Green synthesis of 1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile derivatives using a new bifunctional base–ionic liquid hybrid magnetic nanocatalyst

Article abstract of DOI:10.1002/aoc.5386

The ionic liquid-base N,N,2,2,6,6-hexamethyl-N-(3-(trimethoxysilyl)propyl)piperidin-4-amonium iodide was grafted onto titana-coated NiFe₂O₄ nanoparticles for obtaining an efficient and reusable ionic liquid-base hybrid nanocatalyst.

Full text of DOI:10.1002/aoc.5386

Received: 27 July 2019
DOI: 10.1002/aoc.5386
Revised: 19 October 2019
Accepted: 27 October 2019
F U L L P A P E R
Green synthesis of 1H‐pyrazolo[1,2‐b]phthalazine‐2‐
carbonitrile derivatives using a new bifunctional base–ionic
liquid hybrid magnetic nanocatalyst
1,2
1,2
1,2
Mahdia Hamidinasab
| Mohammad Ali Bodaghifard
| Akbar Mobinikhaledi
1
Department of Chemistry, Faculty of
The ionic liquid‐base N,N,2,2,6,6‐hexamethyl‐N‐(3‐(trimethoxysilyl)propyl)
piperidin‐4‐amonium iodide was grafted onto titana‐coated NiFe O nanoparti-
Science, Arak University, Arak 38156‐
88138, Iran
2
4
2
Institute of Nanosciences and
cles for obtaining an efficient and reusable ionic liquid‐base hybrid nanocatalyst.
The structure of hybrid nanoparticles was characterized using FT‐IR (Fourier‐
transform infrared spectroscopy), field emission scanning electron microscopy,
EDS (energy‐dispersive X‐ray spectroscopy), EDS map scan, Brunauer–
Emmett–Teller surface area analysis, CHN (elemental analysis), vibrating sample
magnetometer and thermogravimetric analysis techniques. Furthermore, this
novel hybrid catalyst was used in one‐pot three‐component synthesis of 3‐
amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile deriva-
tives under green and environmentally benign conditions. This protocol avoids
the use of harmful catalysts, toxic solvents and harsh reaction conditions. The
products were synthesized in excellent yields within short reaction time and iden-
Nanotechnology, Arak University, Arak
8156‐88138, Iran
3
Correspondence
Mahdia Hamidinasab and Mohammad Ali
Bodaghifard, Department of Chemistry,
Faculty of Science, Arak University, Arak
38156‐88138, Iran.
Email: mahdiahamidinasab@yahoo.com;
mbodaghi2007@yahoo.com
1
13
tified using elemental analysis, FT‐IR, H NMR and C NMR spectroscopies.
KEYWORDS
ionic liquid, hybrid nanostructures, heterogeneous catalysis, green synthesis, phthalazine‐dione
[
8–14]
1
| INTRODUCTION
chemical reactions.
The use of magnetic nanoparti-
cles (MNPs) has attracted particular interest in chemical
reactions owing to their super‐paramagnetic behavior
and easy separation from the reaction media, large sur-
Heterocyclic compounds containing two active
pharmacophores including fused pyrazolo and
phthalazine moieties have properties such as antican-
face area, low toxicity, good stability and possible
[1–3]
[4]
[5]
[10,14]
cer,
anticonvulsant, antiflammatory and antimi-
functionalization.
However, the magnetic nanoparti-
[6,7]
crobial activity.
cles are unstable over longer periods of time and tend to
aggregate into large clusters. Encapsulation of magnetic
nanoparticles with a suitable passive material or porous
materials such as polymer, silica and titana is an effective
way to improve their chemical stability and prevent their
Multicomponent reactions (MCRs), in which three or
more different compounds react to give a single product
(so‐called domino), are one of the most convenient and
cost‐effective synthesis methods for preparation of vital
and pharmaceutically important heterocyclic compounds.
As a result, MCRs cut the reaction time and simplify
purification.
Nanocatalysis is a developed field in green chemistry
which involves the use of nanoscale materials as homog-
enous and heterogeneous catalysts for a variety of
[
11–15]
aggregations.
From the initial use of ionic liquids (ILs), which are
made up of cationic and anionic components, they have
found applications in various fields such as environmen-
tally friendly solvents and catalysis. Ionic liquids are
capable of restricting many of the negative effects of the
1
of 12
© 2019 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc
Appl Organometal Chem. 2019;e5386.
https://doi.org/10.1002/aoc.5386

