
Reaction conditions: dimedone (1 mmol), phthalhydrazide (1 mmol), aldehyde (1 mmol) and nanocatalyst
0.03 mmol)
(
Bold rows are optimum conditions
a
Isolated yield
Table 3 Comparison of
a
Entry
Catalyst
Condition
Time
Yield (%)
Refs.
MNPs-titania sulfuric acid with
other catalysts described in
the literature for synthesis of
1
2
3
4
5
6
7
8
9
H PW O
Ionic liquid
30 min
5 h
2 h
10 min
10 min
30 min
35 min
8 min
20 min
5 min
92
85
94
91
86
88
91
87
93
92
[35]
[33]
[34]
[36]
[31]
[32]
[32]
[37]
3
12 40
WO /ZrO2
CH CN (80 °C)
3
3
2
H-indazolo[2,1-b]phthalazine-
CAN
PSA
PEG400 (50 °C)
Solvent-free (100 °C)
Solvent-free (80 °C)
trione via three-component
reaction
p-TSA
H SO
H O-EtOH (reflux)
2
4
4
2
H SO
[bmim]BF4
2
Silica-SO H
Solvent-free (100 °C)
Solvent-free (100 °C)
Solvent-free (80 °C)
3
SO H-FMSM
[38]
Present work
3
1
0
MNPs-Titania
sulfuric acid
Reaction conditions: dimedone (1 mmol), phthalhydrazide (1 mmol), benzaldehyde (1 mmol) and catalyst
Conclusion
In summary, the catalytic activity of four heterogeneous
solid acid catalysts with magnetic core was compared using
one-pot three component synthesis of phthalazine-trione
derivatives under solvent-free condition. Finally, the nano-
NiFe O @TiO -SO H as a novel and retrievable catalyst
2
4
2
3
with high stability was used for synthesis of several phthala-
zine-triones. Mild reaction conditions, operational simplic-
ity, enhanced rates, high isolated yields of pure products,
good thermal and chemical stability of nanocatalyst are main
and remarkable advantages of described protocol.
Scheme 3 Schematic plausible mechanism for synthesis of
H-indazolo[2,1-b]phthalazine-triones in the presence of MNPs-tita-
nia sulfuric acid via three-component condensation reaction
2
1
3

Journal of the Iranian Chemical Society
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Acknowledgements This work was supported by the research council
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