A highly efficient and recyclable cobalt ferrite chitosan sulfonic acid magnetic nanoparticle for one-pot, four-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones

Article abstract of DOI:10.1039/c4ra09984b

A highly efficient magnetic CoFe₂O₄ chitosan sulfonic acid nanoparticle (CoFe₂O₄-CS-SO₃H) was prepared and applied for one-pot, four-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones by condensation of phthalic anhydride, hydrazinium hydroxide, 1,3-cyclohexanedione and aldehydes under solvent-free conditions at 80 °C. The magnetic nanocatalyst could be readily recovered by applying an external magnet and recycled several times without significant loss of its catalytic activity. This journal is

Full text of DOI:10.1039/c4ra09984b

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• Graphical Abstract:
A highly efficient and recyclable cobalt ferrite
chitosan sulfonic acid magnetic nanoparticle for
one-pot,
four-component
synthesis
of
2H-indazolo[2,1-b]phthalazine-triones
Xiao-Na Zhao, Guo-Fei Hu, Meng Tang, Tai-Tai Shi,
Xiao-Li Guo, Tao-Tao Li, Zhan-Hui Zhang*
A
novel magnetical cobalt ferrite chitosan sulfonic acid
(CoFe2O4-CS-SO3H) was prepared and identified as an efficient
catalyst for synthesis of 2H-indazolo[2,1-b]phthalazine-triones by
one-pot, four-component reaction.

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A highly efficient and recyclable cobalt ferrite chitosan sulfonic acid
magnetic nanoparticle for one-pot, four-component synthesis of
2H-indazolo[2,1-b]phthalazine-triones
XiaoꢀNa Zhao, GuoꢀFei Hu, Meng Tang, TaiꢀTai Shi, XiaoꢀLi Guo, TaoꢀTao Li, ZhanꢀHui Zhang*
College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China
Eꢀmail: zhanhui@126.com; Fax: +86 31180787431
Abstract
A highly efficient magnetic CoFe2O4 chitosan sulfonic acid nanoparticle (CoFe2O4ꢀCSꢀSO3H) was
prepared
and
applied
for
oneꢀpot,
fourꢀcomponent
synthesis
of
2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones by condensation of phthalic anhydride, hydrazinium
hydroxide,1,3ꢀcyclohexanedione and aldehydes under solventꢀfree conditions at 80 ºC. The magnetic
nanocatalyst could be readily recovered by applying an external magnet and recycled for several
times without significant loss of its catalytic activity.
Keywords:
Magnetic nanoparticle; Chitosan; Sulfonic acid; Heterogeneous catalyst; Multiꢀcomponent reaction,
2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones
1

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Introduction
Heterogeneous catalysts have gained much importance in recent years due to environmental
and economic considerations. These heterogeneous catalysts are advantageous over homogeneous
catalysts as they can be recovered from the reaction mixture through filtration or centrifugation and
reused after activation, thereby making the process economically viable.1 Compared to other
supports such as silica, alumina, activated carbon, metal oxides, zeolites, clays, polymers, magnetic
nanoparticles (MNPs) are arguably the most extensively investigated and emerged as excellent and
ideal supports with significant industrial potential due to their extraordinary properties such as large
specific surface area, readily disersed in reaction solution, and easy functionalization with various
groups.2 Their superꢀparamagnetic character makes them be effective and easily recovered from the
reaction system using an external permanent magnet, which eliminates the necessity of tedious
filtration, centrifugation or membrane separation steps and enhances the product purity. Thus, a
wide range of the magnetically recyclable nanocatalysts with excellent catalytic activities have been
developed and applied in versatile organic reactions.3 Among the various MNPs as the core
magnetic supports, cobalt ferrite is one of the most versatile magnetic materials as it has moderate
saturation magnetization, high chemical stability and mechanical strength and can be prepared by
simple methods.4
A wide range of organic reactions depend on the use of protic acids as catalysts. However,
difficulties in the separation of the catalyst from the product and generation of enormous quantities
of waste have been limited the applications of these liquid acids. There are many reports on the
preparation and applications of solidꢀsupported acid.5 Recently, chitosan (CS) as one kind of the
widely used bioꢀbased polymers has been attarcing more and more attention.6 It is natural, nonꢀtoxic,
biodegradable, hydrophilic and reproducible molecule, and widely used in many industrial and
manufacturing processes. Chitosan has also been used as effective catalyst in organic synthesis,
2

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however, it can not be separated easily from water due to its low density.7 It is the alkaline
deacetylated product of chitin and comprises a great quantity of hydroxyl and amino groups, which
make it be attached on magnetic nanoparticles ions through chelate mechanism without using any
linkers.8 Thus, combining the attractive properties of magnetic CoFe2O4 and chitosan, the
development of novel, highly active and reusable immobilized catalysts by further functionalization
is therefore an interesting challenge.