HAMIDINASAB ET AL.
2 of 12
conventional organic solvents or other catalysts during
catalytic reactions and have successfully been used in var-
ious catalytic areas affording high catalytic activity.
(nano‐NiFe O @TiO –ILPip) as an efficient hybrid
nanocatalyst under green conditions.
2
4
2
[
16]
Unfortunately, the difficulty of their recovery and
extreme viscosity have restrained their application in cat-
2 | RESULTS AND DISCUSSION
[17,18]
alytic reactions.
Therefore, the heterogenization of
ILs on appropriate porous carriers or suitable magnetic
nanoparticles would be a viable and appealing approach
to fabricate an efficient solid catalyst with superior activ-
In this study, ionic liquid‐base tag was grafted onto nickel
ferrite nanoparticles for the preparation of an efficient
and heterogeneous magnetic nanocatalyst. We found that
these nanoparticles act as an effective hybrid catalyst in
the synthesis of biologically active phthalazine‐trione
derivatives.
[11–14,19]
ity and stability.
Furthermore, heterogenized ILs
on magnetic nanoparticles have found remarkable appli-
cations, such as adsorbents for magnetic solid‐phase
[20]
extraction of sulfonylurea herbicides,
adsorbents for
magnetic dispersive solid‐phase extraction of cephalospo-
[
21]
[22]
rins
and removal of anionic dye from water.
2.1 | Preparation and characterization of
novel nano‐NiFe O @TiO –ILPip as a
Based on the above considerations, the main purpose
of this research is the preparation of a hybrid magnetic
nanostructure (MNPs@TiO –ILPip) with both basic and
2
4
2
catalyst
2
ionic liquid counterparts, allowing the favorable combi-
nation of their properties. To develop the green proce-
dures for the synthesis of valuable heterocyclic
compounds, herein an environmentally benign protocol
is investigated for the synthesis of some phthalazine‐
The schematic preparation of MNPs@TiO –ILPip is pre-
2
sented in Scheme 2. The prepared catalyst was character-
ized by various standard techniques, including Fourier
transform infrared (FT‐IR) spectroscopy, field emission
scanning electron microscopy (FE‐SEM), energy disper-
sive X‐ray spectroscopy (EDS), EDS map scan, vibrating
sample magnetometer (VSM), X‐ray powder diffraction
(XRD), thermogravimetric analysis (TGA) and
Brunauer–Emmett–Teller surface area analysis (BET).
[23–25]
trione derivatives,
of phthalhydrazide, malononitrile and aldehydes
Scheme 1) in the presence of ionic liquid base
via the three‐component reaction
(
grafted onto TiO ‐coated nickel‐ferrite nanoparticles
2
SCHEME 1 The synthetic pathway for
preparation of 3‐amino‐1‐aryl‐5,10‐dioxo‐
1
H‐pyrazolo[1,2‐b]phthalazine‐2‐
carbonitrile derivatives in the presence of
nano‐NiFe @TiO –ILPip particles
2
O
4
2
SCHEME 2 Preparation of hybrid
MNPs@TiO –ILPip
2

3
of 12
HAMIDINASAB ET AL.
The FT‐IR spectra of bare NiFe O4 MNPs,
stretching vibration of metal at octahedral M–O and
2
[
26]
NiFe O @TiO MNPs, nano‐NiFe O @TiO ‐PrCl, nano‐
tetrahedral M–O sites.
1400 and 798 cm in curves b–e are assigned to the
The weak absorption bands at
2
4
2
2
4
2
−
1
NiFe O @TiO ‐4APip and nano‐NiFe O @TiO –ILPip
2
4
2
2
4
2
−
1
[27,28]
that were recorded in the range of 400–4000 cm are
shown in Figure 1. As can be seen in curve (a), the spec-
trum of NiFe O nanoparticles shows strong absorption
stretching vibration of Ti–O–Ti.
The weak band at
−
1
1644 cm
and the broad band in the range of
−
1
3200–3600 cm are due to twisting vibration mode of
H–O–H adsorbed in the titana shell and stretching vibra-
2
4
−
1
bands around 401 and 601 cm corresponding to the
2 4 2 4 2
FIGURE 1 The Fourier‐transform infrared spectroscopy (FT‐IR) spectra of (a) nano‐NiFe O , (b) nano‐NiFe O @TiO , (c) nano‐
NiFe @TiO –PrCl, (d) nano‐NiFe @TiO –4APip and (e) nano‐NiFe @TiO –ILPip.
2
O
4
2
2
O
4
2
2
O
4
2
SCHEME 3 Preparation of 2,2,6,6‐
tetramethyl‐N‐[3‐(trimethoxysilyl)propyl]
piperidin‐4‐amine
FIGURE 2 The FT‐IR spectra of (a) (3‐chloropropyl)trimethoxysilane, (b) 2,2,6,6‐tetramethyl‐N‐(3‐(trimethoxysilyl)propyl)piperidin‐4‐
amine and (c) 2,2,6,6‐tetramethylpiperidin‐4‐amine.

HAMIDINASAB ET AL.
4 of 12
−
1
tion mode of Ti–O, respectively. The presence of the
anchored alkyl groups is confirmed by the weak aliphatic
C–H symmetric and asymmetric stretching vibrations at
1400 cm (curves c–e). In curve e, the strong bending
−
1
band at 1444 cm is attributed to anchored CH groups
on the final MNPs catalyst. In curve c, absorption bonds
at 1040 and 1122 cm
3
−
1
−1
2
920 and 2977 cm
and bending vibrations around
correspond to the stretching
FIGURE 3 The field emission scanning
electron microscopy (FE‐SEM) image of
nano‐NiFe O @TiO –ILPip
2 4 2
2 4 2
FIGURE 4 The energy‐dispersive X‐ray spectroscopy (EDS) spectrum of nano‐NiFe O @TiO –ILPip particles

