Magnetic nanoparticles Fe3O4-supported guanidine as an efficient nanocatalyst for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones under solvent-free conditions

Article abstract of DOI:10.1007/s11164-013-1480-x

Here, the application of guanidine supported on magnetic nanoparticles Fe₃O₄ (MNPs-guanidine) as a novel magnetically separable base nanocatalyst is described. We have investigated the application of this new catalyst for the synthes

Full text of DOI:10.1007/s11164-013-1480-x

Res Chem Intermed
DOI 10.1007/s11164-013-1480-x
Magnetic nanoparticles Fe3O4-supported guanidine
as an efficient nanocatalyst for the synthesis
of 2H-indazolo[2,1-b]phthalazine-triones
under solvent-free conditions
•
Bahareh Atashkar Amin Rostami
•
•
Hoshyar Gholami Bahman Tahmasbi
Received: 12 July 2013 / Accepted: 12 November 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Here, the application of guanidine supported on magnetic nanoparticles
Fe3O4 (MNPs-guanidine) as a novel magnetically separable base nanocatalyst is
described. We have investigated the application of this new catalyst for the syn-
thesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives from the three-compo-
nent, one-pot condensation reaction of phthalhydrazide, cyclic 1,3-dicarbonyl, and
aromatic aldehydes under solvent-free conditions. The products were obtained in
short reaction times with good to high yields. The supported catalyst could be
simply separated and recovered from the reaction mixture with the assistance of an
external magnet and reused 18 times with little loss of activity.
Keywords Magnetic nanoparticles Fe3O4 Á Guanidine Á Basic nanocatalyst Á
2H-Indazolo[2,1-b]phthalazine-trione Á Phthalhydrazide Á Cyclic 1 Á
3-dicarbonyl Á Aromatic aldehydes Á Solvent-free
Introduction
Nanoparticles have recently emerged as efficient alternatives for the immobilization
of homogeneous catalysts and as catalysts themselves [1, 2]. However, particles
with diameters of less than 100 nm are difficult to separate by filtration techniques.
In such cases, expensive ultracentrifugation is often the only way to separate the
product and catalyst. This drawback can be overcome by using magnetic
nanoparticles (MNPs), which can be easily removed from the reaction mixture by
magnetic separation. Magnetic separation of the magnetic nanoparticles is simple,
economical and promising for industrial applications [3]. Among the various
magnetic nanoparticles under investigation, Fe3O4 nanoparticles are arguably the
B. Atashkar Á A. Rostami (&) Á H. Gholami Á B. Tahmasbi
Department of Chemistry, Faculty of Science, University of Kurdistan, 6617715143 Sanandaj, Iran
e-mail: a_rostami372@yahoo.com
123

