Ultrasound promoted facile one pot synthesis of highly substituted pyran derivatives catalyzed by silica-coated magnetic NiFe2O4 nanoparticle-supported H14[NaP5W30O110] under mild condition

Article abstract of DOI:10.1039/c6ra20895a

Silica-coated magnetic NiFe₂O₄ nanoparticle-supported Preyssler heteropolyacid (H₁₄[NaP₅W₃₀O₁₁₀]) catalyzed efficiently the synthesis of highly substituted pyran derivatives under ultrasoni

Full text of DOI:10.1039/c6ra20895a

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Ultrasound Promoted Facile One Pot Synthesis of Highly
Substituted Pyran Derivatives Catalyzed by Silica-Coated Magnetic
NiFe O Nanoparticles-Supported H [NaP W O ] under Mild
2
4
14
5
30 110
Conditions
*
1
1
1
1
Behrooz Maleki , Mehdi Baghayeri , Sedigheh Ayazi Jannat Abadi , Reza Tayebee and
2
Amir Khojastehnezhad
1
Department of Chemistry, Hakim Sabzevari University, Sabzevar, 96179ꢀ76487, Iran
Eꢀmail: malekibehrooz@gmail.com, Tel: +98ꢀ44013324
2
Young Researchers and Elite Club, Mashhad Branch, Islamic Azad University, Mashhad, Iran
Abstract
Silicaꢀcoated magnetic NiFe O
nanoparticlesꢀsupported Preyssler heteropolyacid
2
4
(
H [NaP W O ]) catalyzed efficiently the synthesis of highly substituted pyran derivatives
1
4
5
30 110
under ultrasonic irradiation at room temperature in ethanol. In comparison with conventional
methods, our protocol is convenient and offers several advantages, such as shorter reaction times,
higher yields, milder conditions and environmental friendliness. The catalyst can be recovered by
a simple external magnet and used for four times without a significant loss of catalytic activity.
Keywords: Ultrasonic radiation; NiFe O @SiO ꢀH [NaP W O ]; Oneꢀpot synthesis;
2
4
2
14
5
30 110
magnetically retrievable catalyst; Highly substituted pyrans
1

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Introduction
Use of ultrasound as a means of accelerating reactions has long been known in both industry
and academia. Considering the basic green chemistry concepts, ultrasound technique is being
proved to be an important tool in the arsenal of ‘‘Green Chemistry’’. The use of ultrasound for
improving the traditional reactions that require longer reaction time, unsatisfactory yields,
expensive reagents and high temperature is commonly termed as sonochemistry. The
sonochemistry is a simple, novel and powerful tool for the synthesis of organic compounds and
nanoparticles at low temperature. The chemical and physical effects of ultrasound come from
acoustic cavitations such as the formation, growth and implosive collapse of bubbles in a liquid.
The cavitation collapse creates drastic conditions inside the medium for an extremely short time
and temperature of 2000ꢀ5000 K as well as pressure upto 1800 atm inside the collapsing cavity
have been produced under sonic conditions. The cavitation effect produces effective physical,
chemical and biological transformations. Thus ultrasound has applications in material sciences,
1
ꢀ4
life sciences and medicine.
Recently, multiꢀcomponent reactions (MCRs) have received much attention in the field of
synthetic organic chemistry as well as medicinal chemistry, because the strategies of MCR offer
significant advantages over conventional synthetic methodologies. This ensures high atom
economy, good yields and low costs, in short reaction times, minimization of waste, labor,
5
ꢀ8
energy, and avoidance of tedious purification processes.
Nanomagnetic catalysts are one of the most promising areas in organic synthesis and it has
gained considerable attention in recent times. In this aspect synthesis and use of magnetic
nanoparticles has gained significant attention among academic and industrial community because
2