5
of 12
HAMIDINASAB ET AL.
[
29,30]
vibration of Ti–O–Si and Si–O, respectively.
The NH
spherical with regular shape and have a mean diameter
of about 34 nm.
bending and C–N stretching bands appear at 1591 and
−
1
1
010 cm in curves d and e, respectively.
In order to prove the preparation
nano‐NiFe O @TiO –4APip, and the existence of the
Figure 4 shows the EDS of nano‐NiFe O @TiO –ILPip
2
4
2
of
particles. The presence of Fe, Ni, Ti, Si, N, C, O and I
atoms in the EDs spectrum is shown. Also, the EDS
map scan of nano‐NiFe O @TiO –ILPip particles
2
4
2
tetramethylpiperidine group in this structure, the com-
2
4
2
pound 2,2,6,6‐tetramethyl‐N‐(3‐(trimethoxysilyl)propyl)
(Figure 5) shows the excellent dispersion of the present
piperidin‐4‐amine
was
separately
synthesized
elements on the surface of the MNP catalyst. These
(Scheme 3).
The
FT‐IR
spectra
of
(3‐chloropropyl)
trimethoxysilane, 2,2,6,6‐tetramethyl‐N‐[3‐(trimethoxy-
silyl)propyl]piperidin‐4‐amine and 2,2,6,6‐tetramethylpi-
peridin‐4‐amine are presented in Figure 2. As shown in
−
1
1
curve b, the NH absorption bands at 3272 and 3346 cm
2
−
(Figure 2, curve c) and C–Cl absorption band at 805 cm
(
Figure 2, curve a) are omitted and new stretching
−
1
absorption bands appear at 3425 cm
1
(NH) and
−
1
100 cm (C–N). The results confirm the successful
grafting of functional groups onto the surface of the pre-
pared nanostructure.
Figure 3 shows the FE‐SEM image of nano‐NiFe O @-
FIGURE 6 The XRD patterns of (a) NiFe O nanoparticles and
2
4
2 4
TiO –ILPip nanostructure. The particles are almost
2 4 2
(b) nano‐NiFe O @TiO –ILPip particles
2
2 4 2
FIGURE 5 The EDS map scan of nano‐NiFe O @TiO –ILPip particles

HAMIDINASAB ET AL.
6 of 12
results
confirm
the
successful
formation
of
is found that the particle diameter is about 39 nm, which
is in good agreement with FE‐SEM analysis (Figure 3).
The TGA in Figure 7 shows the stability of the nano‐
NiFe O @TiO –ILPip catalyst. As shown, the initial 3%
nano‐NiFe O @TiO –ILPip catalyst.
2
4
2
The X‐ray diffraction patterns of the synthesized
NiFe O4 nanoparticles and nano‐NiFe O @TiO –ILPip
2
2
4
2
2
4
2
particles are shown in Figure 6. Several diffraction peaks
appeared at (111), (220), (311), (222), (400), (422), (511),
weight loss from room temperature to about 200°C, is
due to the removal of physically adsorbed solvent and
surface hydroxyl groups (Figure 7). The major weight loss
(19%) beyond 200°C to nearly 700°C is attributed to the
decomposition of the organic moieties within the
nanocatalyst structure. Therefore, the catalyst shows rea-
sonable stability up to 200°C and it is safe to carry out the
reaction under heterogeneous conditions.
(
440) and (533) miller planes, which confirms the cubic
[31,32]
crystal structure of NiFe O nanoparticles
forms with the JCPDS file (no. 44‐1485) standard.
and con-
2
4
[
26]
The peak at 2θ = 26.6° indicates the formation of a TiO2
layer in the structure of nano‐NiFe O @TiO –ILPip parti-
2
4
2
[31]
cles (Figure 6b). 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°
The magnetic properties of nanoparticles were charac-
terized using a VSM (Figure 8). The typical room temper-
ature magnetization curves a and b refer to NiFe O
2
4
MNPs and NiFe O @TiO –ILPip. The hysteresis curve
2
4
2
allows determination of the coercivity (H ), remanent
c
(311 plane) is selected to calculate the crystallite size. It
magnetization (M ) and saturation magnetization (M ).
r
s
FIGURE 7 The thermogravimetric
analysis (TGA) curve of nano‐
NiFe O @TiO –ILPip particles
2 4 2
FIGURE 8 Magnetic hysteresis loops of (a) NiFe
2
O
4
MNPs and (b) nano‐NiFe
2
O
4
@TiO
2
–ILPip particles