B. Atashkar et al.
most extensively studied as the core magnetic support because of their simple
synthesis, low cost, and relatively large magnetic susceptibility of Fe3O4 SPNs [4–
10].
During the recent increasing interest in the field of organocatalysis, guanidines
have also been shown to act as organic bases and nucleophilic catalysts [11, 12].
However, the major disadvantage of catalysts based on guanidines is their
separation from the product, which needs solid–liquid or liquid–liquid techniques in
many reactions. This drawback can be overcome by immobilizing these catalysts on
MNPs, which can be easily removed from the reaction mixture by magnetic
separation.
Among a large variety of N-containing heterocyclic compounds, heterocycles
containing hydrazine moieties as ‘fusion site’ have received considerable attention
because of their pharmacological properties and clinical applications [13–18].
Moreover, fused phthalazines have been found to be effective for the inhibition of
p38 MAP kinase [19], selective binding of GABA receptor [20], and as an anti-
anxiety drug [21], antitumor agent [22], and high-affinity ligand to the a2d-1 subunit
of calcium channel [23]. Fused phthalazine derivatives also possess some biological
activities such as anticonvulsant [24], cardiotonic [25], and vasorelaxant [26].
Although many methods have been reported for the synthesis of phthalazines
fused with indazole [27–42], the development of an efficient, versatile and green
method for the preparation of fused phthalazine with indazole is an active ongoing
research area.
Experimental
General
The materials were purchased from Merck and Fluka and were used without any
additional purification. All reactions were monitored by thin layer chromatography
(TLC) on gel F254 plates. Melting points were obtained in open capillary tubes and
were also measured on the Electrothermal 9100 apparatus. The X-ray powder
diffraction (XRD) data were collected on an X’ Pert MPD Philips diffractometer.
The SEM image was obtained by VEGA TESCAN. The thermogravimetric analysis
¨
(TGA) was carried out on a Bahr STA 503 instrument (Germany) under air
atmosphere, at a heating rate of 10 °C/min. The magnetic measurements were
carried out in a vibrating sample magnetometer (VSM, BHV-55; Riken, Japan) at
room temperature.
General procedure for synthesis of 2H-indazolo[2,1-b]phthalazine-triones
MNPs-guanidine (30 mg) was added to a mixture of aromatic aldehyde (1 mmol),
phthalhydrazide (1 mmol), and cyclic 1,3-diones compound (1 mmol), and the
mixture was stirred and heated in an oil bath at 70 °C for an appropriate time.
Completion of the reaction was indicated by TLC (n-hexane/ethylacetate 60:40).
After the indicated reaction time, the reaction mixture was cooled to room
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Magnetic nanoparticles Fe3O4-supported guanidine
temperature. CH2Cl2 (2 9 5 mL) was added and the catalyst was separated by an
external magnet. The resulting solution was concentrated under reduced pressure to
afford the essentially pure products. In some cases, for further purification, the
product was recrystalized from ethanol.
Spectral data of selected products are given below.
3,4-dihydro-3,3-dimethyl-13-(3-methoxyphenyl)-2H-indazolo[2,1-b]phthalazine-
1,6,11(13H)-trione (4d) Green crystal, Mp: 206–208 °C; IR (KBr): 1,659, 1,625,
1
1,354, 1,310, 1,273 cm-1; H NMR (250.1 MHz, CDCl3) d: 1.21 (s, 6H), 2.34 (s,
2H), 3.22 and 3.40 (AB system, JHH = 19.0 Hz, 2H), 3.78 (s, 3H), 6.42 (s, 1H),
2
6.73–6.83 (m, 1H), 6.90–7.02 (m, 2H); 7.19–7.29 (m, 1H) 7.84–7.87 (2H, m),
8.26–8.37 (2H, m). 13C NMR: (62.9 MHz, CDCl3) d: 28.5, 28.7, 34.7, 38.0, 50.9,
55.2, 64.8, 113.1, 113.8, 118.5, 119.4, 127.7, 128.0, 129.0, 129.7, 133.5, 134.5,
138.0, 150.8, 154.3, 156,0, 159.7, 192.2; MS (EI, 70 eV, m/z %): 402 (M?, 15),
380(11), 295(100), 273(14), 104(6), 76(6).