Due to growing concerns over the adverse influence of organic solvents on the environment,
solventꢀfree organic reactions have also attracted tremendous attention. Meanwhile, the construction
of structurally diverse and complex molecular from simple and readily available starting materials
while combining economic aspects with environmental ones is especially important in modern
synthetic organic and medicinal chemistry. Multicomponent reactions (MCRs) involving domino
processes have emerged as powerful tools to reach this near ideal goal. Such transformations reduce
the consumption of catalyst, solvent, time, labor, and energy, thereby minimizing waste compared to
the corresponding series of individual reactions.9 One of these MCRs is the preparation of
indazolo[2,1ꢀb]phthalazineꢀtrione derivatives. These compounds have been shown to possess a
broad spectrum of biological activites.10 They have proved to be promising luminescence materials
and fluorescence probes.11 The synthesis of indazolo[2,1ꢀb]phthalazineꢀtriones can be carried out by
threeꢀcomponent condensation of phthalhydrazide, dimedone, and aromatic aldehydes12ꢀ18 or
fourꢀcomponent reaction of phthalic anhydride, hydrazinium hydroxide, dimedone and aromatic
aldehydes in the presence of various catalysts such as sulfuric acidꢀmodified PEGꢀ6000
(PEGꢀOSO3H),19 Ce(SO4)2·4H2O,20 ZnO nanoparticles,21 celluloseꢀSO3H,22 starch sulfate,23 ionic
liquid N,N,N,Nꢀtetramethylguanidiniumacetate [TMG][Ac],24 1ꢀbutylꢀ3ꢀmethylimidazolium
bromide ([Bmim]Br),25 and 2ꢀpyrrolidonium hydrogensulfate ([Hnhp][HSO4]).26 Despite being
effective, some of these methods involve the use of transtition metal as catalyst, extended reaction
times, unsatisfactory yields of the products, or require additional instruments such as ultra sound.
3

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Therefore, the development of novel, more efficient, cheaper, and more easily recovered catalysts
for this fourꢀcomponent reaction remains highly desirable.
Considering the above subjects and in continuation of our efforts toward the design of magnetic
nanocatalysts27 and sustainable synthesis development,28 we wish to report here a new type of
magnetic CoFe2O4 chitosan sulfonic acid nanoparticle (CoFe2O4ꢀCSꢀSO3H) as a powerful catalyst
for the green and efficient synthesis of indazolo[2,1ꢀb]phthalazineꢀtriones by oneꢀpot,
fourꢀcomponent reaction of phthalic anhydride, hydrazinium hydroxide,1,3ꢀcyclohexanedione and
aldehydes (Scheme 1).
Scheme 1. Oneꢀpot fourꢀcomponent synthesis of 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones
Results and discussion
Preparation and characterization of CoFe2O4-CS-SO3H
The magnetic CoFe2O4 chitosan sulfonic acid nanoparticle (CoFe2O4ꢀCSꢀSO3H) was prepared
by two steps as presented in Scheme 2. The first step is the preparation of magnetic
CoFe2O4ꢀchitosan nanopaticles by oneꢀpot synthesis method. Chitosan was firstly dissolved in 3%
acetic acid solution, then aqueous solution of FeCl3·6H2O and CoCl2·6H2O was added. The mixture
was stirred strongly for 2 h, and then NaOH solution was added. The formed CoFe2O4 has weak
interaction with amino and hydroxyl groups in chitosan. Then, the CoFe2O4ꢀCS served as supported
for the immobilization of SO3H group by the reaction of amino and hydroxyl groups with
chlorosulfonic acid in CH2Cl2 led to sulfonic acidꢀfunctionalized magnetic CoFe2O4 nanoparticles
(CoFe2O4ꢀCSꢀSO3H). It was found that the content of sulfonic acid was 0.50 mmol/g determined by
acidꢀbase titration. Also, the pH of this solid acid (10 %, w/v) was measured using pH meter at 25
ºC. At first 0.5 g solid sulfonic acid was dispersed in 5 ml distilled water by ultrasonic bath for 1 h,
4

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then measured and found to be 1.25.