7
of 12
HAMIDINASAB ET AL.
FIGURE 9
N
2
physisorption isotherms
and pore size distribution (inset) of nano‐
NiFe @TiO –ILPip particles
2
O
4
2
TABLE 1 The optimization of reaction conditions for synthesis of 3‐amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile
a
derivatives
b
Entry
Catalyst (mg)
Solvent
Temperature (°C)
Time
Yield (%)
1
2
3
4
5
6
7
8
9
PTSA (20)
EtOH
EtOH
EtOH
EtOH
Reflux
24 h
30
76
86
89
80
75
46
80
85
85
75
85
85
97
96
90
70
53
30
Piperidine (20)
Reflux
8 h
2,2,6,6‐Tetramethyl‐4‐amino piperidine (20)
Reflux
6 h
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
Nano‐NiFe
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
4
4
4
4
4
4
4
4
4
4
@TiO
@TiO
@TiO
@TiO
@TiO
@TiO
@TiO
@TiO
@TiO
@TiO
2
2
2
2
2
2
2
2
2
2
–ILPip (10)
–ILPip (10)
–ILPip (10)
–ILPip (10)
–ILPip (10)
–ILPip (10)
–ILPip (10)
–ILPip (10)
–ILPip (10)
–ILPip (10)
Reflux
2.5 h
24 h
CHCl
3
Reflux
H
2
O
Reflux
10 h
Toluene
Reflux
24 h
No solvent
No solvent
No solvent
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
EtOH
Room temperature
24 h
70
14 h
10
11
12
13
14
15
16
17
18
19
100
70
10 h
1.5 h
30 min
30 min
10 min
10 min
45 min
4 h
90
110
90
Nano‐NiFe
2
O
4
@TiO
2
–ILPip (20)
Nano‐NiFe
Nano‐NiFe
2
2
O
4
4
@TiO
2
–ILPip (30)
90
O
@TiO
2
–4‐APip (20)
90
NiFe
2
O
4
(20)
90
No catalyst
No catalyst
90
7 h
Reflux
24 h
Note. The bold entry is for optimized reaction condition.
a
Reaction conditions: malononitrile, 1.5 mmol; phthalhydrazide, 1 mmol; 4‐chlorobenzaldehyde, 1 mmol; and nanocatalyst.
b
Isolated yield.

HAMIDINASAB ET AL.
8 of 12
The magnetization of sample could be completely satu-
reaction to synthesize the desired product was tested
(Table 1). The basic catalysts are superior to acidic cata-
lysts (Table 1, entries 1–3).
rated at high fields of up to ±8000.0 Oe and the M of
s
−
1
samples changes from 35.1 to 10.8 emu g owing to the
formation of nano‐NiFe O @TiO –ILPip catalyst. The
The model reaction was carried out in several solvents
2
4
2
hysteresis loops show the super paramagnetic behavior
such as CHCl , EtOH, toluene, PEG400 and H O under
3
2
of the NiFe O and NiFe O @TiO –ILPip particles in
reflux and also under solvent‐free conditions in the pres-
ence of IL‐based nanocatalyst (Table 1). As shown in
Table 1, it was found that conventional heating at 90°C
and the use of PEG400 as a green solvent is more efficient
than other conditions (Table 1, entry 12). The different
amounts of IL‐based nanocatalysts were loaded in the
model reaction. The optimal amount of catalyst was 20 mg
(Table 1, entry 14). To define the role and performance of
IL‐based nanocatalyst, the model reaction was carried out
with 2,2,6,6‐tetramethyl‐4‐amino piperidine, NiFe O
2
4
2
4
2
which M and H are close to zero (M = 119 and
r
c
r
−
1
[33]
8
0 emu g and H = 6.1 and 1.5 Oe, respectively).
c
The surface area of the prepared nanostructure was
achieved by BET analysis. N2 adsorption–desorption
isotherms of nano‐NiFe O @TiO –ILPip particles are
2
4
2
shown in Figure 9. The pore size distribution plot is
shown as an inset in the respective isotherm. The
nano‐NiFe O @TiO –ILPip particles exhibited type IV
2
4
2
adsorption–desorption isotherm with an elongated S‐type
2
4
2
hysteresis loop. The specific surface area (a ) 15.02 m /g
and nano‐NiFe O @TiO –ILPip, nano‐NiFe O @TiO –4‐
s
2
4
2
2
4
2
3
and total pore volume (ρ/ρ ° = 0.990) 0.115 cm /g were
APip and without the catalyst (Table 1, entries 3 and 16–
19). With respect to product yield and reaction time, the
best result was obtained using nano‐NiFe O @TiO –ILPip
observed.
2
4
2
as a hybrid nanocatalyst (Table 1, Entry 14).
2
3
.2 | Synthesis of
‐amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐
With optimized conditions in hand, the scope and
limitation of this method were investigated for the
desired product synthesis. The different aromatic alde-
hydes with electron‐donating and electron‐withdrawing
substituents (2a–m) were reacted with phthalhydrazide
(3) and malononitrile (1) to give the corresponding 3‐
amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b] phthalazine‐
2‐carbonitrile derivatives (4a–m) with good to excellent
yields (Table 2). To prove the benefits of prepared hybrid
catalysts such as simple conditions and excellent yields in
short reaction times, we compared its efficiency with that
b]phthalazine‐2‐carbonitrile derivatives
After characterization of the prepared hybrid nanostruc-
ture, its role as a catalyst was evaluated for synthesis of
3‐amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]
phthalazine‐2‐carbonitriles 4a–m (Scheme 1). The
one‐pot three‐component condensation reaction of
malononitrile (1, 1.5 mmol), 4‐chlorobenzaldehyde (2 g,
1
mmol) and phthalhydrazide (3, 1 mmol) as a model
TABLE 2 The synthesis of 3‐amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile derivatives using nano‐
a
2 4 2
NiFe O @TiO –ILPip
b
Entry
Aldehyde
Product
Time (min)
Yield (%)
M.p (°C), with reference
[
34]
1
2
3
4
5
6
7
8
9
3‐Nitrobenzaldehyde
4a
4b
4c
4d
4e
4f
35
45
35
30
25
25
10
15
15
45
45
60
70
93
95
93
95
93
95
97
95
96
89
85
90
85
265
258
[35]
4‐Nitrobenzaldehyde
3‐Nitro‐4‐hydroxy‐benzaldehyde
Benzaldehyde
259
[
[
[
[
[
[
[
[
[
[
34]
34]
36]
34]
37]
34]
38]
36]
34]
36]
265
252
267
270
255
269
255
265
247
235
2‐Chlorobenzaldehyde
3‐Chlorobenzaldehyde
4‐Chlorobenzaldehyde
2,4‐Dichlorobenzaldehyde
4‐Bromobenzaldehyde
2‐Methoxybenzaldehyde
3‐Methoxybenzaldehyde
4‐Methoxybenzaldehyde
3,4‐Dimethoxybenzaldehyde
4g
4h
4i
1
1
1
1
0
1
2
3
4j
4k
4l
4m
a
Reaction conditions: malononitrile, 1.5 mmol; phthalhydrazide, 1 mmol; 4‐dichlorobenzaldehyde, 1 mmol; and nanocatalyst, 20 mg.
b
Isolated yield.

