Bionanostructure-catalyzed one-pot three-component synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives under solvent-free conditions

Article abstract of DOI:10.1016/j.reactfunctpolym.2016.10.013

In this work, chitosan/graphene oxide as a green bionanocomposite catalyst was synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR) spectra, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC) analysis,

Full text of DOI:10.1016/j.reactfunctpolym.2016.10.013

Bionanostructure-catalyzed one-pot three-component synthesis of 3,4-
dihydropyrimidin-2(1H)-one derivatives under solvent-free conditions
Ali Maleki, Reza Paydar
PII:
S1381-5148(16)30207-3
DOI:
Reference:
doi:10.1016/j.reactfunctpolym.2016.10.013
REACT 3765
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16 October 2016
31 October 2016
Please cite this article as: Ali Maleki, Reza Paydar, Bionanostructure-catalyzed one-pot
three-component synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives under solvent-
free conditions, (2016), doi:10.1016/j.reactfunctpolym.2016.10.013
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Reactive and Functional Polymers
www.sciencedirect.com
Bionanostructure-catalyzed one-pot three-component synthesis of 3,4-
dihydropyrimidin-2(1H)-one derivatives under solvent-free conditions
Ali Maleki * and Reza Paydar
Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran
*Corresponding author. Tel.: +98 21 77240640-50; Fax: +98 21 73021584. E-mail: maleki@iust.ac.ir (A. Maleki).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this work, chitosan/graphene oxide as a green bionanocomposite catalyst was synthesized
and characterized by Fourier transform infrared spectroscopy (FT-IR) spectra, thermal
gravimetric analysis (TGA), differential scanning calorimetry (DSC) analysis, atomic force
microscopy (AFM) and scanning electron microscopy (SEM) images. Then, it was used as a
nanocatalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives by a one-pot
three-component condensation reaction of benzaldehyde, 1,3-ketoesters and urea in excellent
yields and short reaction times under solvent-free conditions. The reaction work-up was simple
and the catalyst could easily be separated from the reaction mixture and reused in subsequent
reactions.
Available online
Keywords:
Bionanocatalyst
Chitosan
Dihydropyridinones
Graphene oxide
Multicomponent reactions
1. Introduction
methodologies suffer from overwhelming drawbacks like long
reaction time, low yield, high reaction temperature, metal
In comparison with classical stepwise strategies in organic
synthesis, multicomponent reactions (MCRs), as processes in
which three or more materials compose to yield a product, have
many advantages and properties such as synthesizing of various
products with different molecular structures in brief reaction
time, saving money, crude materials and so on. MCRs have
represented a rapid and easy access to biologically relevant and
pharmaceutical compounds as a preferred method to design and
discover these compounds [1].
leaching and solubility of the catalyst in the reaction medium.
Recently, paying attention to design and development of green
catalysts and catalytic processes and consequently greener
reaction pathways and methodologies have been increased [23].
In this context, in connection with our previous works [24, 29],
we want to introduce a metal-free organocatalyst as a green
catalytic methodological approach in the field of synthetic
organic chemistry to improve the reaction conditions.
Graphene and graphene oxide (GO) are novel nanomaterials
[30] that have significant applications in nanoelectronics [31],
sensors [32], nanocomposites [33], batteries [34], supercapacitors
and energy storage [35]. In recent years, there has been a rush of
interest in functionalizing GO materials with various polymers
and biopolymers for various applications [24].
Chitosan, as a natural polymer, has attracted considerable
attention due to its unique properties [36, 37]. It also has several
chemical, medicinal and industrial applications [38].
Accordingly, functionalization of GO with chitosan for reaching
the exceptional properties of both materials could be of prime
importance. Accordingly, we have considered GO-chitosan as a
green nanocatalyst for the synthesis of multifunctionalized
DHPMs 4a-s, by a one-pot MCR of various benzaldehydes 1,
1,3-ketoesters 2 and urea 3 at 110 °C under solvent-free
conditions (Scheme 1).
In recent years, dihydropirimidines (DHPMs) have attracted
much attention due to their interesting biologically activities and
properties. Pharmaceutical applications of multifunctionalized
DHPMs are significant such as using for the synthesis of
antiviral, antitumor, antibacterial and antiinflammatory drugs
[2,3]. Recently, many catalysts for the Biginelli reaction and
synthesis of DHPMs have been introduced to improve the
synthesis of this attractive family of compounds such as: 2-oxo-
2-polyfluoroalkylethane-1-sulfones and –sulfamides [4], phytic
acid [5], nanomagnetic-supported sulfonic acid [6], 1-glycyl-3-
methyl imidazolium chloride copper(II) complex [7], pyridine
dicarboxylic acid guanidine–cobalt complex (PDAG-Co) [8],
carbon nanotubes supported by titanium dioxide nanoparticles
[9], cerium(III) trislaurylsulfonate (Ce(LS)3) [10], solid
acidcatalysts [11], trimethylsilyl chloride (TMSCl) [12], solid
silica-based sulfonic acid [13], silica-bonded N-propyl sulfamic
acid [14], magnetic nanoparticles supported imidazolium-based
ionic liquids [15], molybdenum oxide nanoparticle [16], gallium
nafionate [17], phosphonic acid functionalized ordered
mesoporous material [18], phthalimide-N-sulfonic acid [19],
diaryliodonium salts [20], Fe3O4–MWCNT nanocomposite [21]
and ZrO2–Al2O3–Fe3O4 [22]. However, most of these catalytic
Scheme 1. GO-chitosan catalyzed synthesis of DHPMs 4a-s.

