Novel biocompatible core/shell Fe3O4?NFC?Co(ii) as a new catalyst in a multicomponent reaction: An efficient and sustainable methodology and novel reusable material for one-pot synthesis of 4: H -pyran and pyranopyrazole in aqueous media

Article abstract of DOI:10.1039/d0ra04698a

Today, due to the developing need for inexpensive catalysts, recyclable magnetic nanocatalysts immobilized on polysaccharides possess many advantages over classical heterogeneous catalysts. However, cellulose has been an appealing material in catalysis sc

Full text of DOI:10.1039/d0ra04698a

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Novel biocompatible core/shell Fe3O4@NFC@Co(II)
as a new catalyst in a multicomponent reaction: an
efficient and sustainable methodology and novel
reusable material for one-pot synthesis of 4H-
pyran and pyranopyrazole in aqueous media†
Cite this: RSC Adv., 2020, 10, 37086
a
a
b
*
and Hossein Eshghi
Pouya Ghamari Kargar,
Ghodsieh Bagherzade
Today, due to the developing need for inexpensive catalysts, recyclable magnetic nanocatalysts
immobilized on polysaccharides possess many advantages over classical heterogeneous catalysts.
However, cellulose has been an appealing material in catalysis science and technology. In this work, by
controlling the interaction between the inorganic complexes and the support material, we designed
a high activity nanostructured combination of a magnetic nanoparticle Fe3O4@NFC@Co(II) terminated
complex as a multi-nuclear catalyst. This protocol involves an environment friendly approach using
cobalt acetate. The magnetic nanostructure Fe3O4@NFC@Co(II) can be used as a novel, green, and
a powerful catalyst that demonstrates a short reaction time, high yield and easy procedure for the
cascade Knoevenagel–Michael-cyclocondensation reaction for the one-pot synthesis of 4H-pyrans and
pyranopyrazoles. The superparamagnetic nanocomposite could be conveniently separated by using an
external magnet. Moreover, the catalyst could be reused at least five times in new reaction runs without
a noticeable loss of activity. The prepared catalyst was characterized by FT-IR, XRD, VSM, FESEM, EDAX,
TEM, ICP, and TGA techniques. The experiments were achieved with good yields and implied that the
catalytic method was effective and convenient for heterocyclic synthesis.
Received 27th May 2020
Accepted 13th July 2020
DOI: 10.1039/d0ra04698a
rsc.li/rsc-advances
component reactions (MCR) in this area are a promising and
great success in green chemistry.4 In multi-component reac-
Introduction
tions, complex and valuable structures are synthesized very
quickly and efficiently over a short period without limits intro-
duced by intermediates. Therefore, by reducing the synthesis
steps compared to traditional methods, the reaction will be
faster and more efficient.5 MCRs are a special category of
organic reaction in which the product in question is created
during the step of combining raw materials. The interest and
effort from notable chemists towards multi-component reac-
tions has led to the development and advancement of multi-
component reactions to make them more responsive and opti-
mized. Therefore, partial reactions are considered to be the best
techniques in green chemistry. These reactions have become
increasingly important in organic and pharmaceutical chem-
istry and have become one of the most effective and economical
tools for the simultaneous synthesis of compounds.6,7 Pyrans
and pyranopyrazoles are a group of important heterocycles that
have a large number of natural compounds in their structure
and show different biological activity. Pyrans are widely used in
cosmetics, pigments, and medicinal chemistry.8–10 In addition,
its compounds and derivatives play an important role in the
biological-organic and chemical activities of biologics and are
widely used as the main nucleus of photochromic materials.11
In cascade reactions, several raw materials are produced in
several stages without the separation of any intermediates,
changing reaction conditions, or adding reagents. Clean reac-
tion conditions, high atomic economy and efficient complexity
in one step are some advantages of this reaction.1,2 Organic
syntheses with a focus on “green chemistry”, nd this attractive.
Interest in this subject for several years has led to the emergence
of new and benign methods such as water solvent syntheses,
multicomponent reactions and reusable catalysts to save
resources and energy.3 Green chemistry emphasizes the devel-
opment of environmentally benign chemical processes and
technologies. The most important criterion for the efficiency
and feasibility of a process is to minimize the number of
synthesis and purication steps as much as possible. Multi-
aDepartment of Chemistry, Faculty of Sciences, University of Birjand, Birjand,
97175-615, Iran. E-mail: gbagherzade@gmail.com; bagherzadeh@birjand.ac.ir; Fax:
+98 56 32345192; Tel: +98 56 32345192
bDepartment of Chemistry, Faculty of Science, Ferdowsi University of Mashhad,
Mashhad, Iran
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra04698a
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Scheme 2 Synthesis of 4H-pyrans promoted by Fe3O4@NFC@Co(II)
nanocatalyst.
Scheme 1 The synthetic route for Fe3O4@NFC@Co(II).
Scheme
3 Synthesis of pyranopyrazoles promoted by Fe3O4@-
NFC@Co(II) nanocatalyst.
Pyrans and the valuable derivatives of pyrans have been found
in many natural products.12 These compounds have been
considered valuable due to their biological and medicinal
properties,13–20 such as their anti-bacterial,21 anti-microbial,22
anti-allergic,23 anti-rheumatism24 and anti-cancer25 properties.
Also, pyrans are used as memory enhancers to treat neurolog-
ical diseases such as Alzheimer's,26 Huntington's,27 Parkin-
son's28 and Down syndrome.29 Also, pyranopyrazoles oen have
important roles based on their biological activity, which
includes anti-inammation30 and insecticidal effects,31 besides
being identied as a screening kit for the Chk1 kinase inhib-
itor.32 Different methods have been reported33–40 for the
synthesis of these derivatives. However, given the goal of green
chemistry and planning to make more use of green and inex-
pensive compounds, we are looking for a way to introduce
a catalytic system, which is environmentally friendly, cost-
effective, and provides a high power and maximum efficiency
in a short time. Today, nanocomposite catalysts are widely
regarded by researchers as stable catalysts.40 Among them,
superparamagnetic nanoparticles are widely used due to their
easy separation for a variety of organic articial develop-
ments.41–44 Polysaccharides with a common form of more than
ten monosaccharides are very abundant in nature with sources
such as seaweed and plants like wheat, rice, vegetables, etc.45,46
Furthermore, the important benets of these polysaccharides
include safe use, non-toxic nature, easy production, abundant
resources, and low-cost.47 Cellulose is a polysaccharide material
that is extracted from renewable sources and has been widely
considered due to the simplicity of its environmentally-friendly
production and low cost. Some of the most important
commercial applications of cellulose are food paper, textiles,
cosmetics, and pharmaceuticals.48
The goal of our research team is to provide a novel multi-core
catalyst that has high power, short reaction time, recyclability in
multi-stage processes and non-toxic reactivity (Scheme 1). This
protocol from both the economic and synthetic point of view
possesses several advantages like reduced pollution, lower cost,
and simplicity in processing, which are benecial to the
industry as well as to the environment. Water is a desirable
medium due to its features that include eco-friendly, safe, non-
toxic, non-ammable, clean, green, inexpensive, and readily
available. Therefore, the metal is placed on the metal cavities
covered with cellulose to achieve high performance and resis-
tance to the synthesis of 4H-pyran (Scheme 2) and pyranopyr-
azole (Scheme 3) with a safe solvent, which these compounds
Fig.
1 FT-IR spectra of (a) Fe3O4, (b) Fe3O4@NFC and (c)
Fe3O4@NFC@Co(II).
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Fig. 4 FESEM image (a) Fe3O4 and (b) Fe3O4@NFC@Co(II).
Fig. 2 XRD spectra of (a) Fe3O4, (b) CoO and (c) Fe3O4@NFC@Co(II).
have good medicinal properties. This catalyst Fe3O4@-
NFC@Co(II) greatly reduced the cost of this transformation, and
the resulting operation and work-up procedures were greatly
simplied.
Fig. 5 EDX image of Fe3O4@NFC@Co(II).
Result and discussion
absorption at 581 cmꢀ1 is characteristic of the Fe–O stretching
vibration, which illustrates the existence of Fe3O4 components.
