An efficient protocol for the one-pot multicomponent synthesis of polysubstituted pyridines by using a biopolymer-based magnetic nanocomposite

Article abstract of DOI:10.1016/j.crci.2015.09.002

A biopolymer cellulose-based magnetic composite nanocatalyst was prepared and characterized by using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). Then, it was used efficiently in the multicomponent synthesis of polysu

Full text of DOI:10.1016/j.crci.2015.09.002

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Full paper/Memoire
An efficient protocol for the one-pot multicomponent
synthesis of polysubstituted pyridines by using
a biopolymer-based magnetic nanocomposite
b
Ali Maleki a, , Abbas Ali Jafari , Somayeh Yousefi a,b, Vahid Eskandarpour a
*
a Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology,
Tehran 1684613114, Iran
b Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195.741, Iran
A R T I C L E I N F O
A B S T R A C T
biopolymer cellulose-based magnetic composite nanocatalyst was prepared and
Article history:
A
Received 27 July 2015
Accepted after revision 3 September 2015
Available online xxx
characterized by using scanning electron microscopy (SEM) and energy dispersive X-ray
spectroscopy (EDX). Then, it was used efficiently in the multicomponent synthesis of
polysubstituted pyridines under mild reaction conditions and using an easy work-up
procedure at room temperature in ethanol. The nanocatalyst can be recovered easily and
reused several times without significant loss of catalytic activity.
Keywords:
Nanocatalyst
Cellulose
ß 2015 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Multicomponent reaction
Pyridine
Magnetic
1. Introduction
components under reflux condition [5,7], in conventional
heating mode [8,9], or in ionic liquids [10], which usually
Nitrogen heterocycles play important roles in biology.
They have a significant place among natural products and
synthetic compounds because of their exclusive properties
as traditional key elements of numerous drugs [1]. Pyridine
derivatives are an important class of heterocyclic organic
compounds that exist in many active pharmaceuticals and
functional materials [2]. Among them, 2-amino-3-cyano-
pyridine derivatives are known to have multiple biological
activities, such as anti-inflammatory, analgesic and anti-
pyretic properties [3]. They are known as IKK-b inhibitors
[4], adenosine receptor antagonists, potent inhibitor of
HIV-1 integrase [5], and are also used for the synthesis of
antiexcitotoxic agents [6].
requires harsh reaction conditions, long reaction times,
expensive transition metal catalyst or operational com-
plexity.
Magnetic nanoparticles (MNPs) demonstrate high
activity and selectivity (similar to a homogeneous catalyst)
and can be easily separated and recovered. Magnetically
supported catalysts can be recovered with an external
magnet owing to the paramagnetic character of the
support, and the catalysts can be reused in another cycle.
To consider the iron oxide nanoparticles, the iron atoms on
the surface act as Lewis acids and coordinate with
molecules that donate lone pair electrons [11]. Forming
MNPs in polymer media is an acceptable way for applying
them due to their ease of processing, solubility, lesser
toxicity, and also because of the possibility of controlling
the growth of the resulting NPs [12]. The most common
organic polymer that is biocompatible and environmental
friendly is cellulose. It also has characteristic properties
such as hydrophilicity, chirality, degradability, and broad
The preparation of 2-amino-3-cyanopyridine derivati-
ves has been reported in the literature via a reaction of four
*
Corresponding author.
E-mail address: maleki@iust.ac.ir (A. Maleki).
http://dx.doi.org/10.1016/j.crci.2015.09.002
1631-0748/ß 2015 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Maleki A, et al. An efficient protocol for the one-pot multicomponent synthesis of
polysubstituted pyridines by using a biopolymer-based magnetic nanocomposite. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.09.002