9
of 12
HAMIDINASAB ET AL.
of other reported catalysts for synthesis of 3‐amino‐1‐aryl‐
,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile
derivatives in the literature (Table 3). As can be seen, this
hybrid nanocatalyst is superior to other catalysts.
The proposed mechanism of the reaction is illustrated
in Scheme 4. As the initiation step, malononitrile (1)
gives malononitryl anion (1′) assisted by base moiety of
catalyst and the carbonyl group activated by coordination
with the ionic moiety of the catalyst (Scheme 4). Then the
arylidenemalononitrile intermediate (2′) formed by
standard Knoevenagel condensation of malononitrile
anion and aldehyde (2). The subsequent Michael‐type
addition of phthalhydrazide (3) to the intermediate (2′),
followed by cyclization (3′) and tautomerization (4′),
5
[
38,44]
affords the corresponding products (4).
2.3 | Catalyst recovery and reusability
To investigate the recovery and recyclability of the catalyst
for green chemistry and commercial applications, the
TABLE 3 The comparison of ionic liquid‐based hybrid nanocatalyst with other catalysts described in the literature for synthesis of 3‐
a
amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile derivatives via three‐component condensation reaction
b
Entry Catalyst
Condition
CH OH (reflux)
Solvent‐free (100°C)
2–1′‐Methylimidazolium‐3‐yl‐1‐ethyl sulfate (0.05% mol) [Bpy]BF (70°C)
Time (min) Yield (%)
Reference
[
[
[
[
[
[
[
[
[
[
35]
34]
37]
39]
36]
40]
41]
42]
43]
15]
1
2
3
4
5
6
7
8
9
1
1
STA–amine–Si‐MNPs (10 mg)
Fe3 − xTi @SiO @urea MNPs (30 mg)
3
27
10
96
96
89
91
96
94
95
90
98
82
97
x
O
4
2
4
120
168
60
PTSA
Et N (20% mol)
No catalyst
CuFe @SiO
CAN (5% mol)
NaHCO
PbO nanoparticles (5% mol)
Nano‐NiFe @TiO –ILPip (20)
[bmim]Br (100°C)
EtOH (50°C), MW
Glycerol (80°C)
3
50
2
O
4
2
@C
3
‐Imid–C
4
SO
3
–PW (60 mg)
Solvent‐free (120°C)
PEG 400 (100°C)
Solvent‐free (120°C)
Solvent‐free (80°C)
PEG 400 (90°C)
10
50
3
30
0
1
15
2
O
4
2
10
Present work
Note. The presented work in the article is highlighted in bold format.
a
Reaction conditions: malononitrile, phthalhydrazide, 4‐chlorobenzaldehyde and catalyst.
b
isolated yield.
SCHEME 4 The plausible mechanism for synthesis of 3‐amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitriles in the
presence of nano‐NiFe @TiO –ILPip particles as a hybrid catalyst
2
O
4
2

HAMIDINASAB ET AL.
10 of 12
FIGURE 10 (a) The recycling experiment diagram, (b) TGA curve, (c) FT‐IR spectrum and (d) FE‐SEM image of recycled nano‐
NiFe @TiO –ILPip catalyst after five runs
2
O
4
2
three‐component reaction of malononitrile (1.5 mmol),
phthalhydrazide (1 mmol) and 4‐chlorobenzaldehyde
separation of hybrid catalyst with an external magnet,
catalyst reusability without considerable loss of its perfor-
mance and green reaction conditions are the main and
remarkable advantages of the described protocol.
(
1 mmol) in the presence of nano‐NiFe O @TiO –ILPip
2
4
2
catalyst (20 mg) was evaluated. After completion of the
reaction, the nanocatalyst was easily separated using an
external magnet, washed with EtOH and double‐distilled
water, and then dried. Experiments revealed almost the
same catalytic activity of recycled nanocatalyst without sig-
nificant loss of activity. As can be seen, the TGA curve
3.1 | Experimental section
3.1.1 | Chemicals and apparatus
(Figure 10b), FT‐IR spectrum (Figure 10c) and FE‐SEM
image (Figure 10d) of the nanocatalyst after five runs con-
firmed its structure stability and no change in size and
morphology was observed.
All chemicals were purchased from Merck or Fluka
Chemical Company 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 was performed on UV‐active
aluminum‐backed plates of silica gel. FT‐IR spectra were
recorded on a Bruker Alpha spectrophotometer in the
3
| CONCLUSIONS
A novel and efficient bifunctional IL‐based magnetically
separable hybrid nanomaterial was prepared and
characterized. The prepared hybrid catalyst revealed good
catalytic activity in the synthesis of some vital
−
1
1
region 400–4000 cm using pressed KBr disks. H and
1
3
C‐NMR spectra were recorded on a Brucker Avance
1
1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile derivatives.
spectrometer operating at 300 and 75 MHz for H and
13
The hybrid catalyst (NiFe O @TiO –ILPip) could be
C‐NMR, respectively, in DMSO‐d6 with TMS as an
2
4
2
reused five times without a significant decrease in its cat-
alytic activity. The high isolated yield of pure products,
good thermal and chemical stability of nanocatalyst, easy
internal standard. X‐ray diffraction was performed on a
Philips PW1730 Cu‐Kα radiation of wavelength 1.54 Å.
Thermal gravimetric analysis data for nano‐