Scheme 2. Synthesis of CoFe2O4ꢀCSꢀSO3H
XRD analysis. The XRD pattern of the sample is shown in Figure 1. As seen in Fig. 1,
CoFe2O4ꢀCSꢀSO3H show typical characteristic peaks at the 2θ values of 18.2, 29.0, 35.5, 43.6, 57.7
and 61.7 with the corresponding reflection of (111), (220), (311), (400), (511) and (440) crystal
planes. The observed diffraction peaks agree with the cubic structure of CoFe2O4 (JCPDS 221086),4
suggesting that the coating process did not result in the phase change of CoFe2O4.
Fig. 1. XRD pattern of CoFe2O4ꢀCSꢀSO3H
TEM and EDX elemental analysis. The TEM images of the synthesized CoFe2O4ꢀCSꢀSO3H are
shown in Figures 2. The images confirmed the formation of singleꢀphase CoFe2O4 nanoparticles,
with spherical morphology. The average nanopartical diameter of CoFe2O4ꢀCSꢀSO3H was estimated
5

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to be ca. 50ꢀ60 nm based on the TEM image, which is also in accordance with the result calculated
by the Scherrer formula. The presence of C, O, Fe, Co and S atoms was observed in the EDX
spectrum (Fig. 3).
Fig. 2. TEM images of CoFe2O4ꢀCSꢀSO3H
F e
S
C o
O
F e
C o
F e
C
C o
2
4
6
8
K e V
Fig. 3. EDS spectrum of CoFe2O4ꢀCSꢀSO3H
FT-IR analysis. Fig. 4 shows the Fourier transform infrared (FTIR) spectra of CoFe2O4 (a),
CoFe2O4ꢀCS (b) and CoFe2O4ꢀCSꢀSO3H (c). The Co–O and Fe–O stretching vibration near 593
cm−1 was observed in figure 4(a), (b) and (c). The significant features observed for figure 4(b) are
6

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the appearance of the peaks at 1074, 1300, 1606, 2891, 3427 cm−1 corresponding to CꢀOH, CꢀN,
NꢀH, CꢀH, and OH stretching models of the chitosan molecules. The three new bands appered in
figure 4(c) at 650, 1090 and 1160 cmꢀ1 corresponding to the O=S=O asymmetic and symmetric
stretching vibrations and SꢀO stretching vibration of the sulfonic acid groups.
Fig. 4. FTꢀIR spectra of (a) CoFe2O4, (b) CoFe2O4ꢀCS, and (c) fresh and (d) reused
CoFe2O4ꢀCSꢀSO3H
The magnetic properties. The magnetic properties of the samples CoFe2O4 and
CoFe2O4ꢀCSꢀSO3H were measured at room temperature using a vibrating sample magnetometery
(VSM). As shown in Fig. 5, the value of magnetic saturation (Msat) for CoFe2O4ꢀCSꢀSO3H is about
41.5 emu gꢀ1, which is lower than that of bare CoFe2O4 nanoparticles (ca. 49.6 emu gꢀ1). The
reason should be ascribed to the existence of CSꢀSO3H hybrid material shells on CoFe2O4 cores.
Even with this reduction in the saturation magnetization, the prepared catalyst could still be
7

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efficiently separated with the help of an external magnetic force.
Fig. 5. Magnetization curves of CoFe2O4 (a) and CoFe2O4ꢀCSꢀSO3H (b)
Catalytic activity of CoFe2O4-SC-SO3H
In order to evaluate the catalytic reactivity of CoFe2O4@SCꢀSO3H, oneꢀpot fourꢀcomponent
reaction of phthalic anhydride, hydrazinium hydroxide, 5,5ꢀdimethyl 1,3ꢀcyclohexanedione and
4ꢀchlorobenzaldehyde was chosen the model reaction for our investigation, and the results are
displayed in Table 1. In the absence of the catalyst, only a trace amount of the desired product was
observed even after 1 h (Table 1, entry 1), which domonstrated that catalyst plays an important role
in this reaction. Several reaction conditions were tested in order to identify the optimized conditions.