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chemical variability initiated by the high donor reactivity
of the OH groups, which makes it an excellent candidate as
a catalyst support [13,14].
magnetic nanocomposite as a catalyst for the synthesis of
highly substituted pyridines.
In recent decades, multicomponent reactions (MCRs)
have attracted organic chemists because of some remark-
able advantages over conventional bimolecular reactions
owing to their convergence, atom-economy, operational
simplicity, structural diversity and shortness of the
synthetic pathway. MCRs have recently gained a new
dimension in the field of designing methods to produce
elaborate libraries of biologically active compounds and
new molecular frameworks for potential drugs with
diverse pharmacological activities [15].
In continuation of our previous works on the prepara-
tion and application of nanocatalysts in MCRs [16], herein,
we report a simple, efficient and one-pot four-component
protocol for the synthesis of highly substituted pyridines 5
or 6 via the reaction of various aromatic aldehydes 1,
malononitrile 2, cyclic ketones 3 and ammonium acetate 4
in the presence of a catalytic amount of cellulose-based
magnetic composite nanocatalyst (Fe3O4/cellulose) at
room temperature in ethanol (Scheme 1).
2. Results and discussion
The in-situ preparation of cellulose nanocomposite
containing Fe3O4 nanoparticles was described in our
previous work [16a]. Cellulose films were immersed into
FeCl3 solution, Fe3+ could be readily impregnated into the
cellulose films through the pores. The incorporated Fe3+
ions could be bound to cellulose macromolecules via
electrostatic interaction, because the electron-rich oxygen
atoms of the polar hydroxyl of cellulose are expected to
interact with electropositive transition metal cations.
The particle size was studied by scanning electron
microscopy (SEM). As can be seen in Fig. 1, the morphology
of the nanocomposite displayed a homogeneous structure.
So, the iron ions were effectively diffused and adsorbed
into the hydroxyl groups of cellulose by electrostatic
interaction.
In Fig. 2, the energy dispersive X-ray spectroscopy (EDS)
pattern, obtained from SEM, indicates that there were only
C, O and Fe elements in the composite film, suggesting that
the iron oxide has been composed in the cellulose films to
form a suitable nanostructure catalyst.
To the best of our knowledge, not only is there any report
of obtaining the product at room temperature, but also, this
is the first report of application of a cellulose-based
Scheme 1. Synthesis of highly substituted pyridines.
Fig. 1. SEM image of our Fe3O4/cellulose nanocomposite.
Please cite this article in press as: Maleki A, et al. An efficient protocol for the one-pot multicomponent synthesis of
polysubstituted pyridines by using a biopolymer-based magnetic nanocomposite. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.09.002

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3
Fig. 2. EDS pattern of our Fe3O4/cellulose nanocomposite.
Then, we have prepared highly substituted pyridines via
the reaction of aldehydes, cyclic ketones, malononitrile and
ammonium acetate in the presence of catalytic amounts of
the magnetic nanocomposite in ethanol at room tempera-
ture. First, to optimize the reaction conditions, a model
experiment was carried out by starting from 4-methylben-
zaldehyde (1 mmol), cyclohexanone (1 mmol), malononi-
trile (1 mmol) and ammonium acetate (1.5 mmol) at room
temperature (Table 1). To clarify the need for the Fe3O4/
cellulose nanocatalyst, an experiment was conducted in the
absence of Fe3O4/cellulose and also in the presence of
cellulose and Fe3O4 alone (entries 1–3, respectively).
According to our results, the best yield was obtained in
the presence of Fe3O4/cellulose (1 mg). As is evident from
Table 1, by increasing the amount of nanocomposite
catalyst, the yield of the reaction was not improved and
also by decreasing it to 0.5 mg, the desired product was
obtained in lower yield (70%). In addition, various solvents
such as CH3CN, DMF, CHCl3 and EtOH were used to find the
optimum reaction media. It was found that the best results
were obtained in EtOH as a green solvent.
In the previous reports, cyclic ketones, such as
cyclohexanone and cycloheptanone, are rarely used as
starting material to prepare polysubstituted pyridines,
probably because of their low activity. As indicated from
Table 2, we obtained the same products under better
conditions in comparison with literature methods.
After optimizing the reaction conditions, some other
substituted pyridine derivatives were synthesized by using
various aldehydes and ketones. The products 5f and 6e were
characterized by IR, 1H NMR and 13C NMR spectral analysis.
To our knowledge, there is not any report of physical
properties and spectral data of the two above-mentioned
products. The results are summarized in Table 3.
To demonstrate the recyclability of the present
composite nanocatalyst, it was recovered and reused
Table 1
Optimization of the reaction conditions.
Entry
Catalyst
Amount (mg)
Solvent
Time (h)
Yield (%)
–
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
DMF
24
6
6
3
3
3
3
3
6
6
6
32
1
2
3
4
5
6
7
8
9
10
Cellulose
2
Trace
Fe3O4
2
35
Fe3O4/cellulose
Fe3O4/cellulose
Fe3O4/cellulose
Fe3O4/cellulose
Fe3O4/cellulose
Fe3O4/cellulose
Fe3O4/cellulose
Fe3O4/cellulose
2
80
8
70
5
80
1
80
0.5
5
70
No reaction
No reaction
No reaction
5
5
CHCl3
Table 2
Comparison of the nano-Fe3O4/cellulose with other literature reports for 5b and 6b.
Entry
R
Product
Catalyst
Solvent
Temp.
Time (h)
Yield (%)
Ref.
1
2
3
4
5
6
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
5b
5b
5b
6b
6b
6b
[bmim]OH
[bmim]OH
Benzene
Ethanol
Benzene
Ethanol
Ethanol
80 8C
Reflux
r.t.
4
88
46
98
68
90
90
[10]
–
4
[7]
Fe3O4/cellulose
–
3
Present work
[7]
Reflux
70
4
Au/MgO
2.5
3
[9]
Fe3O4/cellulose
r.t.
Present work
Please cite this article in press as: Maleki A, et al. An efficient protocol for the one-pot multicomponent synthesis of
polysubstituted pyridines by using a biopolymer-based magnetic nanocomposite. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.09.002