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are nonꢀtoxic, inexpensive, easily available, recyclable and show significant enhancement in
catalytic activity due to small size, high surface area, active sites. Moreover, these magnetic
nanoparticles can be effectively recovered after completion of reaction, without any loss, which
9
ꢀ10
is the drawback of traditional methods like centrifugation and filtration. Similarly, MCRs are
a popular and greener synthetic tool to access diverse molecular scaffolds. Combining both
concepts, nanomagnetic catalyst in MCRs has emerged as a very useful strategy in organic
1
1ꢀ13
synthesis.
In continuation of our research work on MCRs,
catalytic potential of silicaꢀcoated magnetic NiFe O nanoparticlesꢀsupported H [NaP W O ]
14ꢀ21
we were interested to explore the
2
4
14
5
30 110
(
abbreviated NFSꢀPRS) in our MCRs for easy access to diverse and highly substituted pyrans.
From the literature studies we realized that highly substituted pyrans (tetrahydrobenzo[b]pyrans,
ꢀaminoꢀ3ꢀcyanoꢀ4Hꢀpyrans, and pyrano [2, 3ꢀc]pyrazoles) tethered with –NH and –CN
2
2
functionality in the 2,3ꢀposition, as shown as in Fig. 1, possesses diverse pharmacological
properties.
CN
O
NH2
Fig 1. Core of highly substituted 4Hꢀpyrans with amino and nitrile functionality in the adjacent
position having diverse pharmacological properties
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Compounds bearing a pyran framework are found to possess unique, valuable medicinal
2
2ꢀ23
properties and play crucial roles in biochemical processes.
Amongst the humongous scaffold,
4
Hꢀpyran and its derivatives have occupied a distinctive place in the field of medicinal chemistry
2
4ꢀ27
towards the design of biologically active compounds.
They possess varied pharmacological
2
8
29
30
activities such as antibacterial, spasmolytic, anticoagulant, diuretic activity, antitumor, Antiꢀ
3
1
32
Inflammatory, anti HIV, analgesic and myorelaxant activities. These compounds have been
3
3
an asset in combating Schizophrenia, Alzheimer and mycolonous diseases. Additionally, 4Hꢀ
pyrans find their utility in biodegradable agrochemicals, pigments, cosmetics, photoactive
3
4ꢀ35
materials and fluorescent reagents.
Considering their importance, a considerable number of methods are found in the literature
3
6ꢀ55
for the synthesis of these molecules.
Although a wide range of methods exist in the literature,
still better and more efficient methods that provide easy access to these functionalized molecules
are sought after due to the diverse biological applications of these molecules.
Results and discussion
In this research, we combined the advantages of ultrasonic irradiation and nanotechnology to
find the more convenient and efficient reaction of highly substituted pyrans
(tetrahydrobenzo[b]pyrans, 2ꢀaminoꢀ3ꢀcyanoꢀ4Hꢀpyrans, and pyrano [2, 3ꢀc]pyrazoles) (Scheme
1).
4

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O
O
O
Ar
O
R
R
O
CN
3
R
NH2
R= Me, H
O
R
4a-o
O
Ar
Me
OC H5
CN
2
5
EtO
Me
NH2
O
Me
Me
6a-f
N
NiFe O @SiO @ H [NaP W O110]
O
Ar
2
4
2
14
5
30
N
ArCHO + CH (CN)2
2
CN
)
)))))/EtOH/rt
1
2
N
N
O
NH2
7
8a-f
O
O
Ar
Me
Me
2
OC H5
CN
5
N
NH NH .H O
N
H
2
2
2
O
NH2
9
1
0a-g
Scheme 1. Oneꢀpot synthesis of highly substituted pyran derivatives
A synthetic strategy of silicaꢀcoated magnetic NiFe O nanoparticle supported
2
4
H [NaP W O ] (NiFe O @SiO ꢀH [NaP W O ]) is shown in the Fig. 2. At first, silicaꢀ
1
4
5
30 110
2
4
2
14
5
30 110
coated magnetic NiFe O nanoparticle (NiFe O @SiO ) was prepared according to our previous
2
4
2
4
2
5
6ꢀ58
reports.
The NiFe O @SiO was treated with H [NaP W O ] to yield NiFe O @SiO ꢀ
2 4 2 14 5 30 110 2 4 2
H [NaP W O ]. The catalyst was characterized using various methods.
1
4
5
30 110
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Fig 2. Preparation of NiFe O @SiO ꢀH [NaP W O ]
2
4
2
14
5
30 110
The FTꢀIR spectra of NiFe O @SiO (NFS), Preyssler (H [NaP W O ]) and
2
4
2
14
5
30 110
NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS) are compared in Fig. 3. The FT‐IR spectrum of
2
4
2
14
5
30 110
ꢀ1
NiFe O @SiO (Fig. 3a) exhibits high intense absorption peak 1101 cm and this peak is
2
4
2
assigned to the longitudinal and transverse stretching vibration modes of the Si–O–Si
ꢀ1
ꢀ1
asymmetric bond respectively. Additional bands at 813 cm and 470 cm are also identified as
ꢀ1
the characteristic peaks of Si–O–Si bond respectively. The other peak observed at 939 cm
ꢀ2
59ꢀ60
assigned to the SiO3 vibrations indicates the existence of nonbridging oxygen ions.
The
ꢀ1
spectrum of H [NaP W O ] (Fig. 3b) displayed vibrations at 1,162 and 1,090 cm for PꢀO
1
4
5
30 110
ꢀ1
ꢀ1
stretching in H [NaP W O ] structure, 980 and 906 cm for WꢀOꢀW stretching, 802 cm for
1
4
5
30 110
ꢀ1
61
W=O stretching, and 522 cm for PꢀO bending, also there is a high intense absorption peak
ꢀ1
62
around 1614 cm , which was attributed to adsorbed water. In the FTꢀIR spectrum of
NiFe O @SiO ꢀH [NaP W O ] (Fig. 3c) the appeared peaks in the regions about 3565, 1090,
2
4
2
14
5
30 110
ꢀ1
9
60, 913, 794 and 566 cm confirm the successful immobilization of the H [NaP W O ] on
14 5 30 110
the surface of NiFe O @SiO .
2
4
2
6