Firstly, the influence of different solvents on the reaction was examined, and a good yield was
obtained with EtOH (Table 1, entry 5). Toluene, CH3CN, AcOEt, H2O, PEG 400, glycerol,
[bmin]BF4, and [bmin]PF6 were found to be inferior. To our delight, when the reaction was carried
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o
out under solventꢀfree condition at 80 C, the yield could be improved to 95%. Other experinental
parmeters such as temperature and amount of catalyst were also optimized. It was observed that
only 5% yield of product was obtained at room temperature. The yield of the desired product was
greatly improved with the increasing of temperature. The best yield was observed when the reaction
was performed at 80 oC. Increasing or decreasing the temperature from 80 oC led to a decrease in the
yield (Table 1, entries 13 and 15). With respect to the catalyst loading, 0.5 mol% (10 mg ) was
found to be optimal. When the loading of catalyst was lowered to 0.4 mol%, the reaction would
proceed incompletely (Table 1, entry 17). Any further addition of catalyst had no positive effect on
the overall yield of product. Therefore, on the basis of the above experiments, the most suitable
reaction conditions for this oneꢀpot process included CoFe2O4ꢀSCꢀSO3H (0.5 mol%, 10 mg) as the
catalyst under solventꢀfree conditions at 80 oC (Table 1, entry 14).
Table 1 Optimization of reaction conditionsa
Entry
Catalyst (mol%)
no
Solvent
no
Temp. (oC)
80
Time (min) Yield (%)b
60
10
10
10
10
10
10
10
10
10
10
trace
7
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Toluene
CH3CN
AcOEt
EtOH
80
2
reflux
reflux
reflux
80
33
29
52
10
18
21
31
19
6
3
4
5
H2O
6
PEG 400
Glycerol
80
7
80
8
[bmin]BF4 80
9
[bmin]PF6
no
80
25
10
11
9

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0.5
0.5
0.5
0.5
0.25
0.4
1.0
no
no
no
no
no
no
no
50
60
80
100
80
80
80
6
6
6
6
6
6
6
77
82
95
90
30
60
95
12
13
14
15
16
17
18
a
Experimental conditions: phthalic anhydride (1 mmol), hydrazinium hydroxide (1.2 mmol),
4ꢀchlorobenzaldehyde (1 mmol) and 5,5ꢀdimethyl 1,3ꢀcyclohexanedione (1 mmol), solvent ( 5 ml).
b Isolated yields.
After optimizing of the reaction conditions, the generality and scope of the reaction were
investigated. As illustrated in Table 2, a variety of aromatic aldehydes bearing electronꢀrich and
electronꢀpoor groups at either orthoꢀ, metaꢀ or paraꢀpositions of the aromatic ring were smoothly
converted into 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones in high to excellent yields. A wide range of
synthetically useful functional groups including thioether, halide and trifluoromethyl groups
remained intact during the present reaction conditions. In addition, the presence of three methoxy
electron donating groups on the aromatic ring of the aldehyde performed well and afforded the
desired product in 90% yield. Also, heterocyclic aromatic aldehyde such as picolinaldehyde also
underwent efficient conversion into the targeted product in 86% yield. It should be noted that
aliphatic aldehyde such as cyclohexanecarbaldehyde was also compatible under these reaction
conditions and was successfully transformed into the desired products in 83% yield (entry 17).
Replacement of 5,5ꢀdimethyl 1,3ꢀcyclohexanedione with 1,3ꢀcyclohexanedion under identical
conditions also produced the expected products in high yields (Table 2, entries 18ꢀ22).