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2
2. Results and discussion
FT-IR spectroscopy was used to study and comparison the
bonds of GO-chitosan with GO and chitosan (Figure 1). In the IR
spectrum of GO, the peak at 1739 cm-1 is attributed to the C=O
bonds of carbonyl and carboxyl groups. In the IR spectrum of
chitosan, the peak at 1593 cm-1 is attributed to the C=O bonds of
NHCO. In the spectrum of GO–chitosan, the peak located at
1594 cm-1 is attributed to the C=O bonds of NHCO and the peak
at 1038 cm-1 is attributed to the N–H bending of NH2.
Furthermore, the peak at 1739 cm-1 that is present in the IR
spectrum of GO which indicates the C=O bonds of carboxylic
acids and other carbonyl groups, is absent in the IR spectrum of
GO–chitosan, which means the mass ratio of GO to chitosan is
1:9 [39].
Figure 2. TGA analysis of GO, chitosan and GO-chitosan.
Figure 3. DSC analysis of GO, chitosan and GO-chitosan.
To determine the morphology of GO-chitosan nanocomposite,
scanning electron microscopy (SEM) was used (Figure 4). It is
obvious from SEM photograph that the nanocomposite has a net-
like structure. The wrinkles of GO sheets could easily be
observed in the GO-chitosan SEM image.
Figure 1. FT-IR spectra of GO, chitosan and GO-chitosan.
Thermal properties of the nanocomposite were investigated by
thermal gravimetric analysis (TGA) and differential scanning
calorimetry (DSC). Thermal stability of GO-chitosan is
significantly better than GO and chitosan. As shown in Figure 2,
in GO-chitosan no significant loss of mass is seen even at 300
°C.
Another evidence for the thermal properties improvement of
GO-chitosan in comparison to chitosan is the glass transition
temperatures (Tg) that is obtained from differential scanning
calorimetry (DSC) (Figure 3). The glass transition occurs at 116-
°
°
118 C for pristine chitosan, while it shifts to 162 C for GO-
chitosan composites. Since our reaction is done at high
temperature, GO-chitosan for having better thermal properties is
the best choice as a catalyst.
Figure 4. SEM image obtained from GO-chitosan nanocomposite