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Fig 3. The FTꢀIR spectrum of (a) NiFe O @SiO (NFS), (b) Preyssler (H [NaP W O ]) and
2
4
2
14
5
30 110
(
c) NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS).
2 4 2 14 5 30 110
Fig 4a, b shows transmission electron microscopy (TEM) images of the synthesized
NiFe O @SiO (NFS) and NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS) respectively. In the
2
4
2
2
4
2
14
5
30 110
TEM image of NFSꢀPRS (Fig. 4b), the darker parts prove good immobilizing of
H [NaP W O ] on the NiFe O @SiO . Also, the particle size dispersion diagram (Fig. 4c)
1
4
5
30 110
2
4
2
from the NiFe O @SiO shows that these magnetic nanoparticles have a size between 25 to 97
2
4
2
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nm and mean diameter is 53 nm. Furthermore, the morphological features were studied by SEM
technique.
Fig 4. TEM images of NiFe O @SiO (NFS), and NiFe O @SiO ꢀH [NaP W O ] (NFSꢀ
2
4
2
2
4
2
14
5
30 110
PRS) (a and b) and particle size dispersion of NiFe O @SiO (NFS) (c).
2
4
2
The SEM images before (Fig. 5a) and after (Fig. 5b) supported H [NaP W O ] on the
1
4
5
30 110
NiFe O @SiO (NFS) demonstrate that these magnetic nanoparticles are almost spherical with
2
4
2
8