Table 2 Fourꢀcomponent synthesis of 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones catalyzed by
CoFe2O4ꢀCSꢀSO3Ha
Entry
Aldehydes
R
Product Time (min)
Yield (%)b
MP (ºC)
209ꢀ210 (208ꢀ209)18
219ꢀ220 (218ꢀ209)18
PhCHO
1
2
5a
Me
Me
7
90
92
4ꢀOMeC6H4CHO
5b
6
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4ꢀO(CH2)2MeC6H4CHO
4ꢀO(CH2)4MeC6H4CHO
2,3,4ꢀ(OMe)3C6H2CHO
4ꢀMeC6H4CHO
3
5c
5d
5e
5f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
7
7
8
6
6
7
6
8
7
6
6
6
6
91
89
90
93
91
86
89
90
91
95
89
93
93
159ꢀ160
4
165ꢀ166
5
184ꢀ185
229ꢀ230 (227ꢀ228)18
230ꢀ231 (229ꢀ231)14
271ꢀ222 (270ꢀ272)15
221ꢀ222 (220ꢀ222)18
269ꢀ270 (268ꢀ270)18
206ꢀ207 (204ꢀ206)18
260ꢀ262 (262ꢀ264)18
271ꢀ272 (270ꢀ272)18
225ꢀ226 (222ꢀ225)14
217ꢀ218 (215ꢀ217)25
6
4ꢀSMeC6H4CHO
2ꢀFC6H4CHO
7
5g
5h
5i
8
4ꢀFC6H4CHO
9
2ꢀClC6H4CHO
10
11
12
13
14
15
5j
3ꢀClC6H4CHO
5k
5l
4ꢀClC6H4CHO
3ꢀNO2C6H4CHO
4ꢀNO2C6H4CHO
4ꢀCF3C6H4CHO
5m
5n
5o
16
17
5p
5q
Me
Me
8
86
83
230ꢀ232 (229ꢀ231)15
10
220ꢀ222 (221ꢀ222)18
253ꢀ254 (254ꢀ255)13
243ꢀ245 (244ꢀ246)13
273ꢀ275 (272ꢀ273)12
4ꢀOMeC6H4CHO
4ꢀMeC6H4CHO
4ꢀClC6H4CHO
18
19
20
5r
5s
5t
H
H
H
7
7
7
91
94
92
21
22
5u
H
8
85
240ꢀ242
5v
H
8
88
206ꢀ208
a Reaction conditions: phthalic anhydride (1 mmol), hydrazinium hydroxide (1.1 mmol), aldehydes (1 mmol),
CoFe2O4@CSꢀSO3H (0.01 g), 80 oC.
b Isolated yield.
Recycling of the catalyst
The magnetic property of CoFe2O4@CSꢀSO3H facilitates efficient recovery of the catalyst from
the reaction mixture during workꢀup procedure. After completion of the reaction, ethyl acetate was
added to the reaction mixture. The catalyst was separated by a strong external permanent magnet,
washed with ethyl acetate to remove residual product, dried under vacuum, and reused directly for
the next cycle. The catalyst was used over five runs, and no significant loss of catalytic activity was
observed (Fig. 6). FTꢀIR images of fresh and recovered catalysts indicated that no significant change
had occurred. This indicates that CoFe2O4@CSꢀSO3H was very high chemical stable and can endure
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high temperature condition (Fig. 4).
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
Run
Fig. 6. The recycling of the catalyst
To compare the efficiency of our catalyst with some of the previously employed catalysts, we
have tabulated the results of these catalysts for the synthesis of product 5a in Table 3. As can be
seen in Table 3, the results clearly indicated that our catalyst is an equally or more efficient catalyst
for this fourꢀcompoent reaction.
Table 3 Comparison of our results with previously reported methods
Entry Catalyst
Reaction conditions Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
PEGꢀOSO3H (8 mol%)
solventꢀfree, 80 ºC
solventꢀfree, 125 ºC
solventꢀfree, 60 ºC
solventꢀfree, 60 ºC
solventꢀfree, 80 ºC
solventꢀfree, 80 ºC
13
6
8719
7820
9721
9122
8923
9224
9325
8826
Ce(SO4)2·4H2O (10 mol%)
ZnO (5 mol%)
5
celluloseꢀSO3H (4 mol%)
starch sulfate (0.8 mol%)
[TMG][Ac] (10 mol%)
[Bmim]Br (0.5 g)
7
7
15
ultrasonic irradiation 10
([Hnhp][HSO4]) (5 mol%)
solventꢀfree, 80 ºC
7
7
CoFe2O4ꢀSCꢀSO3H (0.5 mol%) solventꢀfree, 80 ºC
90 (this work)
Conclusions
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In summary, a nanosized magnetic CoFe2O4 chitosan sulfonic acid was prepared and characterized
by XRD, TEM, SEM, EDX and IR spectroscopy. The catalyst showed highly activity for oneꢀpot,
atomꢀeconomical syhthesis of 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones by fourꢀcomponent reaction of
phthalic anhydride, hydrazinium hydroxide,1,3ꢀcyclohexanedione and aldehydes. This simple and
environmentally benign catalysis proceeds under solventꢀfree conditions, requires short reaction
times, and provides products in high to excellent yields. The catalyst could be readily recovered by
applying an external magnet and recycled for several times without appreciable loss of its catalytic
activity, which demonstrated the value of the present CoFe2O4ꢀSCꢀSO3H as a green heterogeneous
catalyst with potential use for industrial applications.