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Table 3
Synthesis of highly substituted pyridines via 4-CR in the presence of a cellulose-based magnetic nanocatalyst in EtOH at room temperature.
Entry
1
RCHO
Product
Time (h)
Yielda (%)
Mp (8C)
Obsd
Lit.
4
93
235–237
234–235 [7]
H
H
O
CN
1a
1b
N
O
NH2
5a
2
3
98
232–234
232–233 [17]
O
CN
O
N
NH2
5b
5c
3
3
80
248–249
248–249 [10]
H
O
CN
1c
N
NH2
4
5
75
256–258
255–256 [10]
Br
O
H
CN
Br
1d
N
NH2
5d
5
5
85
256–258
258–259 [17]
CI
H
O
CN
Cl
1e
NH2
N
5e
6
4
87
245–246
Present work
O
H
S
S
CN
1f
N
NH2
5f
7
1a
4
92
229–230
227–228 [9]
CN
NH2
N
6a
Please cite this article in press as: Maleki A, et al. An efficient protocol for the one-pot multicomponent synthesis of
polysubstituted pyridines by using a biopolymer-based magnetic nanocomposite. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.09.002

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5
Table 3 (Continued )
Entry
RCHO
Product
Time (h)
3
Yielda (%)
Mp (8C)
Obsd
Lit.
8
1b
90
225–227
226–227 [7]
O
N
CN
NH2
6b
6c
9
1c
3
80
236–237
232–233 [7]
CN
N
NH2
10
1d
5
70
233
236–237 [9]
Br
CN
N
N
NH2
6d
6e
11
1f
4
85
245–247
Present work
S
CN
NH2
a
Isolated yields.
has been developed by using various aromatic and
heteroaromatic aldehydes, cyclic ketones, malononitrile
and ammonium acetate in the presence of a catalytic
amount of Fe3O4/cellulose nanocatalyst at room tempera-
ture. This method includes some important advantages
such as the use of an efficient, inexpensive, eco-friendly
and magnetically recyclable composite nanocatalyst and of
EtOH as
a green reaction media, room-temperature
operating conditions, short reaction times, and an easy
work-up procedure. In addition, to best of our knowledge,
this is the first report of synthesizing polysubstituted
pyridines at room temperature.
Fig. 3. Recyclability of the nanocatalyst.
4. Experimental
several times in the model reaction. After completion of
the reaction, the nanocatalyst was simply removed by
using an external magnet, washed with EtOH and reused in
the subsequent fresh reactions. As shown in Fig. 3, there is
no significant loss of catalytic activity after five times.
4.1. General
All solvents, chemicals and reagents were purchased
from Merck, Fluka and Aldrich chemical companies.
Melting points were measured on an Electrothermal
9100 apparatus and are uncorrected. All reactions and
the purity of the products were monitored by thin-layer
chromatography (TLC) using aluminum plates coated with
silica gel F254 plates (Merck) using ethyl acetate and n-
hexane as eluents. The spots were detected either under
3. Conclusions
In summary, a facile, one-pot and four-component
protocol for the synthesis of highly substituted pyridines
Please cite this article in press as: Maleki A, et al. An efficient protocol for the one-pot multicomponent synthesis of
polysubstituted pyridines by using a biopolymer-based magnetic nanocomposite. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.09.002

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UV light or by placing them in an iodine chamber. IR
spectra were recorded on a Shimadzu IR-470 spectrome-
ter. The 1H and 13C NMR spectra were recorded on a Bruker
NMR-500 MHz spectrometer. SEM images were obtained
on a Seron AIS 2100. EDX spectra were recorded on
Numerix DXP-X10P.
88.6, 117.5, 126.3, 128.4, 128.9, 129.3, 137.2, 145.9, 159.0,
168.5.
Acknowledgements
The authors gratefully acknowledge the partial support
from the Research Council of the Iran University of Science
and Technology.
4.2. Preparation of Fe3O4/cellulose nanocomposite
Cellulose was dissolved directly in the NaOH aqueous
solution which was precooled to À8 8C to prepare 4 wt%
cellulose solution. The resulting solution was centrifuged
at 2000 rpm for 30 min for degasification. The cellulose
solution was cast onto a glass plate to give a thickness of
0.5 mm and was then immersed in a 2000-mL H2SO4
(5 wt%) bath for 5 min for the coagulation and the
regeneration of the cellulose films. The resulting films
were washed with running water and subsequently with
distilled water. The wet films obtained were immersed in a
500-mL mixture of aqueous FeCl3 for 24 h; we then washed
out the iron ions adsorbed on the surface of the film with
distilled water. Then, the films were immersed in 500 mL
of aqueous NaOH (4 mol/L) for 20 min and were then
rinsed with distilled water for several times.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
crci.2015.09.002.
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Please cite this article in press as: Maleki A, et al. An efficient protocol for the one-pot multicomponent synthesis of
polysubstituted pyridines by using a biopolymer-based magnetic nanocomposite. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.09.002