11 of 12
HAMIDINASAB ET AL.
NiFe O @TiO –ILPip were recorded on a Netzsch Pro-
3.1.6 | Selected spectroscopic and physical
and data of products
2
4
2
teus System under an N atmosphere at a heating rate
2
−
1
of 10°C min . The FE‐SEM and EDS measurement were
carried out by a Mira III TESCAN‐XMU. The hysteresis
loop was measured at room temperature using a vibrating
sample magnetometer (model 7300 VSM system, Lake
Shore Cryotronic Inc., Westerville, OH, USA). The N2
adsorption–desorption (BET) was analyzed by SIBATA
apparatus, 1100‐SA with adsorption of nitrogen at 77 K.
3
‐Amino‐1‐(3‐nitrophenyl)‐5,10‐dioxo‐5,10‐dihydro‐1H‐
pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile (4a)
−
1
Yellow powder; IR (KBr) (ʋmax, cm ): 3364, 3244, 3193,
030, 2199, 1685, 1664, 1604, 1562, 1443, 1373; δH
3
(
300 MHz, DMSO‐d ) 6.16 (1H, s, CH), 7.47–8.24
6
(
10H, m, ArH and NH ); δ (75 MHz, DMSO‐d ) 60.7,
2
C
6
6
1
2.5, 116.4, 122.3, 123.8, 127.1, 127.7, 128.9, 129.5, 130.6,
34.2, 135.0, 141.2, 148.4, 151.5, 154.3, 157.2.
3
.1.2 | Preparation of the nano‐NiFe
3
‐Amino‐1‐(4‐hydroxy‐3‐nitrophenyl)‐5,10‐dioxo‐5,10‐
O @TiO –PrCl
2
4
2
dihydro‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile
4c)
Light brown powder; IR (KBr) (ʋmax, cm ): 3357, 3295,
186, 3033, 2200, 1664, 1630, 1570, 1436, 1377; δH
300 MHz, DMSO‐d ) 5.99 (1H, s, CH), 6.92–8.05 (9H, m,
(
These nanoparticles were synthesized based on our previ-
ously reported procedure.
−
1
[15]
3
(
6
ArH and NH ), 10.93 (1H, s, OH); δ (75 MHz, DMSO‐d )
2
C
6
3
.1.3 | Preparation of the nano‐NiFe
60.7, 62.3, 116.4, 119.7, 124.5, 127.1, 127.6, 129.0, 129.3,
O @TiO –4‐APip
2
4
2
129.8, 134.18, 134.3, 135.0, 137.2, 151.3, 152.3, 157.1.
A 1 g aliquot of NiFe O @TiO ‐PrCl was dispersed in dry
2
4
2
3
‐Amino‐1‐(2‐chlorophenyl)‐5,10‐dioxo‐5,10‐dihydro‐
toluene (30 ml) for 45 min. Then 10 mmol 2,2,6,6‐
tetramethyl‐4‐amino piperidine (0.86 ml) was added to
this suspension. The mixture was refluxed for 24 h. The
nano‐NiFe O @TiO ‐Pr‐Pip‐4‐amine was isolated using
1
H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile (4e)
−
1
Yellow powder; IR (KBr) (ʋmax, cm ): 3372, 3235, 3175,
025, 2209, 1683, 1659, 1567, 1437, 1382; δH (300 MHz,
3
2
4
2
DMSO‐d ) 6.27 (1H, s, CH), 7.03–8.08 (10H, m, ArH and
NH ); Anal. calcd for C H ClN O : C, 61.64; H, 3.16; Cl,
1
6
an external magnet, rinsed with dry toluene (3 × 10 ml)
and dried at 80°C.
2
18 11
4 2
0.11; N, 15.97; found: C, 61.71; H, 3.21; Cl, 10.15; N, 16.05.
3
‐Amino‐1‐(2,4‐dichlorophenyl)‐5,10‐dioxo‐5,10‐dihydro‐
3
.1.4 | Preparation of the nano‐NiFe
1
H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile (4h)
O @TiO –ILPip
2
4
2
−1
Yellow powder; IR (KBr) (ʋmax, cm ): 3371, 3305, 3262,
3
192, 3030, 2197, 1658, 1563, 1437, 1381; δH (300 MHz,
A 1 g aliquot of NiFe O @TiO –4‐APip was dispersed in
dried toluene (30 ml) for 45 min, Then 10 mmol methyl
iodide (1 ml) was added to the suspension. The mixture
2
4
2
DMSO‐d ) 6.25 (1H, s, CH), 6.25–8.07 (9H, m, ArH and
NH ); δ (75 MHz, DMSO‐d ) 59.7, 70.2, 116.0, 125.5,
6
2
C
6
127.1, 127.8, 128.4, 128.7, 129.2, 122.6, 132.7, 132.9,
was mixed for 24 h. The MNPs@TiO –ILPip was isolated
2
134.0, 134.3, 135.2, 151.7, 154.0, 157.1.
by external magnet and rinsed with dry toluene
(3 × 10 ml) and dried at 80°C.
3
‐Amino‐1‐(3,4‐dimethoxyphenyl)‐5,10‐dioxo‐5,10‐
dihydro‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitrile
4m)
Yellow powder; IR (KBr) (ʋmax, cm ): 3370, 3292, 3262,
033, 2184, 1658, 1602, 1567, 1437, 1379; δH (300 MHz,
DMSO‐d ) 3.55 (6H, s, OCH ), 5.88 (1H, s, CH), 6.68–8.04
(
3
.1.5 | General procedure for the synthesis
of 3‐amino‐1‐aryl‐5,10‐dioxo‐1H‐pyrazolo
1,2‐b]phthalazine‐2‐carbonitriles
−
1
3
[
6
3
(
5
1
9H, m, ArH and NH ); δ (75 MHz, DMSO‐d ) 55.9,
6.1, 61.8, 63.4, 111.2, 111.9, 116.6, 119.9, 126.9, 127.6,
29.2, 131.0, 134.0, 135.05, 149.1, 149.2, 150.9, 154.1, 157.1.
2
C
6
A
mixture of malononitrile (0.1 g, 1.5 mmol),
phthalhydrazide (0.18 g, 1 mmol), aldehyde (1 mmol),
and nanocatalyst (20 mg) was heated at 80°C, in
PEG400 (5 ml) as a solvent. The reaction progress was
followed using thin‐layer chromatography technique.
After cooling, PEG400 was removed by distilled water
ACKNOWLEDGEMENTS
(
3 × 10 ml) and the catalyst separated easily by an exter-
We clarify that the authors listed on the manuscript are
not employed by a government agency that has a primary
nal magnet. The products were recrystallized in ethanol.