In the FT-IR spectrum of Fe3O4@NFC (Fig. 1b), the existence
of the anchored nanober cellulose is conrmed by the
stretching vibration of the aliphatic C–H group that appears at
2920 cmꢀ1, and also the broad band emerging at 3396–
3432 cmꢀ1 and 1064 cmꢀ1, which is related to the O–H and C–O
stretching vibrations, respectively. The FT-IR spectrum of cata-
lyst Fe3O4@NFC@Co(II) (Fig. 1c) is proof that metal cobalt has
been successfully attached. In the FT-IR of the catalyst, the C–O
The design of organic reactions in aqueous environments is
another area of progress in green chemistry. Water is a highly
soluble and environmentally friendly solvent. This protocol
provides exibility in regulating complexity and molecular
diversity. Aer the reactions were complete, the pure product
was simply crystallized from ethanol without the use of any
chromatographic method almost immediately. FT-IR spectra
for the samples of Fe3O4 MNPs (a), Fe3O4 functionalized with
nanober cellulose (Fe3O4@NFC) (b), Fe3O4@NFC@Co(II) (c)
are shown in Fig. 1. The FT-IR spectrum for the MNPs (a) shows
bond shied to a lower wavenumber and appears at 1036 cmꢀ1
,
a stretching vibration of the –OH group at about 3440 cmꢀ1
which are attached to the surface iron atoms. The strong
,
which illustrates the formation of NFC@Co(II) complexes. The
Fig. 3 TG/DTG thermogram for Fe3O4@NFC@Co(II) catalyst.
37088 | RSC Adv., 2020, 10, 37086–37097
Fig. 6 VSM pattern (a) Fe3O4 and (b) Fe3O4@NFC@Co(II).
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crystallographic phases in XRD pattern are related to CoO.49
Also, new peaks appeared at 2q ¼ 18.7 and 20.3, which are
attributed to the cellulose species. The XRD diagram of reused
catalyst shows that the structure of the catalyst is stable during
the reaction.
Thermogravimetric analysis (TGA) was used to determine the
thermal stability and percentage of chemisorbed organic func-
tional groups on the surface of the magnetic nanoparticles.
Fig. 3 shows the TG/DTG thermogram for the Fe3O4@-
NFC@Co(II) catalyst. The weight loss of about 4% in the TGA
curve of Fe3O4, at temperatures below 300 ꢁC is assigned to the
removal of physically adsorbed organic solvents and surface
–OH groups (Fig. 3). Moreover, the weight loss of about 3% in
ꢁ
the temperature range between 300 and 700 C may be due to
the thermal crystal phase alteration from Fe3O4 to g-Fe2O3.24
There are three weight loss steps in the TGA curve of Fe3O4@-
NFC@Co(II) (Fig. 3b). Firstly, a weight loss of about 1.5% below
200 ꢁC is observed, which is owing to the removal of water
molecules from the catalyst surface. The second and third steps
of weight losses at 200–800 ꢁC may correspond to the degra-
dation of a nanober cellulose complex.
Fig. 7 TEM image (a and b) and particle size distribution histogram (c)
of Fe3O4@NFC@Co(II).
The FESEM images of the Fe3O4@NFC@Co(II) nanocatalyst
at different magnications are shown in Fig. 4. According to
Fig. 5, the surface morphology of the catalyst shows similar and
spherical particles with a size of less than 24 nm. The energy
dispersive X-ray spectroscopy (EDS) spectrum shows the pres-
ence of various elements in the catalyst (Fig. 5).
The magnetic property of Fe3O4 nanoparticles and Fe3O4@-
NFC@Co(II) were recorded at room temperature using the
vibrating sample magnetometer (VSM) technique (Fig. 6). The
magnetic measurement shows that Fe3O4@NFC@ Co(II) has
a saturated magnetization value of 53.23 emu gꢀ1. The VSM
curve of the Fe3O4 nanoparticles is 63.23 emu gꢀ1, which has
structure of the synthesized nanocatalyst was investigated by X-
ray powder diffraction analysis (XRD) (Fig. 2). The XRD pattern
shows the characteristic peaks of bare Fe3O4 at 2q ¼ 30.3ꢁ, 35.8ꢁ,
43.6ꢁ, 54.8ꢁ, 57.3ꢁ, and 63.2ꢁ corresponding to the reections of
the (220), (311), (400), (422), (511), and (440) planes. The XRD
pattern of Fe3O4@NFC@Co(II) catalyst matches well with the
characteristic peaks of bare Fe3O4, which indicates the reten-
tion of the crystalline spinel ferrite core structure during func-
tionalization of MNPs. Strong peaks at 2q ¼ 36.71ꢁ, 42.47ꢁ and
61.64ꢁ corresponding to the (111), (200) and (220)
Table 1 Optimization of the catalyst, synthesis condition, and solvent for the synthesis of 4H-pyran in the model reactiona
Entry
Solvent
Catalyst (mol%)
Temp (ꢁC)
Time (min)
Con. yieldb
Yieldc (%)
1
2
3
4
5
6
7
8
EtOH
DMF
THF
Dioxane
CH3CN
Toluene
PEG-400
H2O
Neat
Neat
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
1
1
1
1
1
1
1
1
70
100
60
100
100
100
70
70
70
70
70
70
70
70
25
45
55
65
75
60
30
60
60
60
60
60
15
60
30
45
30
15
15
60
30
15
15
15
85
70
40
90
60
90
95
100
98
75
90
95
100
100
80
75
65
25
75
45
80
88
98
90
60
80
87
97
98
65
85
97
98
98
9
1
1
10
11
12
13
14
15
16
17
18
19
0.5
0.7
1
1.2
1
1
1
1
1
93
100
100
100
a
Reaction conditions: aldehyde (1.0 mmol), malononitrile (1.0 mmol), ethyl acetoacetate (1.0 mmol), catalyst (1 mol%) and H2O (2 mL), 55 ꢁC.
Conversion yield (%). c Isolated yield (%).
b
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Table 2 Optimization of the catalyst, synthesis conditions, and solvent for the synthesis of pyranopyrazole in the model reactiona
Entry
Solvent
Catalyst (mol%)
Temp (ꢁC)
Time (min)
Con. yieldb
Iso. yieldc
1
2
3
4
5
6
7
8
EtOH
DMF
THF
Dioxane
CH3CN
Toluene
PEG-400
H2O
Neat
Neat
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
1
1
1
1
1
1
1
1
70
100
60
100
100
100
70
70
70
70
70
70
70
70
25
40
50
60
75
60
30
60
60
60
60
60
15
60
30
45
30
15
15
60
30
15
15
15
75
85
83
90
60
97
97
100
95
65
90
98
100
100
80
67
75
70
80
50
91
91
98
90
55
85
90
98
98
70
85
98
95
95
9
1
1
10
11
12
13
14
15
16
17
18
19
0.5
0.7
1
1.2
1
1
1
1
1
95
100
100
100
a
Reaction conditions: hydrazine hydrate 96% (1 mmol) and ethyl acetoacetate (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), water (2 mL)
catalyst (1 mol%) and H2O (2 mL), 50 ꢁC. b Conversion yield (%): calculated based on benzaldehyde consumption. c Isolated yield (%): calculated
based on the product pyranopyrazole.
a higher magnetic value in comparison with the synthesized
nanocatalyst. Reduction in the magnetic property of Fe3O4@-
NFC@Co(II) is due to the coating of cellulose and the attached
organic layers on Fe3O4 nanoparticles. The morphology and
nanoparticle size of the catalyst were characterized by scanning
electron microscopy.
Catalytic study
Aer the preparation of Fe3O4@NFC@Co(II), its catalytic activ-
ities were evaluated for the 4H-pyrane and pyranopyrazole
reaction. For this purpose, hydrazine hydrate, ethyl acetoace-
tate, benzaldehyde, and malononitrile were used in the model
pyranopyrazole reaction and malononitrile, ethyl acetoacetate
The loading amount of Co on the Fe3O4@NFC was deter-
mined by inductively coupled plasma atomic emission spec-
trometry (ICP-AES). The ICP analysis showed that the amount of
cobalt in the catalyst was 1.63 ꢂ 10ꢀ3 mol gꢀ1. The particle size
distribution of Fe3O4@NFC@Co(II) was evaluated using TEM,
which demonstrated that the average diameter of the particles
was 16 nm. TEM images also showed that the NPs are spherical
and relatively monodispersed (Fig. 7).