Experimental
Materials and instruments
Chemicals were purchased from and used without further purification. The known products
were characterized by comparision of their spectral and physical data with those reported in the
1
literature. H NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded on a Bruker
DRXꢀ500 spectrometer in CDCl3 solution with TMS as an internal standard. Xꢀray power
diffraction (XRD) analysis was carried out on a PANalytical X’Pert Pro Xꢀray diffractometer. FTꢀIR
spectra were obtained with potassium bromide pellets on potassium bromide pellets in the range
400ꢀ4000 cmꢀ1 with a BrukerꢀTENSOR 27 spectrometer. Surface morphology and particle size were
studied using a Hitachi Sꢀ4800 SEM instrument. Transmission electron microscope (TEM) images
was obtained using Hitachi Hꢀ7650 microscope at 80 KV for characterization of the catalyst.
Elemental compositions were determined with a Hitachi Sꢀ4800 scanning electron microscope
equipped with an INCA 350 energy dispersive spectrometer (SEMꢀEDS) presenting a 133 eV
resolution at 5.9 keV. Melting points were determined using an Xꢀ4 apparatus and are uncorrected.
Elemental analyses were performed by using a Vario EL III CHNOS elemental analyzer.
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Preparation of magnetic CoFe2O4 chitosan sulfonic acid nanoparticle (CoFe2O4-CS-SO3H)
Chitosan coated CoFe2O4 nanoparticles (CoFe2O4ꢀCS) were prepared as follow: 1.50 g of
chitosan was dissolved in 3% acetic acid solution (100 ml) in a 500 ml threeꢀnecked flask equipped
with a stirrer and dropping funnel. Then, the aqueous solution of 2.70 g of FeCl3·6H2O and 1.19 g
of CoCl2·6H2O (50 ml) was slowly added into the mixture. The mixture was stirred strongly for 2 h,
and then NaOH (3 mol/L) solution was added until the pH increased to 12. The reaction mixture
was then continually stirred under refluxing condition for 1 h. After cooling the solution to room
temperature, the chitosan coated CoFe2O4 NPs were collected using a permanent magnet and
washed with water, ethanol, then dried under vacuum at 50 oC for 24 h.
CoFe2O4ꢀCSꢀSO3H was prepared by the reaction of CoFe2O4ꢀCS and chlorosulfonic acid.
Typically, a mixture of CoFe2O4ꢀCS (1.2 g) was suspended in dichloromethane (5 mL) in a 100 mL
round bottom flask equipped with a gas outlet tube and a dropping funnel containing a solution of
chlorosulfonic acid (2 mL) in dichloromethane (15 mL). The chlorosulfonic acid solution was added
dropꢀwise over a period of 30 min at 0 oC. After the addition was complete, the mixture was shaken
for 1 h until all HCl was removed from reaction vessel. Then, the product was separated by
magnetic decantation and washed with EtOH to remove unattached substrates. Finally, the obtained
CoFe2O4ꢀCSꢀSO3H NPs were dried under vacuum at 80 oC for 24 h.
General procedure for synthesis of amides
Aldehyde (1 mmol), 1,3ꢀdicarbonyl compounds (1 mmol), and CoFe2O4ꢀCSꢀSO3H (0.005
mol, 10 mg) was added to a mixture of hydrazinium hydroxide (1.2 mmol) and phthalic anhydride
(1 mmol). The reaction mixture was heated at 80 oC. After completion of the reaction (monitored by
TLC), the reaction mixture was cooled to room temperature and ethyl acetate (5 ml) was added. The
catalyst was separated by an external magnet, washed with ethyl acetate, dried and reꢀused for a
consecutive run under the same reaction conditions. Evaporation of the solvent of the filtrate under
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reduced pressure gave the crude product. The pure product was obtained by column chromatography
on silica gel with hexane/ethyl acetate.