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regular in shape. However, aggregation of nano particles was found and this aggregation might
occur during the coating and supporting process. Moreover, in the energy dispersive Xꢀray
spectrum (EDX) of NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS) (Fig. 5c), the tungsten peaks
2
4
2
14
5
30 110
confirm the successful immobilization of the H [NaP W O ] on the surface of
1
4
5
30 110
NiFe O @SiO . These observations are in agreement with FTꢀIR results.
2
4
2
Fig 5. SEM images of NiFe O @SiO (NFS), and NiFe O @SiO ꢀH [NaP W O ] (NFSꢀ
2
4
2
2
4
2
14
5
30 110
PRS) (a and b) and EDX spectrum of NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS) (c).
2
4
2
14
5
30 110
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In XRD pattern of NiFe O (Fig. 6), the characteristic peaks at 2θ= 30, 35, 43, 54, 57 and 63
2
4
6
4ꢀ65
are similar to the previously reported data for nonmagnetic particles NiFe O4
and in XRD
2
pattern of NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS), the appeared broad peak at 2θ= 20–30,
2
4
2
14
5
30 110
could be assigned an amorphous silica phase in the shell of NiFe O . However, there are no
2
4
6
2
characteristic peaks of H [NaP W O ] in this XRD pattern. These observations indicate
1
4
5
30 110
which H [NaP W O ] is wellꢀdispersed on the surface of NiFe O @SiO and there is no
1
4
5
30 110
2
4
2
crystalline phase of this H [NaP W O ] to be detected by XRD analysis.
1
4
5
30 110
Fig 6. XRD pattern of NiFe O and NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS)
2
4
2
4
2
14
5
30 110
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It is important that the core/shell material should possess sufficient magnetic and
superparamagnetic properties for its practical applications. Magnetic hysteresis measurements
for the NiFe O were done in an applied magnetic field at r.t, with the field sweeping from
2
4
−10000 to +10000 Oersted. As shown in Fig. 7, the M (H) hysteresis loop for the samples was
completely reversible, showing that the nanoparticles exhibit superparamagnetic characteristics.
The hysteresis loops of them reached saturation up to the maximum applied magnetic field. The
−
1
magnetic saturation values of the NiFe O are 16.71 emug at r.t. These nonmagnetic particles
2
4
showed high permeability in magnetization and their magnetization was sufficient for magnetic
separation with a conventional magnet.
Fig 7. VSM curve of NiFe O at room temperature.
2
4
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To achieve the optimization reaction conditions, at first, a mixture benzaldehyde (1 mmol),
malononitrile 2 (2 mmol) and dimedone 3 (1 mmol), as model reaction, was stirred in ethanol (2
ml) in the presence of different amounts of NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS) under
2
4
2
14
5
30 110
reflux conditions (Table 1, entries 1ꢀ3). We also tasted this obtained condition (0.02 g of NFSꢀ
PRS) in the present of different solvents (2 ml, entries 4ꢀ6). As it is shown as Table 1, indicates
that ethanol is more suitable solvent in the synthesis of 4a. When the reaction was performed
under solventꢀfree conditions, a low yield of target product was obtained (Entry 7). To improve
the yield and decrease the reaction time, the ultrasonic conditions was examined using
NiFe O @SiO ꢀH [NaP W O ] NFSꢀPRS (0.02 g) in ethanol at room temperature (entry 8).
2
4
2
14
5
30 110
To further improve the yield and decrease the reaction time, we tried to increase the reaction
temperature under ultrasound irradiation (entries 9ꢀ10). It can be seen from the Table 1 that there
was no remarkable temperature effect on this reaction. The use of NiFe O (NFS), and
2
4
H [NaP W O ] as the catalysts in this reaction resulted in low yields of the product after
1
4
5
30 110
longer reaction times (entries 11–12). In an effort to evaluate the catalytic activity, several other
heteropoly, inorganic and organic acids were examined in this reaction and the results are
summarized in Table 1. As can be seen from this table, among the catalysts screened,
NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS) with 0.02 g catalyst loading proved to be superior
2
4
2
14
5
30 110
to others in producing the best yield (92 %) at room temperature under ultrasoundꢀirradiation
condition (entry 8). When the reaction was attempted without a catalyst, it was found that only a
trace amount of product was obtained (entries 16ꢀ17).
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Table 1. Optimization of Reaction Conditions
O
CHO
O
CN
Conditions
+
CH (CN) +
2 2
H C
3
H C
3
NH2
H C
3
O
H C
3
O
1
2
3
4a
a
Entry Catalyst (g)
NFSꢀPRS (0.02 g)
NFSꢀPRS (0.03 g)
Conditions
Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
Ethanol/reflux
Ethanol/reflux
Ethanol/reflux
Water/reflux
20
20
20
20