Scheme 4 Possible reaction mechanism for one-pot synthesis of Scheme 5 Possible reaction mechanism for one-pot synthesis of
polyfunctionalized 4H-pyrans over Fe3O4@NFC@Co(II).
polyfunctionalized pyranopyrazole over Fe3O4@NFC@Co(II).
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and various aldehydes were used in a model 4H-pyrane reaction dimethylformamide (DMF), tetrahydrofuran (THF), poly-
to optimize the reaction conditions; the results are discussed in ethylene glycol (PEG-400), acetonitrile (CH3CN), toluene,
Table 1. The reaction of benzaldehyde (1 mmol) with malono- dioxane, ethanol, and no solvent were examined (entries 1–9) in
nitrile (1 mmol) and ethyl acetoacetate (1 mmol) for 4H-pyrane the presence of 1 mol% of Fe3O4@NFC@Co(II).
and benzaldehyde (1 mmol), hydrazine hydrate (1 mmol),
In solvents like PEG, water or no solvent (entries 6–9), high
malononitrile (1 mmol), and ethyl acetoacetate (1 mmol) for yields were observed, but the highest yields were obtained in
pyranopyrazole was chosen as a simple model reaction to water for the 4H-pyrane and pyranopyrazole reactions. Exami-
optimize the reaction conditions, including catalyst amount, nation of the effect of solvent (Tables 1 and 2) for the 4H-pyrane
solvent, base, and effect of temperature (Table 1). When the and pyranopyrazole reaction shows that the conversion yield is
reactions were attempted without a catalyst, it was found that a function of solvent polarity. Reactions in non-polar solvents
only a low yield of product was obtained even aer 1 h. This have low conversion and in polar solvents, more complete
result suggests that a catalyst plays a critical role in these conversion is achieved, except for in dioxane, tetrahydrofuran
reactions. Initially, different solvents such as H2O, and toluene. When we analyzed the products, unfortunately
Table 3 Multicomponent reaction for the synthesis of tri-substituted 4H-pyrans and tetra-substituted pyranopyrazoles
Mp (ꢁC)
Entry
Aldehyde
Product
Time (min)
Yielda (%)
TON
TOF
Obtained
Reported
Ref.
1
2
3
4
5
6
7
8
Benzaldehyde
1a
1b
1c
1d
1e
1f
1g
1h
1i
15
15
10
15
20
20
10
15
15
15
10
15
15
15
15
20
20
25
15
20
20
20
20
20
97
93
92
90
95
85
94
88
83
90
95
95
98
95
90
90
88
88
90
95
92
95
85
83
107.7
103.3
102.2
100
105.5
94.4
104.4
97.7
92.2
430
209–210
172
178–179
177
208–210
172–174
178
51
51
52
53
52
51
51
54
55
56
55
55
57
57
58
59
60
61
62
60
60
57
60
61
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Hydroxybenzaldehyde
4-Methoxybenzaldehyde
4-Methylbenzaldehyde
4-Fluorobenzaldehyde
4-Nitrobenzaldehyde
3-Nitrobenzaldehyde
2-Nitrobenzaldehyde
2-Chlorobenzaldehyde
2-Bromobenzaldehyde
Benzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Hydroxybenzaldehyde
4-Methoxybenzaldehyde
4-Methylbenzaldehyde
4-Fluorobenzaldehyde
4-Nitrobenzaldehyde
3-Nitrobenzaldehyde
2-Nitrobenzaldehyde
2-Chlorobenzaldehyde
2-Bromobenzaldehyde
413.2
638.8
400
319.8
286.2
652.7
391.1
368.8
400
659.7
422.2
435.5
422.2
400
175–177
135–137
175–177
274–277
180–183
189–191
181–183
193–195
185–187
261–263
231
172–174
255–257
210–212
212–215
240–242
246–248
192–194
216–218
240–242
232–235
137
174–176
274–276
182–183
190
181–182
194–195
186
262–263
231–233
172–174
254–256
211–212
213–215
239–241
247–249
194
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1j
1k
1l
100
105.5
105.5
108.8
105.5
100
100
97.7
97.7
100
105.5
102.2
105.5
94.4
2a
2b
2c
2d
2e
2f
2g
2h
2i
303
296.3
234
400
319.8
309.7
319.8
286.2
279.5
2j
2k
2l
216
241–243
232–233
92.2
a
Isolated yield.
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instead of completing the reaction, a mixture of product and
alkylidyne intermediate (I) and (III) (Schemes 4 and 5) was
created. CH3CN is a polar solvent, so in the process of reacting,
we found that due to its low nucleophilic power, it may not be
a suitable solvent for the development of the reaction.50 As
a result, we noticed an isolated yield in PEG, water and no
solvent, where water has a good conversion yield for both
reactions. In the next step, this model reaction was examined
with different temperatures including room temperature, 40,
ꢁ
50, 60, and 80 C for both reactions, and the best results were
ꢁ
ꢁ
obtained at 55 C for 4H-pyrane and 50 C for pyranopyrazole.
Increasing the temperature to 75 ꢁC did not effectively increase
the yield of the product (Tables 1 and 2, entry 19). Finally, to
optimize the catalyst amount, different quantities of catalyst
were appraised in the model reaction. As shown in Tables 1 and
2 for the 4H-pyrane and pyranopyrazole reactions, the lack of
catalyst resulted in a low yield of the product aer 24 h but
experiments showed that 1 mol% of catalyst for both 4H-pyrane
and pyranopyrazole is an adequate amount for the completion
of the reactions. Using more of the catalysts did not effectively
increase the yield or decrease the time of the reactions (Tables 1
and 2, entry 11–14). The 4H-pyrane derivatives and pyranopyr-
azole derivatives were obtained in satisfactory yields and the
results are summarized in Table 3. However, the results of the
4H-pyrane and pyranopyrazole reactions depend on the type of
halide, the positions of the substitution groups on the aromatic
ring, the effect of various electron donating and electron with-
drawing groups, and the catalyst activity. The suggested mech-
anism for the 4H-pyrane and pyranopyrazole reaction in the
presence of the Fe3O4@NFC@Co(II) catalyst is outlined in
Schemes 2 and 3.28
Fig. 8 Recycling activity of the Fe3O4@NFC@Co(II) NPs.
malononitrile, and an ethyl acetoacetate compound (Scheme 4)
and the synthesis of polyfunctionalized pyranopyrazole from
aldehydes, malononitrile, hydrazine hydrate and an ethyl ace-
toacetate compound (Scheme 5). In Scheme 4, the surface metal
ions of the catalyst act as active Lewis acids to enolize malo-
nonitrile and acetyl acetate in the reaction pathways to prepare
the corresponding enols as powerful nucleophiles. Then, the
enol of malononitrile attacks benzaldehyde to form an olen
intermediate (I). Therefore, the Knoevenagel condensation
reaction takes place between malononitrile and benzaldehyde
to form intermediate (I). The Michael addition reaction
happens between intermediate (I) and enol (II), forming acetyl
acetate derivates to yield intermediate (III). Then, with subse-
quent steps of intramolecular nucleophilic addition and tau-
tomerization, intermediates (IV) and (V) are formed. Finally, the
polyfunctionalized 4H-pyrans are obtained by H+ abstraction
Recyclability of the catalyst
The recycling of the heterogeneous catalysts is an important
aspect for commercial applications. To analyze this, the
recovery and reusability of the catalyst were examined for the
4H-pyrane reaction of benzaldehyde with malononitrile and
ethyl acetoacetate, and the pyranopyrazole reaction of benzal-
dehyde, hydrazine hydrate, malononitrile, and ethyl acetoace-
tate as model reactions under the optimized conditions. Aer
the completion of the reaction, the catalyst was simply sepa-
rated from the reaction mixture using an external magnet and
washed with water and ethanol to remove organic residuals,
dried, and reused for the next runs. As shown in Fig. 8, the
recycled catalyst does not show any signicant changes in its
activity, which showed that the catalyst was stable and can be
reused for the next successive cycles. The catalyst Fe3O4@-
NFC@Co(II) was analyzed aer ve steps of recycling by IR and
FESEM, as shown in Fig. 9. As shown in the recycling table,
there was not much change in the structure of the catalyst
morphology or the IR spectrum with several washing steps in
these reactions.