HAMIDINASAB ET AL.
12 of 12
function other than research and education. Also, the
authors are not submitting this manuscript as an official
representative or on behalf of the government. This work
was supported by the research council of Arak University.
There are no financial conflicts of interest to disclose.
[21] H. Sahebi, E. Konoz, A. Ezabadi, New J. Chem. 2019, 43, 13554.
[22] J. Fu, H. Zang, Y. Wang, S. Li, T. Chen, X. Liu, Ind. Eng. Chem.
Res. 2012, 51, 6377.
[
[
[
[
[
[
[
[
[
23] M. A. Zolfigol, M. Mokhlesi, S. Farahmand, J. Iran. Chem. Soc.
013, 10, 577.
2
24] A. Khoraamabadi‐Zad, M. Azadmanesh, R. Karamian, M.
Asadbegy, M. Akbari, RSC Adv. 2014, 4, 47721.
ORCID
25] O. S. Zaky, M. A. Selim, M. M. Ebied, K. U. Sadek, J. Heterocycl.
Chem. 2019, 19. https://doi.org/10.1002/jhet
Mahdia Hamidinasab
279
Mohammad Ali Bodaghifard https://orcid.org/0000-0001-
732-4746
Akbar Mobinikhaledi
282
https://orcid.org/0000-0002-4281-
26] R. Sen, P. Jain, R. Patidar, S. Srivastava, R. Rana, N. Gupta,
8
Mater. Today 2015, 2, 3750.
27] M. Chellappa, U. Anjaneyulu, G. Manivasagam, U.
9
Vijayalakshmi, Int. J. Nanomed. 2015, 10, 31.
https://orcid.org/0000-0002-9732-
28] Z. Li, H. Wang, X. Wei, X. Liu, Y. Yang, W. Jiang, J. Alloy.
Comp. 2016, 659, 240.
7
29] A. Mirabedini, S. M. Mirabedini, A. A. Babalou, S. Pazokifard,
REFERENCES
Prog. Org. Coatings. 2011, 72, 453.
30] D. Kannaiyan, S. T. Kochuveedu, Y. H. Jang, Y. J. Jang, J. Y.
[
[
[
1] M. Behalo, I. Gad El‐karim, R. Rafaat, J. Heterocycl. Chem.
017, 54, 3591.
2] N. Wasfy, A. Aly, M. Behalo, N. Mohemed, Der Pharma Chem.
013, 5, 82.
Lee, J. Lee, J. Lee, J. Kim, Polymer 2010, 2, 490.
2
31] H. Kim, D. Kim, B. Kwak, G. Han, M. Um, M. Kang, Chem.
Eng. J. 2014, 243, 272.
2
[32] K. Nejati, R. Zabihi, Chem. Cent. J. 2012, 6, 23.
3] X. Zhang, Q.‐R. Zhang, H.‐M. Liu, D.‐Q. Xue, X.‐Y. Zhang, C.‐J.
Wang, L.‐Y. Ma, N. Zhu, P. He, K.‐P. Shao, P.‐J. Chen, Y.‐F.
Gu, X.‐S. Zhang, C.‐F. Wang, C.‐H. Ji, Artic. Eur. J. Med. Chem.
[33] K. Petcharoen, A. Sirivat, Mater. Sci. Eng., B 2012, 177, 421.
[34] D. Azarifar, O. Badalkhani, Y. Abbasi, M. Hasanabadi, J. Iran.
Chem. Soc. 2017, 14, 403.
2
014, 85, 235.
[
[
[
4] S. Grasso, G. De Sarro, A. De Sarro, N. Micale, M. Zappalà, G.
Puja, M. Baraldi, C. De Micheli, J. Med. Chem. 2000, 43, 2851.
[35] P. Arora, J. K. Rajput, Appl. Organomet. Chem. 2018, 32, e4001.
[
[
[
[
[
[
36] M. R. Nabid, S. J. Tabatabaei Rezaei, R. Ghahremanzadeh, A.