20
20
20
5
74
65
56
54
70
32
53
92
90
86
28
59
30
48
NFSꢀPRS (0.01 g)
NFSꢀPRS (0.02 g)
NFSꢀPRS (0.02 g)
NFSꢀPRS (0.02 g)
NFSꢀPRS (0.02 g)
NFSꢀPRS (0.02 g)
NFSꢀPRS (0.02 g)
NFSꢀPRS (0.02 g)
NFS (0.02 g)
Methanol/reflux
Acetonitrile/reflux
0
Solventꢀfree/80 C
Ethanol/US/rt
0
Ethanol/US/35 C
5
0
0
1
2
3
4
Ethanol/US/45 C
5
Ethanol/US/rt
Ethanol/US/rt
Ethanol/US/rt
Ethanol/US/rt
10
10
10
10
PRS (0.02 g)
H SO (3 drops)
2
4
Oxalic acid (0.02 g)
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1
5
6
7
CH COOH (0.1 ml)
Ethanol/US/rt
Ethanol/reflux
Ethanol/US/rt
10
60
60
24
3
b
1
ꢀꢀ
trace
trace
b
1
ꢀꢀ
a
b
Isolated yield. This reaction was carried out in the absence of NFSꢀPRS.
The reaction was successful both with and without ultrasound in ethanol, but, the use of
ultrasound afforded higher yields. Ethanol irradiated with ultrasound can produce tiny bubbles
that can undergo a violent collapse known as cavitation, which generates localized microscopic
“hot spots” with transient high temperatures and pressures to induce favorable conditions for
reactions. The reason for the choice of solvent is explained on the basis of the fact that solvent
affects the transition state, and when polar substrates are used in the synthesis, the transition state
is better solvated by polar solvent and the reaction rate increases, which increases the product
yield. Also EtOH is the most suitable solvent for the even dispersion of catalyst.
Under the optimized reaction conditions (Table 1, entry 8),
a
range of
tetrahydrobenzo[b]pyrans and 2ꢀaminoꢀ3ꢀcyanoꢀ4Hꢀpyrans (4a-o, 6a-f) were synthesized via the
oneꢀpot condensation of malononitrile, various aldehydes, and 1,3ꢀdicarbonyl compounds (1,3ꢀ
cyclohexanedione or 5,5ꢀdimethylꢀ1,3ꢀcyclohexanedione or ethyl acetoacetate) under ultrasonic
irradiation (Table 3). In this reaction system, electron withdrawing substituents and lower steric
hindrance gave higher yields than the derivatives contain electronꢀdonating groups and higher
steric hindrance.
Finally, we have developed this synthetic method for oneꢀpot efficient synthesis of
pyrano[2,3ꢀc]pyrazoles (8a-f) by replacing 1,3ꢀdicarbonyl compounds (1,3ꢀcyclohexanedione or
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5,5ꢀdimethylꢀ1,3ꢀcyclohexanedione or ethyl acetoacetate) with 3ꢀmethylꢀ1ꢀphenylꢀ2ꢀpyrazolineꢀ
5ꢀone (7) under previous optimized condition. All reactions proceeded efficiently and the desired
products (8a-f) were obtained from high to excellent yields in relatively short times without any
formation of byꢀproducts (Table 3).
After successfully synthesizing of a series of pyrano[2,3ꢀc]pyrazoles (8a-f) in good yields,
we replaced 3ꢀmethylꢀ1ꢀphenylꢀ2ꢀpyrazolineꢀ5ꢀone (7) with hydrazine hydrate (9) and ethyl
acetoacetate (5) in same conditions for synthesis of (10a-g) compounds in the presence of a
catalytic amount of NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS). In order to optimize reaction
2
4
2
14
5
30 110
conditions, the reaction of synthesis 10a was chosen as a model reaction and the effect of
different amount of catalyst, temperatures and solvents, was studied. It seems that 0.02 g of NFSꢀ
PRS under ultrasonic irradiation at room temperature has acted better than other conditions and
EtOH showed better result as solvent (Table 2). Under these optimal conditions, the scope and
specificity of this protocol was further investigated by application of various aldehydes (Table
3).
Table 2. Optimization of Reaction Conditions for synthesis of 10a
Me
O
O
CN
Conditions
2
ArCHO + CH (CN)2
+
+
NH NH .H O
2 2 2
N
Me
OC H5
2
N
H
O
NH2
1
2
5
9
10a
a
Entry
1
NFSꢀPRS (g)
0.02
Conditions
Ethanol/reflux
Time (min)
40
Yield (%)
72
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2
0.03
0.01
0.02
0.02
0.02
0.02
0.02
Ethanol/reflux
Ethanol/reflux
Water/reflux
40
40
40
40
40
10
10
61
52
50
67
32
90
90
3
4
5
Methanol/reflux
Acetonitrile/reflux
Ethanol/US/rt
6
7
0
8
Ethanol/US/35 C
a
Isolated yield.
Table 3. Oneꢀpot and green synthesis of tetrahydrobenzo[b]pyrans, 2ꢀaminoꢀ3ꢀ
cyanoꢀ4Hꢀpyrans, and pyrano [2, 3ꢀc]pyrazoles under both conventional and
ultrasonic waves conditions
a
b
0
Entry Products
Time
Yield
(%)
Mp ( C)
(
4a-o, 6a-f, 8a-f, 10a-g) (min)
Found
Lit.
I-II
I-II
4
4
5ꢀ20
92ꢀ74
227ꢀ228 227ꢀ239
O
CN
Me
Me
1
NH2
O
4a
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4
4
Cl
5ꢀ20
91ꢀ67
207ꢀ209 207ꢀ209
O
2
CN
Me
Me
NH2
O
4b
4
4
Me
10ꢀ30
84ꢀ62
212ꢀ214 212ꢀ214
O
3
CN
Me
Me
NH2
O
4c
4
4
NO2
5ꢀ15
94ꢀ80
177ꢀ178 180ꢀ182
O
4
CN
Me
Me
NH2
O
4d
4
4
NO2 5ꢀ15
94ꢀ78
207ꢀ209 210ꢀ211
O
CN
5
Me
Me
NH2
O
4e
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4
4
Br
10ꢀ25
89ꢀ66
199ꢀ201 195ꢀ197
O
6
CN
Me
Me
NH2
O
4f
4
5
Br
10ꢀ20
90ꢀ78
225ꢀ227 228ꢀ230
O
CN
7
Me
Me
NH2
O
4g
4
0
10ꢀ30
80ꢀ57
215ꢀ216 214ꢀ216
O
Cl
CN
Me
Me
8
NH2
O
4h
4
4
OMe
5ꢀ20
91ꢀ73
195ꢀ197 216ꢀ218
O
9
CN
Me
Me
NH2
O
4i
18