Suggested reaction mechanism
Based on our results, we proposed a mechanism for the one-pot
Fig. 9 FESEM image and FTIR spectra of Fe3O4@NFC@Co(II): (a) fresh
synthesis of polyfunctionalized 4H-pyrans from aldehydes, (IR), (b) after 4H-pyran and (c) after pyranopyrazole.
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Table 4 Comparison of the present approach with literature reported method for 4H-pyrans synthesis
Entry
Catalyst (mol%)
Solvent
Time (min)
Temp. (ꢁC)
Yield (%)
Ref.
1
2
3
4
5
6
KF–Al2O3
Fe3O4@gC3N4
Piperazine
Fe3O4@GA@isinglass
[2-aemim][PF6]
Fe3O4@NFC@Co(II)
EtOH
EtOH
H2O
EtOH
M.W
H2O
180
190
7
50
3
r.t
60
90
Reux
100
50
77
80
96
88
87
98
64
65
66
51
67
15 min
This work
from the catalyst. In Scheme 5, the proposed mechanism Transmission electron microscopy (TEM) was performed on
consists of two parts: the rst part involves the formation of a Philips EM208 microscope and was operated at 100 kV.
pyrazolone from the hydrazine with ethyl acetate, which is
converted to pyrazole if Fe3O4@NFC@Co(II) is present. The
Preparation of the magnetic Fe3O4 nanoparticles (MNPs)
other part is the formation of phenylidene malononitrile from
MNPs were synthesized through the co-reduction of Fe(III) and
the concentration of malononitrile from the Knoevenagel
Fe(II) ions with a molar ratio of 2 : 1 in the presence of ammo-
condensation with benzaldehyde in the presence of the Fe3-
nium hydroxide. In general, a 100 mL solution containing
O4@NFC@Co(II) catalyst. At the end of the reaction, the
FeCl3$6H2O (2 mmol) and FeSO4$7H2O (1 mmol) was prepared
and heated at 80 ꢁC under N2 atmosphere and strongly stirred.
Then, 5 mL of 25% NH4OH was slowly injected into this mixture
Michael's addition combination of (II) was created by interme-
diates (III) and (IV), which, aer an intramolecular nucleophilic
attack on the nitrile group, rst formed a ring and then a tau-
tomerization gave the pyranopyrazole.
in one step. The black MNPs were instantly formed aer adding
the ammonia solution to the Fe2+/Fe3+ salt solution. The
mixture was stirred for 120 min and then cooled to ambient
Experimental section
temperature. Then, dark MNPs were magnetically separated
Materials and methods
from the solution and washed three times with deionized
water.62
Cellulose nanobers were purchased from Sigma Aldrich.
Iron(III) chloride, iron(II) sulfate, cobalt(II) acetate, and sodium
hydroxide were purchased from Sigma Aldrich. All chemicals Preparation of the NFC@Fe3O4 (nanober Cellulose@Fe3O4)
were used without further purication. The FT-IR spectra were
recorded on a JASCO FT/IR 4600 FT-IR spectrometer. The
To a suspension of Fe3O4 nanoparticles (1.15 g, 5.0 mmol) in
deionized water (50 mL), 50 mL of NFC (0.5 g, 2.5 mmol) solu-
thermal analysis (TGA) was carried out using a TGA Q600 TA
tion was added drop-wise at room temperature. The mixture
instrument at a heating rate of 10 ꢁC minꢀ1 in air. The powder
was vigorously stirred for 2 h at room temperature and then
X-ray diffraction (XRD) was performed with a Philips PW1730.
neutralized with water.63 Aer the foam had subsided, the
The scanning electron microscopy (FESEM) and the energy
resulting Fe3O4@NFC precipitate was isolated using an external
dispersive X-ray spectroscopy (EDS) characterization of catalysts
magnet, washed twice with deionized water, and dried at 60 ꢁC
was performed using an electron microscope Tescan MIRA3.
under vacuum for 6 h.
The melting points of the products were measured by an elec-
trothermal 9100 apparatus. ICP experiments were accom-
Preparation of the Fe3O4@NFC@Co(II)
plished using a Varian Vista Pro CCD simultaneous ICP-OES
instrument. Magnetic properties of the nanoparticles were Based on this method, an excess amount of cobalt(II) acetate in
measured with a vibrating sample magnetometer (VSM). 5 mL ethanolic solution was used to disperse 1 g of Fe3O4@NFC
Table 5 Comparison of the present approach with literature reported method for pyranopyrazole synthesis
Entry
Catalyst (mol%)
Solvent
Time (h/min)
Temp. (ꢁC)
Yield (%)
TOF
1.075
56.25
26
56.25
3.19
36.8
66.4
3.24
53.12
435.5
Ref.
1
2
3
4
5
6
7
8
9
10
Urea (10)
Isonicotinic acid (10)
Et3N (10)
EtOH : H2O
SF
EtOH
H2O
H2O
EtOH : H2O
H2O
EtOH
SF
H2O
8 h
r.t
89
Reux
Reux
Reux
80
r.t
Reux
70
86
90
65
90
80
92
83
73
85
98
68
69
70
71
72
73
74
75
10 min
15 min
10 min
50 min
15 min
10 min
45 min
10 min
15 min
L-Proline (10)
g-Alumina (30)
b-Cyclodextrin (10)
Piperidine (5)
HDBAC (30)
B(OH)3 (10)
Fe3O4@NFC@Co(II) (0.9)
76
50
This work
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and allowed to react for 2 h at 80 ꢁC under vigorous stirring. 1689.50 (C]O), 1645.77, 1608.19, 1483.62, 1374.06, 1262.54,
Finally, the solid product was separated from the residual cobalt 1180.44, 1068.31 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6) d ¼ 1.31–
solution by a magnet. Then, the obtained solid product was 1.39 (3H, CH3, t), 2.29 (3H, CH3, s), 3.88–4.00 (2H, CH2, q), 4.55
washed several times with ethanol and dried in an oven at 60 ꢁC (H, CH, s), 6.96 (2H, NH2, s), 7.29–7.89 (4H, H-Ar, d, d) ppm. 13C-
for 12 h.
NMR (100 MHz, DMSO-d6): d ¼ 14.39, 17.33, 38.15, 58.42, 61.54,
107.84, 119.15, 131.25, 131.51, 143.58, 156.50, 159.25,
165.41 ppm.
Catalytic procedure for synthesis of 4H-pyran derivatives
Ethyl 6-amino-5-cyano-4-(4-hydroxyphenyl)-2-methyl-4H-pyran-
3-carboxylate (Table 3, entry 4). 1H-NMR (400 MHz, DMSO-d6)
d ¼ 0.84–0.89 (3H, CH3, t), 2.25 (3H, CH3, s), 3.77–3.87 (2H, CH2, q),
4.24 (H, CH, s), 6.59 (2H, NH2, s), 6.71–6.90 (4H, H-Ar, d, d), 9.09
(OH, s) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.25, 17.00,
37.52, 58.29, 61.48, 107.87, 115.31, 119.15, 131.24, 136.61, 155.14,
156.77, 159.20, 164.92 ppm.
A mixture of aldehyde (1.0 mmol), malononitrile (1.0 mmol),
ethyl acetoacetate (1.0 mmol), water (2 mL), and Fe3O4@-
NFC@Co(II) (1 moꢁl%) were stirred magnetically in an oil-bath
maintained at 55 C for an appropriate time as mentioned in
Table 2. Aer completion of the reaction as monitored by TLC
using n-hexane : ethyl acetate (60 : 40) as the eluent, the reac-
tion mixture was allowed to cool to room temperature and then
crystallized with ethanol to form a pure crystal of the 4H-pyran
(1a–l). The catalyst used in the reaction was reusable for up to 5
cycles (as shown in Fig. 8).