Some selected spectra data for non-reported products
3,3-Dimethyl-13-(4-propoxy-phenyl)-2,3,4,13-tetrahydro-indazolo[1,2-b]phthalazine-1,6,11-tri
1
one (5c). Yellow needles; IR (KBr): 2953, 1667, 1366, 700 cmꢀ1; H NMR (CDCl3, 500 MHz) δ
0.93 (t, J = 7.0 Hz, 3H), d=1.23 (s, 3H), 1.25 (s, 3H), 1.73ꢀ1.79 (m, 2H), 2.37 (s, 2H), 3.26 and 3.44
(AB system, JAB = 19.0 Hz, 2H), 3.92 (t, J = 6.5 Hz, 2H), 6.44 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H),
7.34 (d, J = 8.5 Hz, 2H), 7.86ꢀ7.88 (m, 2H), 8.29ꢀ8.30 (m, 1H), 8.36ꢀ8.38 (m, 1H) ppm; 13C NMR
(CDCl3, 125MHz) δ 14.0, 22.4, 28.2, 28.5, 28.7, 28.9, 34.7, 38.1, 51.0, 64.6, 67.9, 114.6, 118.6,
127.7, 127.9, 128.0, 128.5, 129.0, 129.2, 133.5, 134.5, 150.7, 154.3, 156.1, 159.4, 192.3 ppm. Anal.
Calcd for C26H26N2O4: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.28; H, 5.89; N, 6.70; ESIꢀMS: m/z
= 431 (M+1)+.
3,3-Dimethyl-13-(4-pentyloxy-phenyl)-2,3,4,13-tetrahydro-indazolo[1,2-b]phthalazine-1,6,11-tr
1
ione (5d). Yellow needles; IR (KBr): 2961, 2363, 1659, 1358, 1312, 1250, 702 cmꢀ1; H NMR
(CDCl3, 500 MHz) δ 1.02 (t, J = 7.5 Hz, 3H), d=1.23 (s, 3H), 1.25 (s, 3H), 1.27ꢀ1.30 (m, 2H),
1.76ꢀ1.81 (m, 2H), 2.20 (s, 2H), 2.37 (s, 2H), 3.26 and 3.44 (AB system, JAB = 19.0 Hz, 2H), 3.89 (t,
J = 6.5 Hz, 2H), 6.44 (s, 1H), 6.87 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.86ꢀ7.88 (m, 2H),
8.29ꢀ8.30 (m, 1H), 8.36ꢀ8.38 (m, 1H) ppm; 13C NMR (CDCl3, 125MHz) δ 10.5, 22.5, 28.3, 28.5,
28.7, 29.7, 30.9, 34.7, 38.1, 51.0, 53.8, 64.6, 69.4, 118.7, 127.7, 127.9, 128.1, 128.5, 129.0, 129.2,
129.8, 133.5, 134.5, 150.8, 154.3, 156.1, 159.4, 192.3 ppm. Anal. Calcd for C28H30N2O4: C, 73.34;
H, 6.59; N, 6.11. Found: C, 73.53; H, 6.40; N, 5.92; ESIꢀMS: m/z = 459 (M+1)+.
3,3-Dimethyl-13-(2,3,4-trimethoxy-phenyl)-2,3,4,13-tetrahydro-indazolo[1,2-b]phthalazine-1,6,
1
11-trione (5e). Yellow needles; IR (KBr): 2967, 2654, 1665, 1364, 1285, 1098, 799 cmꢀ1; H NMR
(CDCl3, 500 MHz) δ 1.20 (s, 3H), 1.23 (s, 3H), 2.34 (d, J = 2.5 Hz, 2H), 3.26 and 3.42 (AB system,
JAB = 18.5 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 6.58 (s, 1H), 6.67 (d, J = 9.0 Hz, 1H),
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7.08 (d, J = 8.5 Hz, 1H), 7.86ꢀ7.88 (m, 2H), 8.29ꢀ8.31 (m, 1H), 8.38ꢀ8.40 (m, 1H) ppm; 13C NMR
(CDCl3, 125MHz) δ 28.4, 28.6, 30.9, 34.7, 38.1, 51.0, 55.8, 56.1, 60.6, 60.9, 62.0, 118.3, 127.6,
127.9, 129.0, 129.2, 133.4, 134.4, 142.1, 151.0, 152.0, 154.0, 154.1, 156.1, 157.2, 192.3 ppm. Anal.