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RSC Advances
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DOI: 10.1039/C6RA20895A
4
4
OH 15ꢀ35
81ꢀ60
232ꢀ234 236ꢀ238
O
CN
1
0
Me
Me
NH2
O
4j
4
4
5ꢀ20
90ꢀ60
229ꢀ231 234ꢀ236
O
CN
1
1
NH2
O
4k
4
4
Cl
5ꢀ20
89ꢀ66
226ꢀ227 224ꢀ226
O
1
2
CN
NH2
O
4l
4
4
NO2
5ꢀ15
92ꢀ78
232ꢀ233 230ꢀ232
O
1
3
CN
NH2
O
4m
19

RSC Advances
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DOI: 10.1039/C6RA20895A
4
4
NO2
5ꢀ15
91ꢀ80
236ꢀ238 237ꢀ239
O
1
4
CN
NH2
O
4n
3
8
OMe
10ꢀ30
90ꢀ70
189ꢀ190 190ꢀ192
O
1
5
CN
NH2
O
4o
4
4
20ꢀ300
86ꢀ60
189ꢀ191 190ꢀ192
O
CN
EtO
1
5
Me
O
NH2
6a
5
2
NO2
15ꢀ180
92ꢀ72
184ꢀ187 187ꢀ188
O
CN
1
6
EtO
Me
O
NH2
6b
20

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5
2
NO2
15ꢀ180
91ꢀ74
174ꢀ176 175ꢀ175
O
1
7
CN
EtO
Me
O
NH2
6c
5
2
Cl
20ꢀ240
87ꢀ66
177ꢀ179 180ꢀ181
O
CN
1
8
EtO
Me
O
NH2
6d
5
2
Br
20ꢀ240
86ꢀ64
182ꢀ184 180ꢀ181
O
1
9
CN
EtO
Me
O
NH2
6e
5
2
Me
35ꢀ360
83ꢀ56
175ꢀ176 175ꢀ176
O
2
0
CN
EtO
Me
O
NH2
6f
21

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4
4
5ꢀ30
89ꢀ62
165ꢀ167 165ꢀ166
Me
CN
2
1
N
N
O
NH2
8a
4
4
Cl
O
5ꢀ30
90ꢀ72
184ꢀ186 182ꢀ184
2
2
Me
CN
N
N
NH2
8b
4
4
Br
5ꢀ30
92ꢀ78
184ꢀ186 187ꢀ188
Me
2
3
CN
N
N
O
NH2
8c
22