Ethyl
6-amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-4H-
1
pyran-3-carboxylate (Table 3, entry 5). H-NMR (400 MHz, DMSO-
d6) d ¼ 1.31–1.35 (3H, CH3, t), 2.12 (3H, CH3, s), 3.74 (CH3, s), 3.93–
3.4 (2H, CH2, q), 4.44 (H, CH, s), 6.83 (2H, NH2, s), 6.91–7.10 (4H,
H-Ar, d, d) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.59, 17.61,
38.45, 55.25, 56.48, 61.64, 108.25, 114.30, 119.58, 130.90, 136.73,
155.38, 157.85, 159.72, 165.25 ppm.
General procedure for synthesis pyranopyrazole derivatives
A mixture of hydrazine hydrate 96% (1 mmol), ethyl acetoace-
tate (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol),
water (2 mL) and Fe3O4@NFC@Co(II) (1 mol%) as catalyst were
added successively at room temperature under an open atmo-
sphere with vigorous stirring. Aer completion of the reaction,
the reaction mixture was dissolved in ethanol and then the
catalyst was separated magnetically. The magnetic Fe3O4
nanoparticles were washed three times with ethanol and then
Ethyl
6-amino-5-cyano-2-methyl-4-(p-tolyl)-4H-pyran-3-carbo
1
xylate (Table 3, entry 6). H-NMR (400 MHz, DMSO-d6) d ¼ 1.31–
1.35 (3H, CH3, t), 2.12 (3H, CH3, s), 2.35 (CH3, s), 3.93–4.05 (2H,
CH2, q), 4.44 (H, CH, s), 6.83 (2H, NH2, s), 7.07–7.57 (4H, H-Ar, d,
d) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.59, 17.61, 21.43,
38.13, 58.36, 61.48, 107.31, 119.58, 128.36, 135.99, 141.51, 155.63,
159.87, 165.71 ppm.
ꢁ
dried at 50 C for 5 h. The product obtained was pure by TLC.
Ethyl 6-amino-5-cyano-4-(4-uorophenyl)-2-methyl-4H-pyran-
3-carboxylate (Table 3, entry 7). 1H-NMR (400 MHz, DMSO-d6)
d ¼ 1.13–1.24 (3H, CH3, t), 2.46 (3H, CH3, s), 4.02–4.07 (2H, CH2,
q), 4.34 (H, CH, s), 6.91 (2H, NH2, s), 7.12–7.43 (4H, H-Ar, d,
d) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 13.81, 17.61, 37.93,
However, the products were further puried by recrystallization
from ethanol to form a pure crystal of the pyranopyrazole (2a–l).
Selected spectral data
The physical and spectral data of selected products are repre- 56.81, 61.48, 107.31, 115.77, 119.14, 130.90, 139.45, 155.72,
sented below.
159.12, 159.26, 165.14 ppm.
Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3 carbo
Ethyl 6-amino-5-cyano-2-methyl-4-(4-nitrophenyl)-4H-pyran-
1
xylate (Table 3, entry 1). Off-white solid; IR (KBr): 3402.49 (NH2), 3-carboxylate (Table 3, entry 8). H-NMR (400 MHz, DMSO-d6)
3329.96 (NH2), 2972.32 (C–H), 2190.34 (C^N), 1692.10 (C]O), d ¼ 1.13–1.24 (3H, CH3, t), 2.40 (3H, CH3, s), 3.94–4.01 (2H, CH2,
1652.27, 1609.54, 1375.88, 1259.12, 1120.31, 1062.19 cmꢀ1. 1H- q), 4.28 (H, CH, s), 6.88 (2H, NH2, s), 7.50–8.11 (4H, H-Ar, d,
NMR (400 MHz, DMSO-d6) d ¼ 1.21–1.30 (3H, CH3, t), 2.50 (3H, d) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.84, 17.61, 38.47,
CH3, s), 3.81–4.05 (2H, CH2, q), 4.60 (H, CH, s), 6.26 (2H, NH2, 58.05, 61.48, 107.91, 119.58, 124.03, 127.03, 144.60, 150.69,
s), 7.67–7.88 (5H, H-Ar, m) ppm. 13C-NMR (100 MHz, DMSO-d6): 155.74, 159.68, 165.58 ppm.
d ¼ 12.53, 15.37, 55.53, 61.81, 108.85, 119.22, 125.51, 125.72,
127.53, 127.78, 142.85, 152.53, 154.37, 166.85 ppm.
Ethyl-6-amino-4-(4-chlorophenyl)-5-cyano-2-methyl-4H-
Ethyl 6-amino-5-cyano-2-methyl-4-(3-nitrophenyl)-4H-pyran-
3-carboxylate (Table 3, entry 9). H-NMR (400 MHz, DMSO-d6)
d ¼ 1.12–1.21 (3H, CH3, t), 2.12 (3H, CH3, s), 3.94–4.01 (2H, CH2,
1
pyran-3-carboxylate (Table 3, entry 2). Off-white solid; IR (KBr): q), 4.29 (H, CH, s), 6.91 (2H, NH2, s), 6.91–8.40 (4H, H-Ar,
3409.17 (NH2), 3332.69 (NH2), 2979.48 (C–H), 2193.69 (C^N), m) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.90, 17.61,
1693.41 (C]O), 1650.55, 1609.34, 1489.39, 1335.42, 1266.26, 37.32, 58.05, 61.88, 107.91, 119.77, 120.81, 121.81, 134.61,
1174.09, 1120.47 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6) d ¼ 1.01– 143.59, 145.89, 155.81, 159.72, 165.14 ppm.
1.09 (3H, CH3, t), 2.50 (3H, CH3, s), 3.81–4.03 (2H, CH2, q), 4.28
Ethyl 6-amino-5-cyano-2-methyl-4-(2-nitrophenyl)-4H-pyran-
(H, CH, s), 6.26 (2H, NH2, s), 7.29–7.52 (4H, H-Ar, d, d) ppm. 13C- 3-carboxylate (Table 3, entry 10). 1H-NMR (400 MHz, DMSO-
NMR (100 MHz, DMSO-d6): d ¼ 14.33, 17.37, 38.18, 58.53, 61.65, d6) d ¼ 1.12–1.22 (3H, CH3, t), 2.12 (3H, CH3, s), 3.94–4.01 (2H,
107.85, 118.82, 128.54, 128.72, 130.53, 130.78, 131.51, 141.88, CH2, q), 4.24 (H, CH, s), 6.91 (2H, NH2, s), 7.21–7.82 (4H, H-Ar,
155.55, 158.67, 165.85 ppm.
m) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.84, 17.61, 34.41,
Ethyl 6-amino-4-(4-bromophenyl)-5-cyano-2-methyl-4H-pyran- 58.36, 61.16, 107.77, 119.58, 124.66, 126.23, 129.88, 130.19,
3-carboxylate (Table 3, entry 3). Off-white solid; IR (KBr): 134.16, 146.78, 155.92, 160.60, 165.71 ppm.
3408.10 (NH2), 3330.18 (NH2), 2979.27 (C–H), 2194.09 (C^N),
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Ethyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-methyl-4H-pyran-
RSC Advances
6-Amino-3-methyl-4-(p-tolyl)-2,4-dihydropyrano[2,3-c]pyra
3-carboxylate (Table 3, entry 11). Off-white solid; IR (KBr): zole-5-carbonitrile (Table 3, entry 18). 1H-NMR (400 MHz, DMSO-
3425.19 (NH2), 3330.20 (NH2), 2963.27 (C–H), 2194.16 (C^N), d6) d ¼ 1.93 (3H, CH3, s), 2.16 (3H, CH3, s), 4.64 (1H, CH-pyrano,
1684.50 (C]O), 1642.77, 1610.19, 1473.62, 1265.54, s), 6.79 (2H, NH2, s), 7.05–7.49 (4H, H-Ar, d, d), 11.48 (1H, NH,
1185.44 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6) d ¼ 0.84–0.91 (3H, s) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.59, 26.49, 59.89,
CH3, t), 2.33 (3H, CH3, s), 3.78–3.94 (2H, CH2, q), 4.87 (H, CH, s), 113.07, 117.81, 125.64, 128.72, 132.24, 135.19, 139.59, 162.81,
6.74 (2H, NH2, s), 6.94–7.14 (4H, H-Ar, m) ppm. 13C-NMR (100 176.28 ppm.