5] Da‐Ch. Liu, G.‐H. Gong, Ch‐X. Wei, X.‐J. Jin, Zh‐Sh. Quan,
Bioorg. Med. Chem. Lett. 2016, 26, 1576.
Bazgir, Ultrason. Sonochem. 2010, 17, 159.
37] Y. Wan, C. Wang, X. Zhang, J. Shi, S. Huang, G. Liu, L. Chen,
6] B. Glišić, L. Senerovic, P. Comba, H. Wadepohl, A. Veselinovic,
D. R. Milivojevic, M. I. Djuran, J. Nikodinovic‐Runic, J. Inorg.
Biochem. 2016, 155, 115.
L. Zhao, H. Wang, J. Het. Chem. 2015, 51, E77.
38] H. Kefayati, S. Amlashi, R. Kazemi‐Rad, C. R. Chim. 2014, 17,
8
94.
39] R. Ghahremanzadeh, G. Shakibaei, A. Bazgir, Synlett 2008,
008, 1129.
[
7] P. Sagar Vijay Kumar, L. Suresh, G. V. P. Chandramouli,
J. Saudi Chem. Soc. 2017, 21, 306.
2
[
8] A. Amoozadeh, S. Golian, S. Rahmani, RSC Adv. 2015, 5, 45974.
40] A. Mulik, M. Deshmukh, D. Chandam, P. Patil, S. Jagdale, D.
[
9] V. Polshettiwar, T. Asefa, Synthesis and Applications, Hoboken,
New Jersey: John Wiley & Sons 2013.
Patil, S. Sangpal, Der Pharma Chem. 2013, 5, 19.
41] N. Hosseininasab, A. Davoodnia, F. Rostami‐Charati, A.
Khojastehnezhad, Russ. J. Gen. Chem. 2017, 87, 2436.
[
[
[
[
[
10] M. Gawande, R. Luque, R. Zboril, ChemCatChem 2014, 6, 3312.
11] W. Xie, H. Wang, Renewable Energy 2020, 145, 1709.
12] W. Xie, F. Wan, Chem. Eng. J. 2019, 365, 40.
[42] M. Kidwai, R. Chauhan, J. Heterocycl. Chem. 2014, 51, 1689.
[43] A. Vafaee, A. Davoodnia, M. Pordel, M. R. Bozorgmehr, Orient.
J. Chem. 2015, 31, 2153.
13] W. Xie, X. Zang, Food Chem. 2018, 257, 15.
[44] N. Azgomi, M. Mokhtary, J. Mol. Catal. A: Chem. 2015, 398, 58.
14] M. A. Bodaghifard, M. Hamidinasab, N. Ahadi, Curr. Org.
Chem. 2018, 22, 234.
[
[
[
15] M. Hamidinasab, A. Mobinikhaledi, ChemistrySelect 2019, 4, 17.
16] R. Vekariya, J. Mol. Liq. 2017, 227, 44.
How to cite this article: Hamidinasab M,
Bodaghifard MA, Mobinikhaledi A. Green
synthesis of 1H‐pyrazolo[1,2‐b]phthalazine‐2‐
carbonitrile derivatives using a new bifunctional
base–ionic liquid hybrid magnetic nanocatalyst.
Appl Organometal Chem. 2019;e5386. https://doi.
org/10.1002/aoc.5386
17] M. Vafaeezadeh, Z. Bahrami Dizicheh, M. Mahmoodi
Hashemi, Catal. Commun. 2013, 41, 96.
[
[
18] W. Cheng, X. Chen, J. Sun, J. Wang, S. Zhang, Catal. Today
2
013, 200, 117.
19] R. Hosseinzadeh‐Khanmiri, Y. Kamel, Z. Keshvari, A.
Mobaraki, G. H. Shahverdizadeh, E. Vessally, M. Babazadeh,
Appl. Organomet. Chem. 2018, 32, 1.
[
20] Z. He, D. Liu, Z. Zhou, P. Wang, J. Sep. Sci. 2013, 36, 3226.