3,4-dihydro-3,3-dimethyl-13-(2-nitrophenyl)-2H-indazolo[2,1-b]phthalazine-
1,6,11(13H)-trione (4l) Yellow crystal, Mp: 236–238 °C; IR (KBr): 1,679, 1,648,
1
1,500, 1,530, 1,352, 1,305, 1,262 cm-1; H NMR (250.1 MHz, CDCl3) d: 1.19 (s,
2
3H), 1.21 (s, 3H), 2.32 (s, 2H), 3.25 and 3.39 (AB system, JHH = 19.1 Hz, 2H),
7.33–7.58 (m, 4H), 7.85–7.95 (m, 3H), 8.24–8.38 (m, 2H). 13C NMR: (62.9 MHz,
CDCl3) d: 28.5, 28.6, 34.7, 38.1, 50.8, 60.6, 116.9, 125.2,127.8,128.2, 128.6,129.0,
129.5,130.7,133.1, 133.8,134.7,149.3,152.0, 154,4,156.0,191.9; MS (EI, 70 eV, m/
z %): 417 (M?, 15), 400 (100), 370 (37), 299 (75), 104 (55), 76 (60).
13-(3-(2,2-dimethyl-1,6,11-trioxo-2,3,4,6,11,13-hexahydro-1H-indazolo[1,2-
b]phthalazin-13yl)phenyl)-2,2-dimethyl-2,3-dihydro-1H-indazolo[1,2-b]phthal-
azine-4,6,11(13H)-trione (4o) Yellow powder, Mp: 284–286 °C; IR (KBr):
1
1,663, 1,628, 1,602, 1,359, 1,308, 1,264 cm-1; H NMR (250.1 MHz, CDCl3)
2
d: 1.15 (s, 6H), 1.20 (s, 6H), 2.18 and 2.37 (AB system, JHH = 16.2 Hz, 4H),
2
3.20 and 3.33 (AB system, JHH = 18.8 Hz, 4H), 6.42 (s, 2H), 7.26–7.46 (m,
4H), 7.65–7.80 (m, 4H), 8.17–8.29 (m, 4H); 13C NMR (62.9 MHz, CDCl3) d:
28.4, 28.8, 34.6, 37.9, 50.9, 64.2, 118.0, 125.9, 127.6, 127.9, 129.0, 133.4,
134.3, 136.5, 151.1, 156.0, 192.0; MS (EI, 70 eV, m/z %): 666 (M?, 15), 664
(15), 295 (100), 279 (20), 239 (10).
Results and discussion
We recently reported the synthesis, characterization, and catalytic properties of
magnetic nanoparticle-supported guanidine (MNPs-guanidine) in the cyanosilyla-
tion of carbonyl compounds [43], and the synthesis of a,b-unsaturated carbonyl
compounds, chromene derivatives [44], a-hydroxyphosphonates, and a-acet-
oxyphosphonates [45]. In this research, we report catalytic application of MNPs-
guanidine as a magnetically heterogeneous nanocatalyst for the synthesis of 2H-
indazolo[2,1-b]phthalazine-trione derivatives from one-pot, three-component con-
densation of phthalhydrazide, aromatic aldehydes, and cyclic 1,3-dione compounds
under solvent-free conditions at 70 °C (Scheme 1).
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B. Atashkar et al.
N H 2
O
O
O
Fe3O4NP
N
N H 2
Si
MNPs-guanidine
O
O
O
Ar
O
O
O
N
MNPs-guanidine (Cat.)
Solvent-Free, 70 °C
NH
NH
ArCHO
N
R
R
R
O
R
2 (a-u)
1
4(a-u)
3
R = Me (a-p)
R = H (q-u)
Scheme 1 The synthesis of 2H-indazolo [2,1-b] phthalazine-trione derivatives in the presence of MNPs-
guanidine
Table 1 Optimization of the amounts of MNPs-guanidine for synthesis of 2H-indazolo[2,1-b]phthal-
azine-trione from benzaldehyde (1 mmol), phthalhydrazide (1 mmol), and dimedone (1 mmol) under
solvent-free conditions at 70 °C
Entry
Catalyst (mg, mol%)
Time/min
Yield (%)
1
2
3
4
5
6
7
8
9
None
[1,440
30
No reaction
MNPs-guanidine (60, 4.68)
MNPs-guanidine (50, 3.9)
MNPs-guanidine (40, 3.12)
MNPs-guanidine (30, 2.34)
MNPs-guanidine (25, 1.95)
MNPs (5.4, 2.34)
94
94
93
93
50
30
93
93
32
33
35
60
240
60
SiO2-guanidine (25, 2.34)
Guanidinium chloride (2.2, 2.34)
45
In order to optimize the reaction conditions, we evaluated the influence of
different amounts of catalyst on the model reaction between benzaldehyde
(1 mmol), phthalhydrazide (1 mmol), and dimedone (1 mmol) under solvent-free
conditions at 70 °C in terms of time and product yield (Table 1). In the absence of
catalyst, no reaction was observed even after prolonged reaction time (entry 1,
Table 1). An amount of 30 mg of catalyst was found to be ideal for the synthesis of
2H-indazolo [2,1-b] phthalazine-triones (entry 5, Table 1). In order to compare the
catalytic activity of magnetic nanoparticles Fe3O4 (MNPs), guanidine and silica-
supported guanidine in the model reaction were also tested under the same reaction
conditions (entries 7–9). The results show that the most active catalyst is MNPs-
guanidine.
We then examined the generality of the reaction in the optimal conditions. The
results from the reactions of phthalhydrazide 1, aromatic aldehydes 2, and cyclic
123