MHz, DMSO-d6): d ¼ 13.79, 18.03, 56.02, 60.04, 105.44, 119.05,
127.75, 128.35, 129.25, 129.75, 131.81, 142.08, 157.74, 158.45, c]pyrazole-5-carbonitrile (Table 3, entry 19). 1H-NMR (400 MHz,
165.11 ppm.
6-Amino-4-(4-uorophenyl)-3-methyl-2,4-dihydropyrano[2,3-
DMSO-d6) d ¼ 1.83 (3H, CH3, s), 5.19 (1H, CH-pyrano, s), 6.81
Ethyl 6-amino-4-(2-bromophenyl)-5-cyano-2-methyl-4H-pyran- (2H, NH2, s), 7.13–8.50 (4H, H-Ar, d, d), 11.76 (1H, NH, s) ppm.
3-carboxylate (Table 3, entry 12). Off-white solid; IR (KBr): 13C-NMR (100 MHz, DMSO-d6): d ¼ 13.50, 26.49, 59.32, 114.30,
3422.29 (NH2), 3328.93 (NH2), 2964.12 (C–H), 2191.86 (C^N), 115.23, 117.81, 131.24, 139.92, 159.20, 164.11, 178.10 ppm.
1685.40 (C]O), 1642.27, 1611.12, 1474.10, 1261.14,
6-Amino-3-methyl-4-(4-nitrophenyl)-2,4-dihydropyrano[2,3-c]
1174.34 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6) d ¼ 2.52–2.56 (3H, pyrazole-5-carbonitrile (Table 3, entry 20). 1H-NMR (400 MHz,
CH3, t), 2.31 (3H, CH3, s), 3.48–3.92 (2H, CH2, q), 4.87 (H, CH, s), DMSO-d6) d ¼ 1.97 (3H, CH3, s), 5.08 (1H, CH-pyrano, s), 6.52 (2H,
6.84 (2H, NH2, s), 7.33–7.51 (4H, H-Ar, d, d) ppm. 13C-NMR (100 NH2, s), 7.72–9.06 (4H, H-Ar, d, d), 11.58 (1H, NH, s) ppm. 13C-
MHz, DMSO-d6): d ¼ 13.61, 18.06, 37.55, 56.14, 60.06, 106.19, NMR (100 MHz, DMSO-d6): d ¼ 13.06, 25.77, 59.89, 114.22,
119.03, 122.60, 128.35, 128.66, 129.74, 132.46, 143.78, 157.70, 117.19, 123.53, 129.51, 139.59, 141.40, 146.78, 163.20,
158.35, 165.11 ppm.
176.28 ppm.
6-Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c] pyrazole-
6-Amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano[2,3-c]
5-carbonitrile (Table 3, entry 13). Off-white solid; IR (KBr): 3400 pyrazole-5-carbonitrile (Table 3, entry 21). 1H-NMR (400 MHz,
(NH2), 3200 (NH), 2195 (C^N), 1640 (C]N), 1610–1490 (C]C), DMSO-d6) d ¼ 2.17 (3H, CH3, s), 5.15 (1H, CH-pyrano, s), 6.53 (2H,
1390 (C–N), 1055 (C–O) cmꢀ1. 1H-NMR (400 MHz, DMSO-d6) d ¼ NH2, s), 7.58–8.37 (4H, H-Ar, m), 11.53 (1H, NH, s) ppm. 13C-NMR
2.52 (3H, CH3, s), 4.71 (1H, CH-pyrano, s), 6.81 (2H, NH2, s), 7.09– (100 MHz, DMSO-d6): d ¼ 13.50, 25.64, 56.48, 113.69, 117.19,
7.27 (5H, H-Ar, m), 11.15 (1H, NH, s) ppm. 13C-NMR (100 MHz, 120.38, 121.75, 133.29, 139.25, 139.59, 139.92, 147.60, 163.60,
DMSO-d6): d ¼ 13.40, 26.49, 59.32, 113.63, 117.81, 125.64, 128.72, 177.07 ppm.
129.45, 135.71, 139.45, 163.20, 176.81 ppm.
6-Amino-3-methyl-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]
6-Amino-4-(4-chlorophenyl)-3-methyl-2,4-dihydropyrano [2,3- pyrazole-5-carbonitrile (Table 3, entry 22). 1H-NMR (400 MHz,
1
c]pyrazole-5-carbonitrile (Table 3, entry 14). H-NMR (400 MHz, DMSO-d6) d ¼ 2.11 (3H, CH3, s), 4.96 (1H, CH-pyrano, s), 6.79 (2H,
DMSO-d6) d ¼ 1.89 (3H, CH3, s), 4.98 (1H, CH-pyrano, s), 6.53 (2H, NH2, s), 7.55–7.95 (4H, H-Ar, m), 11.48 (1H, NH, s) ppm. 13C-NMR
NH2, s), 7.32–7.44 (4H, H-Ar, d, d), 11.58 (1H, NH, s) ppm. 13C- (100 MHz, DMSO-d6): d ¼ 13.50, 20.83, 59.34, 113.63, 116.99,
NMR (100 MHz, DMSO-d6): d ¼ 14.02, 24.51, 59.34, 113.07, 125.64, 128.36, 129.51, 132.24, 134.79, 139.92, 149.72, 163.60,
117.19, 125.64, 129.51, 131.24, 134.79, 139.93, 164.11, 176.02 ppm.
176.62 ppm.
6-Amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano [2,3-
6-Amino-4-(4-bromophenyl)-3-methyl-2,4-dihydro
pyrano c] pyrazole-5-carbonitrile (Table 3, entry 23). Off-white solid; IR
1
[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 15). H-NMR (400 (KBr): 3420 (NH2), 3200 (NH), 2192 (C^N), 1635 (C]N), 1600–
MHz, DMSO-d6) d ¼ 1.89 (3H, CH3, s), 5.12 (1H, CH-pyrano, s), 1490 (C]C), 1390 (C–N), 1054 (C–O) cmꢀ1. H-NMR (400 MHz,
1
6.60 (2H, NH2, s), 7.32–7.84 (4H, H-Ar, d, d), 11.62 (1H, NH, DMSO-d6) d ¼ 2.084 (3H, CH3, t), 4.24 (1H, CH-pyrano, s), 6.37
s) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 12.78, 25.64, 59.89, (2H, NH2, s), 7.13–7.55 (5H, H-Ar, m), 11.01 (1H, NH, s) ppm. 13C-
113.63, 116.99, 120.38, 132.24, 134.16, 140.85, 163.04, NMR (100 MHz, DMSO-d6): d ¼ 13.50, 20.09, 59.89, 113.07,
176.28 ppm.
117.81, 126.23, 127.52, 128.36, 131.24, 140.85, 144.51, 162.81,
175.44 ppm.
6-Amino-4-(4-hydroxyphenyl)-3-methyl-2,4-dihydropyrano
1
[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 16). H-NMR (400
6-Amino-4-(2-bromophenyl)-3-methyl-2,4-dihydropyrano[2,3-
1
MHz, DMSO-d6) d ¼ 1.88 (3H, CH3, s), 4.34 (1H, CH-pyrano, s), c]pyrazole-5-carbonitrile (Table 3, entry 24). H-NMR (400 MHz,
6.79–6.84 (2H, H-Ar, d), 6.94 (2H, NH2, s), 7.05–7.08 (2H, H-Ar, DMSO-d6) d ¼ 1.88 (3H, CH3, s), 4.66 (1H, CH-pyrano, s), 6.07 (2H,
d), 9.06 (1H, OH, s), 11.99 (1H, NH, s) ppm. 13C-NMR (100 NH2, s), 7.15–7.55 (4H, H-Ar, m), 11.26 (1H, NH, s) ppm. 13C-NMR
MHz, DMSO-d6): d ¼ 13.50, 26.49, 59.34, 112.35, 116.25, 117.81, (100 MHz, DMSO-d6): d ¼ 13.06, 25.64, 59.89, 113.07, 116.99,
127.03, 130.19, 138.90, 155.81, 162.81, 176.28 ppm.
123.53, 127.03, 131.24, 132.24, 139.92, 141.40, 164.11,
176.02 ppm.