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accordingly, the catalyst is indiscernible from the product
sediment and makes some difficulties in the synthesis
procedures. Next, to investigate the efficiency and applicability
of the catalyst in the three-component synthesis of
multifunctionalized DHPMs 4a-s, the Biginelli reaction was
extended to other substituted benzaldehydes and 1,3-ketoesters at
110 °C under solvent-free conditions (Table 2). The results
summarized in Table 2 clearly indicate the scope and generality
of the reaction with respect to various benzaldehydes and 1,3-
ketoesters. It is important to note, methyl acetoacetate give the
product in high yields with short reaction times (Table 2, entries
1-12). The reaction time of some products has been compared
with the literature (Table 2). For example, the reaction time of 4a
in this work is 10 min while the same product in the literature has
been obtained after 20 min (entry 1).
Figure 5. AFM image of GO-chitosan nanocomposite.
Table 1. Optimization of conditions in the reaction of benzaldehyde 1,
1,3-ketoesters 2 and urea 3 at 110 oC
For the confirmation of the nanostructured surface of the
catalyst also atomic force microscopy (AFM) was obtained. As
shown in Figure 5, the average size distribution of GO-chitosan
nanocomposite is 50 nm.
Entry
Catalyst
GO-chitosan
GO-chitosan
GO-chitosan
GO-chitosan
GO-chitosan
GO-chitosan
GO-chitosan
GO
Loading (mg)
Time (min)
Yield (%)
nil
1
2
3
4
5
6
7
8
9
-
50
50
40
30
20
10
10
10
10
1
trace
50
To explore the catalytic effect of GO-chitosan, a pilot
experiment was carried out using the one-pot three-component
reaction of benzaldehyde 1, methyl acetoacetate 2 and urea 3.
5
8
90
10
15
20
15
15
92
According to our investigations, the optimized amount of the
catalyst is 15 mg and the best temperature for this method is 110
°C (Table 1, entry 6).
95
95
GO and chitosan also was used as a catalyst in the pilot
experiment and the same conditions were tested for them but the
results were not as good as GO-chitosan (Table 1, entries 8 and
9). Furthermore, at the time of separation, GO sticks to filter
paper and consequently, reusability decreases. The color of
chitosan, in some cases, is similar to the product sediment and
88
chitosan
85
Table 2. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones 4a-s using GO-chitosan nanocatalyst under solvent-free conditions at 110 °C.
Entry
1
R'
Me
Me
Me
Me
Me
Me
Me
Me
Et
R
Product
4a
4b
4c
Time (min)
Isolated yield (%)
Mp (°C)
213-215
249-250
209-210
199-200
220-222
251-252
284-258
246-246
216-217
222-224
209-212
207-209
216-218
238-239
233-234
215-216
209-211
248–250
187-189
phenyl
10
35
40
30
45
30
10
45
45
45
30
50
40
65
25
65
75
50
45
86
88
85
80
86
83
89
82
80
83
88
75
79
81
89
78
80
76
82
2
3-chlorophenyl
4-chlorophenyl
4-methoxyphenyl
4-methylphenyl
4-hydroxyphenyl
3-nitrophenyl
4-nitrophenyl
4-chlorophenyl
2-chlorophenyl
phenyl
3
4
4d
4e
5
6
4f
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
Et
4j
Et
4k
4l
Et
4-methoxyphenyl
4-methylphenyl
4-hydroxyphenyl
3-nitrophenyl
4-nitrophenyl
2-nitrophenyl
2,4-dichlorophenyl
3-hydroxyphenyl
Et
4m
4n
4o
4p
4q
4r
Et
Et
Et
Et
Et
Et
4s