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4
4
OMe
5ꢀ30
90ꢀ74
172ꢀ173 170ꢀ172
Me
2
4
CN
N
N
O
NH2
8d
4
4
NO2
5ꢀ20
94ꢀ80
189ꢀ190 190ꢀ192
Me
CN
2
5
N
N
O
NH2
8e
NO2
5ꢀ20
93ꢀ82
196ꢀ197 197ꢀ199
2
6
Me
CN
N
N
O
NH2
8f
2
3

RSC Advances
Page 24 of 40
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4
4
1
0ꢀ40
90ꢀ72
244ꢀ245 244ꢀ245
Me
N
CN
2
7
N
O
NH2
H
10a
4
4
OMe
10ꢀ30
91ꢀ75
212ꢀ214 213ꢀ215
2
8
Me
CN
N
N
H
O
NH2
10b
4
4
Br
10ꢀ30
92ꢀ71
248ꢀ250 246ꢀ248
2
9
Me
N
CN
N
O
NH2
H
10c
2
4

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4
4
1
0ꢀ30
92ꢀ78
224ꢀ226 225ꢀ226
S
Me
N
CN
3
0
N
O
NH2
H
10d
4
4
Br
10ꢀ30
92ꢀ72
223ꢀ225 224ꢀ226
Me
CN
3
1
N
N
H
O
NH2
10e
4
4
NO2
10ꢀ25
94ꢀ81
251ꢀ253 250ꢀ252
3
2
Me
N
CN
N
O
NH2
H
10f
2
5

RSC Advances
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4
4
NO2
10ꢀ25
94ꢀ80
228ꢀ230 231ꢀ233
Me
N
3
3
CN
N
O
NH2
H
10g
a
Reaction under ultrasonic irradiation at room temperature and the ultrasonic
power 250 W, irradiation frequency 40 kHz (I), under reflux conditions in
b
ethanol (II). Isolated yields.
In all reactions mentioned above, the reaction procedure was simple, clean and completion of
the reaction was identified by TLC. Generally the product formed after completion of the
reaction is separated from catalyst by tedious work up procedures which are not energy efficient
and green. Further the purification of products by traditional methods (column chromatography)
does not support green chemistry principles as large amount of organic solvent was used. But in
our protocol the catalyst was separated from reaction product using external magnet within
seconds.
The recovery and reusability of catalyst is an important aspect for chemists from economic,
cost effectiveness and environmental point of view. For this purpose, the recycling of NFSꢀPRS
was investigated using the synthesis of 4a and 8c. After the completion of the reaction, the NFSꢀ
PRS catalyst was separated from the reaction mixture by use of an external magnetic field, dried
0
at 100 C for 2 h, and reꢀused in the same reaction. It was reꢀused in the model reactions to give
2
6

Page 27 of 40
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DOI: 10.1039/C6RA20895A
4a and 8c in yields of 92%, 92%, 90%, 89% and 92%, 90%, 90%, 88% respectively, for four
consecutive runs.
Environmentally friendly is becoming increasingly important in modern organic synthesis.
This requires us to avoid the use of toxic solvents and reagents, minimize the energy
requirement, and utilize renewable catalysts. The use of ultrasonic irradiation and
NiFe O @SiO ꢀH [NaP W O ] are items that can fulfill these requirements. NiFe O @SiO ꢀ
2
4
2
14
5
30 110
2
4
2
H [NaP W O ] is easily separated using a magnet and can be reꢀused without loss of activity.
1
4
5
30 110
It is very stable due to moisture insensitivity, highly efficient due to its greater surface area and
inexpensive because of the reꢀusability. These properties make NiFe O @SiO ꢀ
2
4
2
H [NaP W O ] attractive as novel magnetically separable catalyst for the synthesis of highly
1
4
5
30 110
substituted pyran derivatives. Also, the ultrasound can be raised the rate of reaction and therefore
reduced the energy consumption.
We herein propose a mechanism in Scheme 2 for the formation of highly substituted pyran
derivatives under the reaction conditions where NiFe O @SiO ꢀH [NaP W O ] (NFSꢀPRS)
2
4
2
14
5
30 110
catalyst acts as an acid.
2
7