6-Amino-4-(4-methoxyphenyl)-3-methyl-2,4-dihydropyrano
1
[2,3-c]pyrazole-5-carbonitrile (Table 3, entry 17). H-NMR (400
MHz, DMSO-d6) d ¼ 1.92 (3H, CH3, s), 4.04 (1H, CH-pyrano, s),
6.78 (2H, NH2, s), 6.79–7.64 (4H, H-Ar, d, d), 11.67 (1H, NH,
s) ppm. 13C-NMR (100 MHz, DMSO-d6): d ¼ 13.50, 26.49, 56.48,
58.36, 113.63, 114.30, 124.03, 127.03, 130.67, 140.56, 157.37,
163.49, 177.30 ppm.
Comparison of the catalyst
To investigate the catalytic activity of Fe3O4@NFC@Co(II), we
compared the results of the reaction of 4H-pyrane and the
reaction of pyranopyrazole (Tables 4 and 5) with the previously
reported. Table 4 lists the approaches in the catalyst literature.
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They each have their advantages, but some of them suffer from
various demerits such as the use of an expensive catalyst, harsh
reaction condition, toxic chemical and longer reaction time.
Catalysts in the literature and their results are given in Table 5.
Overall, the obtained catalyst showed better yield and higher
TOF values in a shorter reaction time than other catalysts re-
ported in the literature. Thus, the present protocol (Table 5,
entry 10) has several advantages as a greener, economic, simple
reactions. John Wiley & Sons, 2006; (e) A. Domling, Chem.
Rev., 2006, 106, 17.
7 J. P. Wan, S. F. Gan, G. L. Sun and Y. J. Pan, J. Org. Chem.,
2009, 74, 2862.
8 Y. Morinaka and k. Takahashi, Jpn. Kokai Tokkyo Koho,
JP52017498, 1977transChem. Abstr., 1977, 87, 102299.
9 E. C. Witte, P. Neubert and A. Roesch, Ger Offen, DE3427985,
1986transChem. Abstr., 1986, 104, 224915f.
reaction set-up, and product isolation by simple magnet as 10 E. A. Hafez, M. H. Elnagdi, A. A. Elagamey and F. A. El-
compared to reported methods for the synthesis of 4H-pyran
Taweel, Heterocycles, 1987, 26, 903907.
and pyranopyrazole derivatives.
11 (a) R. Y. Guo, Z. M. An, L. P. Mo, R. Z. Wang, H. X. Liu,
S. X. Wang and Z. H. Zhang, ACS Comb. Sci., 2013, 15, 557;
(b) S. Wang, Q. Qi, C. Li, G. Ding and S. H. Kim, Dyes
Pigm., 2011, 89, 188.
Conclusion
12 (a) D. Lu, Y. Li and Y. Gong, J. Org. Chem., 2010, 75, 6900; (b)
K. Nicolaou, J. Pfefferkorn, A. Roecker, G. Q. Cao,
S. Barluenga and H. Mitchell, J. Am. Chem. Soc., 2000, 122,
9939; (c) H. T. Nguyen, M. C. Lallemand, S. Boutefnouchet,
S. Michel and F. Tillequin, J. Nat. Prod., 2009, 72, 527; (d)
A. W. Schuppe, Y. Zhao, Y. N. Liu and T. R. Newhouse, J.
Am. Chem. Soc., 2019, 141, 9191; (e) S. J. Kalita, N. Saikia,
D. C. Deka and H. Mecadon, Res. Chem. Intermed., 2016,
42, 6863.
In summary, this powerful multi-core catalyst Fe3O4@-
NFC@Co(II) can be used as a novel, green, efficient, and reus-
able nanocatalyst for 4H-pyrane and pyranopyrazole reactions.
This catalyst offers several advantages including high catalytic
activity, excellent yields, short reaction time, and mild reaction
conditions. Furthermore, the catalyst could be simply recovered
from the reaction mixture using an external magnet and reused
up to 5 times without a signicant loss in activity.
13 J. Zamocka, E. Misikova and J. Durinda, Pharmazie, 1991, 46,
610613.
Conflicts of interest
14 J. L. Wang, D. Liu, Z. J. Zhang, S. Shan, X. Han,
S. M. Srinivasula, C. M. Croce, E. S. Alnemri and Z. Huang,
Proc. Natl. Acad. Sci. U. S. A., 2007, 97, 71247129.
15 A. M. M. El-Saghier and M. B. Naili, ARKIVOC, 2007, 16, 83–
91.
16 R. R. Kumar, S. Perumal, P. Senthilkumar, P. Yogeeswari and
D. Sriram, Bioorg. Med. Chem. Lett., 2007, 17, 64596462.
17 I. J. S. Fairlamb, L. R. Marrison, J. M. Dickinson, F. J. Lu and
J. P. Schmidt, Bioorg. Med. Chem., 2004, 12, 42854299.
18 M. D. Aytemir, D. D. Erol, R. C. Hider and M. Ozalp, Turk. J.
Chem., 2003, 27, 757764.
There are no conicts to declare.
Acknowledgements
We gratefully acknowledge the nancial support of the research
council of the University of Birjand and we also thank the
University of Ferdowsi.
References
1 A. R. Moosavi-Zare, M. A. Zolgol, O. Khaledian, 19 M. Kidwai, S. Saxena, M. K. R. Khan and S. S. Thukral, Bioorg.
V. Khakyzadeh, M. D. Farahani and H. G. Kruger, New J.
Chem., 2014, 38(6), 2342–2347.
2 A. R. Moosavi-Zare, M. A. Zolgol, O. Khaledian,
V. Khakyzadeh, M. H. Beyzavi and H. G. Kruger, Chem. Eng.
J., 2014, 248, 122–127.
Med. Chem. Lett., 2005, 15, 42954298.
20 (a) D. Kumar, V. B. Reddy, S. Sharad, U. Dube and S. Kapur,
Eur. J. Med. Chem., 2009, 44, 3805; (b) N. P. Selvam,
T. H. Babu and P. T. Perumal, Tetrahedron, 2009, 65, 8524.
21 L. R. Morgan, B. S. Jursic, C. L. Hooper, D. M. Neumann,
K. Thangaraj and B. LeBlanc, Bioorg. Med. Chem. Lett.,
2002, 12, 3407.
3 (a) M. Bakherad, A. Keivanloo, A. H. Amin and P. Ghamari
kargar, Iran. J. Catal., 2018, 3, 179–187; (b) A. Khazaei,
A. R. Moosavi-Zare, Z. Mohammadi, V. Khakyzadeh and 22 G. Zhang, Y. Zhang, J. Yan, R. Chen, S. Wang, Y. Ma and
J. Afsar, J. Chin. Chem. Soc., 2016, 63(2), 165–170. R. Wang, J. Org. Chem., 2012, 77, 878–888.
4 M. Dabiri, P. Salehi, S. Otokesh, M. Baghbanzadeh, 23 C. W. Smith, J. M. Bailey, M. E. Billingham,
G. Kozehgary and A. A. Mohammadi, Tetrahedron Lett.,
2005, 46(36), 6123–6126.
5 (a) P. A. Wender, S. T. Handy and D. L. Wright, Chem. Ind.,
S. Chandrasekhar, C. P. Dell, A. K. Harvey, C. A. Hicks,
A. E. Kingston and G. N. Wishart, Bioorg. Med. Chem. Lett.,
1995, 5, 2783.
1997, 765; (b) B. M. Trost, Angew. Chem., Int. Ed., 1995, 34, 24 K. Niknam and A. Piran, Green Sustainable Chem., 2013, 3, 1–
259.
8.
6 (a) S. Tu, B. Jiang, Y. Zhang, R. Jia, J. Zhang, C. Yao and 25 H. Gourdeau, L. Leblond, B. Hamelin, C. Desputeau,
S. Feng, Org. Biomol. Chem., 2007, 5, 355; (b) D. Tejedor
and F. Garcia-Tellado, Chem. Soc. Rev., 2007, 36, 484; (c)
K. Dong, I. Kianicka, D. Custeau, C. Boudreau, L. Geerts
and S. X. Cai, Mol. Cancer Ther., 2004, 3, 1375.