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4
A possible mechanism for the synthesis of DHPMs 4a-s is
were recorded on a Shimadzu IR-470 spectrometer by the method
of KBr pellet. 1H and 13C NMR spectra were recorded on a
Bruker DRX-500 Avance spectrometer at 500 and 125 MHz,
respectively. The thermal properties of the samples were
shown in Scheme 2 [40]. The formation of N-acylimine
intermediate I, which was produced by the reaction of the
aldehyde with urea, is the first step, which is the key rate-
determining step. This intermediate is activated by the hydrogen
atoms existing in ammonia and the hydroxyl groups of GO–
chitosan. Subsequently, the enol tautomer of ethyl acetoacetate
attack to the imine that is sufficiently electrophilic and an open-
chain ureide II is produced. Then, the intermediate II is
cyclocondensed to the DHPMs 4a-s with expulsion of water.
conducted using
a
thermogravimetric analyzer (TGA-
°
DSC/Mettler Toledo) ranging from room temperature to 700 C
°
at a rate of 10 C/min under N2 atmosphere. The tip radii were
obtained from direct AFM measurements of the tip apex region
in tapping mode. The shell surface was mounted on the AFM
stage and the Triboscope recording unit with transducers and
leveling device was placed on the top of a NanoScope III E 164 |
164 mm2 XY piezo scan base. SEM images were obtained on a
Seron AIS 2100. The products were identified by comparison of
their spectroscopic and analytical data with authentic samples.
One of the most important reasons for choosing this active,
non-toxic and eco-friendly heterogeneous nanocatalyst is its high
degree of reusability. As shown in Figure 6, the GO–chitosan
could be recovered and reused several times in the subsequent
runs using the same recovered catalyst without a considerable
loss of catalytic activity.
3.1. Synthesis of GO
GO was prepared according to Hummers’ method [41]. 40 mL
H3PO4 (85.0%) and 360 mL of concentrated H2SO4 were shed
into the three neck-flask charged with 2 g graphite powder under
stirring conditions. 12 g KMnO4 was gently added into the
reaction pot that was cooled via an ice bath. The cooling bath was
°
removed and the reaction mixture was kept at 45 C for 48 h
being sure that oxidation of graphite has been completed. The
reaction mixture was quenched by 2 L of ice containing 20 mL of
H2O2. The color of the mixture changed from dark brown to
bright yellow that indicates formation of GO. The solid was
gained via centrifugal separation and it washed three times with
10% HCl aqueous solution followed by distilled water until pH
of 5-6 was gained. Ultimately, the resulting GO was washed with
acetone and then dried at 60 °C under vacuum for 30 h.
3.2. Preparation of GO-chitosan nanocomposite
100 mg GO and 2 g chitosan were poured into a 200 mL
round-bottom flask charged with 100 mL DMF. The mixture was
sonicated for 1 h, 0.9 g N,N'-dicyclohexylcarbodiimide (DCC)
and 0.6 g 4-dimethylaminopyridine (DMAP) were then added
into the above suspension and the resulting solution was kept at
room temperature for 48 h. The resulting solid was isolated by
centrifugation and then washed with ortho-dichlorobenzene
(ODCB) (3×100 mL) to remove unreacted chitosan. The mixture
was subsequently washed completely with water (100 mL),
methanol (100 mL) and acetone (100 mL), sequentially. Finally,
it was dried at 60 °C for 24 h under vacuum conditions.
Scheme 2. Proposed mechanism for the synthesis of 3,4-
dihydropyrimidin-2(1H)-ones 4a-s using GO-chitosan nanocomposite.
3.3. General procedure for the synthesis of 3,4-
dihydropyrimidin-2(1H)-ones
The mixture of benzaldehyde (3 mmol), 1,3-ketoester (3.6
°
mmol), urea (4.5 mmol) was heated at 110 C (bath temperature)
in the presence of GO-chitosan (0.015 g) under solvent-free
conditions. After the completion of the reaction, as indicated by
TLC, the resulting reaction mixture was dissolved in 10 mL of
EtOH and filtered to separate the catalyst. The filtered solution
retaining product was placed in the refrigerator to obtain pure
crystalline products in good-to-high yields.
Figure 6. Reusability of GO-chitosan for synthesis of 3,4-
dihydropyrimidin-2(1H)-one 4a-s using GO-chitosan nanocomposite.
3.4. Product characterization data
3. Experimental
Methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-
°
tetrahydropyrimidine-5-carboxylate (4c): m.p.: 209–210 C;
All the solvents, chemicals and reagents were purchased from
Merck, Fluka and Aldrich. Melting points were measured on an
Electrothermal 9100 apparatus and are uncorrected. IR spectra
IR (KBr) υmax (cm-1): 3424 (NH), 3248 (NH), 1705 (C=O), 1647
1
(C=O), 1223 (C–O), 1092 (C–N); H NMR (500 MHz, CDCl3):
δH (ppm) = 2.31 (s, 3H), 3.59 (s, 3H), 5.26 (d, J = 3.5 Hz, 1H),