RSC Advances
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DOI: 10.1039/C6RA20895A
O
O
O
Ar
H
CN
NH
H+
R
R
R
R
O
H
OH
OH
Me
R
O
R
H
Ar
O
O
O
O
O
H+
O
CN
NH
EtO
O
Ar
H
EtO
Me
EtO
H
H+
Me
H
Ar
H
N
Ar
CN
CN
NFS
Ar
O
H
Me
N
Me
N
H
CH3
NC
H+
H+
N
O
OH
OH
N
N
HN
N
C
H
H
C
NC
NH
C
CN
Ar
O
H
Me
N
Me
N
CH3
NC
HN
OH
Me
O
O
H+
O
H+
NH NH .H O
2
2
2
N
O
N
H
N
H
N
H
EtO
Me
O
EtO
H
Ar
Me
Ar
Ar
O
Ar
O
Me
CN
NH2
CN
CN
NH2
CN
N
EtO
N
Tautomerism
R
N
O
N
H
O
NH2
NH2
O
R
Me
4a-o
6a-f
8a-f
10a-g
Scheme 2. Proposed mechanism for the synthesis of highly substituted pyran derivatives
In order to examine the efficiency of the present method for the synthesis of highly
substituted pyran derivatives, compounds 4a, 4e, 4l, 8c and 10c were compared with some of
those reported in the literature (Table 4). As can be seen, the reaction catalyzed by
NiFe O @SiO ꢀH [NaP W O ] gives a comparable yield and requires less time than other
2
4
2
14
5
30 110
protocols. Even other functionalized magnetic nano particles does not show better results than
our catalyst.
2
8

Page 29 of 40
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DOI: 10.1039/C6RA20895A
Table 4. Comparison of present method with other reported protocols for the synthesis of highly
substituted pyran derivatives
Time Yield
Ref
Product Reaction conditions
Fe O @SiO –imid–PMA/H O/Us/rt
a
(min) (%)
7
120
15
40
12
20
120
5
96
81
86
90
92
93
90
92
95
92
89
90
98
94
94
89
84
82
89
85
87
90
90
92
[36]
[37]
3
4
2
2
Tetraꢀmethyl ammonium hydroxide/H O/rt
2
NH H PO /Al O /EtOH/Reflux
[40]
4
2
4
2
3
Fe O @SiO @NHꢀNH ꢀPW/H O/Reflux
[41]
3
4
2
2
2
4
a
Magnetic La0.7Sr0.3MnO
3
nanoparticles/EtOH/Us/rt
[42]
0
Fe O @SiO @TiO /Solventꢀfree/100 C
[45]
3
4
2
2
Urea/EtOH: H O (1:1, v:v)/rt
[55]
2
NiFe O @SiO @H [NaP W O ]/EtOH/Us/rt
Present work
[36]
2
4
2
14
5
30 110
Fe O @SiO –imid–PMA/H O/Us/rt
7
3
4
2
2
Tetraꢀmethyl ammonium hydroxide/H O/rt
120
45
15
8
[37]
2
Potassium phosphate/EtOH: H O (80:20, v:v)/rt
[38]
2
4
4
8
e
NH
4
H
2
PO
4
/Al
2
O
3
/EtOH/Reflux
[40]
Magnetic La Sr MnO nanoparticles/EtOH/Us/rt
[42]
0
.7 0.3
3
Nano Na CaP O /H O/Reflux
10
5
[50]
2
2
7
2
NiFe O @SiO @H [NaP W O ]/EtOH/Us/rt
Present work
[38]
2
4
2
14
5
30 110
Potassium phosphate/EtOH: H O (80:20)/rt
60
25
25
5
2
l
NH
4
H
2
PO
/Al
4
2
O
3
/EtOH/Reflux
[40]
NiFe O @SiO –H PW O /EtOH/Reflux
[44]
2
4
2
3
12 40
NiFe O @SiO @H [NaP W O ]/EtOH/Us/rt
Present work
[40]
2
4
2
14
5
30 110
0
NH H PO /Al O /Solventꢀfree/80 C
20
11
5
4
2
4
2
3
Magnetic La Sr MnO nanoparticles/EtOH/Us/rt
[42]
0
.7 0.3
3
c
NiFe
2
O
4
@SiO
2
–H
PW12O
3
40/EtOH/Reflux
[44]
Nano Na CaP O /H O/Reflux
15
5
[50]
2
2
7
2
NiFe O @SiO @H [NaP W O ]/EtOH/Us/rt
Present work
2
4
2
14
5
30 110
2
9