D. J. Ramon and Y. Miguel, Angew. Chem., Int. Ed., 2005, 26 M. Saha and A. Pal, Synth. Commun., 2013, 43, 1708.
44, 1602; (d) J. Zhu and H. Bienayme, Multicomponent
37096 | RSC Adv., 2020, 10, 37086–37097
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
27 J. L. Wang, D. Liu, Z. J. Zhang, S. Shan, X. Han, 53 J. M. Khurana and A. Chaudhary, Green Chem. Lett. Rev.,
S. M. Srinivasula, C. M. Croce, E. S. Alnemri and Z. Huang,
Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 7124.
28 M. E. A. Zaki, H. A. Soliman, O. A. Hiekal and A. E. Z. Rashad,
Z. Naturforsch., C: J. Biosci., 2006, 61, 1.
29 E. S. Tamany, F. A. El-Shahed and B. H. Mohamed, J. Serb.
Chem. Soc., 1999, 6, 918.
30 N. Foloppe, L. M. Fisher, R. Howes, A. Potter, G. S. Robertson
2012, 5, 633–638.
54 D. Kumar, V. B. Reddy, S. Sharad, U. Dube and S. Kapur, Eur.
J. Med. Chem., 2009, 44, 3805–3809.
55 P. B. Hiremath and K. Kantharaju, ChemistrySelect, 2020, 5,
1896–1906.
56 X. S. Wang, Z. S. Zeng, M. M. Zhang, Y. L. Li, D. Q. Shi,
S. J. Tu, X. Y. Wei and Z. M. Zong, J. Chem. Res., 2006, 228.
and A. E. Surgenor, Bioorg. Med. Chem., 2006, 14, 47924802. 57 A. R. Moosavi-Zare, M. A. Zolgol, R. Salehi-Moratab and
31 Y. M. Litvinov, A. A. Shestopalov, L. A. Rodinovskaya and
A. M. Shestopalov, J. Comb. Chem., 2009, 11(5), 914–919.
32 S. W. Kshirsagar, N. R. Patil and S. D. Samant, Synth.
Commun., 2011, 41, 1320–1325.
33 M. B. M. Reddy, V. P. Jayashankara and M. A. Pasha, Synth.
Commun., 2010, 40, 2930–2934.
34 J. M. Khurana, B. Nand and S. Kumar, Synth. Commun., 2011,
41, 405–410.
35 Y. Peng, G. Song and R. Dou, Green Chem., 2006, 8, 573–575.
E. Noroozizadeh, J. Mol. Catal. A: Chem., 2016, 415, 144–150.
58 G. M. Reddy and J. Raul Garcia, J. Heterocycl. Chem., 2017, 54,
89–94.
59 A. R. Moosavi-Zare, M. A. Zolgol and A. Mousavi-Tashar,
Res. Chem. Intermed., 2016, 42, 7305–7312.
60 Y. A. Tayade, S. A. Padvi, Y. B. Wagh and D. S. Dalal,
Tetrahedron Lett., 2015, 56, 2441–2447.
61 G. M. Reddy and J. Raul Garcia, J. Heterocycl. Chem., 2017, 54,
89–94.
36 L. G. Sharanina, L. G. Promonenkov, V. V. Puzanova and 62 X. Yu, S. Tong, M. Ge, J. Zuo, C. Cao and W. Song, J. Mater.
Y. A. Sharanona, Chem. Heterocycl. Compd., 1982, 18, 607–
611.
37 M. M. Heravi, Y. S. Beheshtiha, Z. Pirnia, S. Sadjadi and
M. Adibi, Synth. Commun., 2009, 39, 3663–3667.
38 H. Valizadeha and A. A. Azimib, J. Iran. Chem. Soc., 2011, 8,
123–130.
39 A. Maleki, R. Taheri-Ledari, J. Rahimi, M. Soroushnejad and
Z. Hajizadeh, ACS Omega, 2019, 4, 1062939.
40 A. Maleki, Polycyclic Aromat. Compd., 2018, 38(5), 402–409.
Chem. A, 2013, 1, 959–965.
63 (a) P. Ghamari kargar, G. Bagherzade and H. Eshghi, RSC
Adv., 2020, 10, 32927–32937; (b) F. F. Kaid, A. T. Totti
Silveira Junior and H. E. Toma, ACS Appl. Nano Mater.,
2020, 10(6), 530.
64 I. Kharbangar, R. Rohman, H. Mecadon and B. Myrboh, Int.
J. Org. Chem., 2012, 2, 282–286.
65 N. Azizi, T. S. Ahooie, M. M. Hashemi and I. Yavari, Synlett,
2018, 29, 645–649.
41 A. Maleki, M. Aghaei and T. Kari, Polycyclic Aromat. Compd., 66 M. R. Youse, O. Goli-Jolodar and F. Shirini, Piperazine,
2019, 39(3), 266–278. Bioorg. Chem., 2018, 81, 326–333.
42 S. Parvaz, R. Taheri-Ledari, M. S. Esmaeili, M. Rabbani and 67 Y. Peng and G. Song, Catal. Commun., 2007, 8, 111–114.
A. Maleki, Life Sci., 2020, 240, 117099.
43 A. Maleki, Z. Varzi and F. Hassanzadeh-Afruzi, Polyhedron,
2019, 171, 193–202.
44 Y. Yu, M. Shen, Q. Song and J. Xie, Carbohydr. Polym., 2018,
183, 91–101.
68 G. Brahmachari and B. Banerjee, ACS Sustainable Chem.
Eng., 2014, 2, 411–422.
69 M. A. Zolgol, M. Tavasoli, R. A. Moosavi-Zare, P. Moosavi,
H. G. Kruger, M. Shirid and V. Khakyzadeh, RSC Adv.,
2013, 3, 25681.
45 A. Kumar, K. M. Rao and S. S. Han, Carbohydr. Polym., 2018, 70 Y. M. Litvinov, A. A. Shestopalov, L. A. Rodinovskaya and
180, 128–144. A. M. Shestopalov, J. Comb. Chem., 2009, 11, 914–919.
46 A. Nouri, M. T. Yaraki, M. Ghorbanpour and S. Wang, Int. J. 71 H. Mecadon, M. R. Rohman, M. Rajbangshi, B. Myrboh,
Biol. Macromol., 2018, 115, 227–235.
47 F. Nemati, M. M. Heravi and A. Elhampour, RSC Adv., 2015,
5, 45775–45784.
48 A. Ghorbani-Choghamarani, Z. Darvishnejad and
M. Norouzi, Appl. Organomet. Chem., 2015, 29, 170–175.
49 G. P. Glaspell, P. W. Jagodzinski and A. Manivannan, J. Phys.
Chem. B, 2004, 108(28), 9604–9607.
I. Kharkongor and B. M. Laloo, Tetrahedron Lett., 2011,
52(25), 3228–3231.
72 H. Mecadon, M. R. Rohman, M. Rajbangshi and B. Myrboh,
Tetrahedron Lett., 2011, 52, 2523–2525.
73 Y. A. Tayade, S. A. Padvi, Y. B. Wagh and D. S. Dalal,
Tetrahedron Lett., 2015, 56, 2441–2447.
74 G. Vasuki and K. Kumaravel, Tetrahedron Lett., 2008, 49(39),
5636–5638.
¨
50 A. Sidorenko, N. Li-Zhulanov, P. Maki-Arvela, T. Sandberg,
A. Kravtsova, A. Peixoto and D. Murzin, ChemCatChem, 75 K. Ablajan, W. Liju, A. Tuoheti and Y. Kelimu, Lett. Org.
2020, 12(9), 2605–2609. Chem., 2012, 9, 639–643.
51 E. Pourian, S. Javanshir, Z. Dolatkhah, S. Molaei and 76 A. R. Moosavi-Zare, H. Afshar-Hezarkhani and M. M. Rezaei,
A. Maleki, ACS Omega, 2018, 3, 5012–5020.
Polycyclic Aromat. Compd., 2017, 1–9.
52 L. F. Gutierrez, E. Nope, H. A. Rojas, J. A. Cubillos,
´
A. G. Sathicq, G. P. Romanelli and J. J. Martınez, Res.
Chem. Intermed., 2018, 44, 5559–5568.
This journal is © The Royal Society of Chemistry 2020
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