Calcd for C26H26N2O6: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.51; H, 5.66; N, 6.07; ESIꢀMS: m/z
= 463 (M+1)+.
3,3-Dimethyl-13-(4-methylsulfanyl-phenyl)-2,3,4,13-tetrahydro-indazolo[1,2-b]phthalazine-1,6,
1
11-trione (5g). Yellow needles; IR (KBr): 2959, 2374, 1663, 1362, 1269, 698 cmꢀ1; H NMR
(CDCl3, 500 MHz) δ 1.23 (s, 6H), 2.36 (s, 2H), 2.46 (s, 3H), 3.26 and 3.43 (AB system, JAB = 19.0
Hz, 2H), 6.43 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.87ꢀ7.88 (m, 2H),
8.28ꢀ8.30 (m, 1H), 8.37ꢀ8.38 (m, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ 15.5, 28.3, 28.5, 28.7,
34.7, 38.1, 50.9, 64.6, 118.4, 126.6, 127.6, 127.7, 128.0, 129.0, 133.0, 133.6, 134.6, 136.0, 139.3,
151.0, 154.3, 156.0, 192.3 ppm. Anal. Calcd for C24H22N2O3S: C, 68.88; H, 5.30; N, 6.69. Found: C,
68.77; H, 5.51; N, 6.70; ESIꢀMS: m/z =419 (M+1)+.
13-Thiophen-2-yl-2,3,4,13-tetrahydro-indazolo[1,2-b]phthalazine-1,6,11-trione (5u). Yellow
needles; IR (KBr): 3295, 1640, 1549, 743 cmꢀ1; 1H NMR (CDCl3, 500 MHz) δ 2.39ꢀ2.43 (m, 2H)),
2.59ꢀ2.70 (m, 2H), 3.39ꢀ3.46 (m, 1H)), 3.66ꢀ3.73 (m, 1H), 6.93 (s, 1H), 7.09 (d, J = 4.5 Hz, 1H),
7.34 (d, J = 5.0 Hz, 1H), 7.42 (d, J = 3.5 Hz, 2H), 7.94ꢀ8.00 (m, 2H), 8.42ꢀ8.46 (m, 2H) ppm; 13C
NMR (CDCl3, 125 MHz) δ 22.3, 24.5, 29.7, 30.9, 36.9, 59.5, 118.5, 125.9, 127.1, 127.8, 128.1,
128.2, 133.6, 134.6, 138.8, 153.0, 154.4, 156.1, 192.5 ppm. Anal. Calcd for C19H14N2O3S: C, 65.13;
H, 4.03; N, 7.99. Found: C, 64.96; H, 3.90; N, 8.21; ESIꢀMS: m/z = 351 (M+1)+.
13-(5-Bromothiophen-2-yl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione
(5v). Yellow needles; IR (KBr): 3448, 1661, 1359, 1260, 1142, 1108, 1001, 801, 699 cmꢀ1; 1H NMR
(CDCl3, 500 MHz) δ 2.29ꢀ2.34 (m, 2H), 2.52ꢀ2.61 (m, 2H), 3.28ꢀ3.35 (m, 1H), 3.56ꢀ3.62 (m, 1H),
6.73 (s, 1H), 6.94 (d, J = 3.5 Hz, 1H), 7.06 (d, J = 4.5 Hz, 1H), 7.86ꢀ7.92 (m, 2H), 8.34ꢀ8.37 (m, 2H)
ppm; 13C NMR (CDCl3, 125MHz) δ 22.3, 24.5, 36.9, 59.5, 113.2, 117.7, 127.8, 128.2, 128.5, 128.8,
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128.9, 129.9, 133.8, 134.7, 140.1, 153.4, 154.4, 156.0, 192.4 ppm. Anal. Calcd for C19H13BrN2O3S:
C, 53.16; H, 3.05; N, 6.53. Found: C, 52.98; H, 2.96; N, 6.72; ESIꢀMS: m/z = 430 (M+1)+.
Acknowledgments
We are grateful for the financial support for this research from the National Natural Science
Foundation of China (No. 21272053).
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