Magnetic nanoparticles Fe3O4-supported guanidine
Table 2 Synthesis of 1H-indazolo [1,2-b] phthalazine-triones catalyzed by MNPs-guanidine
b
Entry
ArCHO
R
Product
Time (min)
Yield (%)a
Mp/ °C Lit.
1
2
C6H5CHO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
4a
4b
4c
4d
4e
4f
35
60
40
40
35
30
45
55
45
65
40
50
40
45
45
30
45
45
40
50
40
93
91
90
87
89
88
85
87
93
91
90
82
86
83
80
84
86
88
90
83
89
206–207 [22, 31]
242–244 [23]
228–230 [27]
206–208 [35]
220–222 [24]
186–188 [24]
224–226 [27]
263–265 [22]
261–263 [22, 31]
220–221 [25, 31]
219–221 [28]
236–238 [35]
270–272 [22, 31]
222–224 [22, 31]
284–286 [35]
251–253 [24, 31]
223–224 [24]
244–246 [24]
251–253 [24]
252–254 [28]
259–261 [24]
2-CH3C6H4CHO
4-CH3C6H4CHO
3-CH3OC6H4CHO
4-CH3OC6H4CHO
3,4-(CH3O)2C6H4CHO
3-Br C6H4CHO
2-Cl C6H4CHO
4-Cl C6H4CHO
2,4-(Cl)2C6H4CHO
4-FC6H4CHO
3
4
5
6
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
2-NO2C6H4CHO
3-NO2C6H4CHO
4-NO2C6H4CHO
Isophthaladehydec
2-naphtaldehyde
C6H5CHO
4m
4n
4o
4p
4q
4r
4-CH3C6H4CHO
4-CH3OC6H4CHO
4-NO2C6H4CHO
4-FC6H4CHO
H
H
4s
4t
H
H
4u
Reaction conditions: aromaticaldehydes (1 mmol),phthalhydrazide (1 mmol),dimedone (1 mmol) and
MNPs-Guanidine (30 mg), 70 °C, solvent-free
a
Isolated yields
b
References for spectroscopic data and melting point of products
c
Reaction conditions: aromatic aldehydes (1.1 mmol), phthalhydrazide (2 mmol), dimedone (2 mmol)
and MNPs-Guanidine (60 mg), 100 °C, solvent-free
1,3-diones 3, in the presence of a catalytic amount of MNPs-guanidine at 70 °C
under solvent-free conditions are shown in Table 2. Various aromatic aldehydes
bearing either electron-donating or electron-withdrawing groups on the aromatic
ring were investigated. Substitution groups on the aromatic ring have no obvious
effect on the yields and reaction times under the above optimal conditions. In all
cases, the reactions gave the corresponding products in short reaction times and
good to excellent yields.
We examined the recycling of MNPs-guanidine for the synthesis of 2,2-dimethyl-
13-(4-methylphenyl)-2,3-dihydro-1H-indazoleo[2,1-b]phthalazine-4,6,11(13H)-tri-
one. After the completion of the reaction, CH2Cl2 (5 mL) was added, the catalyst
was separated easily and rapidly from the product by exposure to an external
magnet (within 5 s), and the reaction solution was decanted. The remaining
magnetic nanoparticles were further washed with the CH2Cl2, dried under vacuum,
and subjected to the next run. The efficient separation using this method minimizes
123

B. Atashkar et al.
105
100
95
90
85
80
75
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Run Number
Fig. 1 Recycling of MNPs-guanidine for condensation reaction of phthalhydrazide, benzaldehyde, and
dimedone at 70 °C under solvent-free conditions for 35 min
the loss of catalyst during separation. The recycled catalyst was used for up 18 runs
without any significant loss of activity (Fig. 1).
Conclusions
In conclusion, the MNPs-guanidine is easily synthesized and can efficiently catalyze
the green synthesis of 2H-indazolo[1,2-b]phthalazine-triones via a one-pot, three-
component condensation reaction of aromatic aldehydes, phthalhydrazide, and
cyclic 1,3-diones under solvent-free conditions at 70 °C. The catalyst can be
recycled and reused for 18 times with little loss of activity.
Acknowledgment We are grateful to the University of Kurdistan Research Councils for partial support
of this work.
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