ACCEPTED MANUSCRIPT
7.26 (m, 4H), 7.51 (s, 1H, NH), 9.11 (s, 1H, NH); 13C NMR
(125 MHz, CDCl3); δC (ppm) = 18.79, 52.60, 57.70, 98.98,
121.23, 123.60, 127.58, 135.00, 142.60, 146.66, 152.62.
catalytic amount of GO-chitosan under solvent-free conditions. A
large number of unique properties in this catalyst have caused to
short reaction time, easy work-up procedure, high reusability of
the nanocatalyst, high atom economy, excellent yields and
environmentally benign reaction conditions. In addition, to the
best of our knowledge, this is the first report of using this
nanocomposite in the synthesis of DHPMs via MCRs.
Ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-
°
tetrahydropyrimidine-5-carboxylate (4k): m.p.: 209–212 C;
IR (KBr) υmax (cm-1): 3424 (NH), 3235 (NH), 1705 (C=O), 1647
1
(C=O), 1223 (C–O), 1092 (C–N); H NMR (500 MHz, CDCl3):
Acknowledgements
δH (ppm) = 1.07 (t, J = 7.1 Hz, CH3), 2.15 (s, 3H, CH3), 3.95 (q,
J = 7.1 Hz, 2H, CH2), 5.40 (s, 1H, CH), 7.25–7.33 (m, 5H, Ar–
H), 7.74 (NH), 9.2 (NH); 13C NMR (125 MHz, CDCl3): δC
(ppm) = 13.70, 17.79, 57.70, 63.60, 100.99, 126.23, 126.60,
127.58, 135.90, 142.60, 146.60, 152.60.
The authors gratefully acknowledge the partial support from
the Research Council of the Iran University of Science and
Technology.
Supporting Information
Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4l): m.p.: 207–209 °C; IR
(KBr) υmax (cm-1): 3424 (NH), 3235 (NH), 1707 (C=O), 1645
Electronic Supplementary Information includes copies of the
1H and 13C NMR analysis of the prepared products.
1
(C=O), 1225 (C–O), 1095 (C–N); H NMR (500 MHz, CDCl3):
δH (ppm) = 1.17 (t, J = 7.1 Hz, 3H), 2.33 (s, 3H), 3.78 (s, 3H),
4.45 (q, J = 7.1 Hz, 2H), 5.41 (d, 1H), 5.65 (s, 1H, NH), 6.18 (d, J
= 3.5 Hz, 2H), 7.22 (d, J = 7.1 Hz, 2H), 7.74 (s, 1H, NH), 13C
NMR (125 MHz, CDCl3): δC (ppm) =14.60, 18.79, 52.60, 57.70,
60.79, 108.99, 121.23, 123.60, 127.28, 135.00, 142.60, 146.60,
162.60.
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nanocatalyst applicable in the organic synthesis. Then, efficient
synthesis of 3,4-dihydropyrimidin-2(1H)-one were carried out
starting from simple and readily available precursors including
benzaldehydes, 1,3-ketoesters and urea in the presence of a

ACCEPTED MANUSCRIPT
6
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ACCEPTED MANUSCRIPT
Bionanostructure-catalyzed one-pot three-component synthesis of 3,4-
dihydropyrimidin-2(1H)-one derivatives under solvent-free conditions
Ali Maleki* and Reza Paydar
Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and
Technology, Tehran 16846-13114, Iran
Graphical abstract

ACCEPTED MANUSCRIPT
8
Highlights
 An environmentally benign biopolymer-based nanocomposite was prepared.
 It was characterized by FT-IR, TGA, DSC, SEM and AFM analyses.
 The first use of this nanocatalyst in the synthesis of dihydropyridinones.
 The products were obtained in high atom economy and easy work-up procedure.