Imidazole functionalized magnetic Fe3O4 nanoparticles as a novel heterogeneous and efficient catalyst for synthesis of dihydropyrimidinones by Biginelli reaction

Article abstract of DOI:10.1007/s00706-013-1085-5

Dihydropyrimidinone derivatives were synthesized in moderate to high yields in one-pot three-component condensation reactions from the corresponding aldehydes, 1,3-dicarbonyl compounds, and urea in the presence of catalytic amounts of imidazole functional

Full text of DOI:10.1007/s00706-013-1085-5

Monatsh Chem (2013) 144:1877–1882
DOI 10.1007/s00706-013-1085-5
ORIGINAL PAPER
Imidazole functionalized magnetic Fe O nanoparticles as a novel
3
4
heterogeneous and efficient catalyst for synthesis
of dihydropyrimidinones by Biginelli reaction
Simin Nazari
Maryam Gorjizadeh
Mozhgan Afshari
•
Shervin Saadat
•
•
Pegah Kazemian Fard
•
•
Eshagh Rezaee Nezhad
Received: 22 April 2013 / Accepted: 4 September 2013 / Published online: 1 October 2013
Ó Springer-Verlag Wien 2013
Abstract Dihydropyrimidinone derivatives were synthe-
sized in moderate to high yields in one-pot three-
component condensation reactions from the corresponding
aldehydes, 1,3-dicarbonyl compounds, and urea in the
presence of catalytic amounts of imidazole functionalized
on magnetic nanoparticles as an efficient, non-toxic, reus-
able, and easily available catalyst under solvent-free
conditions at 80 °C. Compared to the classical Biginelli
reaction, this new method consistently has the advantage of
excellent yields, short reaction times, and methodological
simplicity. Furthermore, the nanomagnetic catalyst could
be readily handled and removed from the reaction mixture
via application of an external magnet, allowing straight-
forward recovery and reuse.
Introduction
The Biginelli reaction was first reported more than a century
ago and recently reviewed [1]; it involves the synthesis of
3,4-dihydropyrimidin-2(1H)-ones (DHPMs) by multicom-
ponent cyclocondensation reaction of ethylacetoacetate,
benzaldehyde, and urea in ethanol.
The dihydropyrimidinone derivatives have attracted
considerable interest in recent years because of promising
biological activities as calcium channel blockers and as
antihypertensive, antibacterial, antiviral, antitumor, anti-
oxidant, and antiinflammatory agents [2–6]. In addition,
several alkaloids containing the dihydropyrimidine core
unit, which also exhibit interesting biological properties,
have been isolated from marine source [7–9]. Therefore,
DHPM compounds have not only attracted much attention
from chemists for synthesis, but also represent an inter-
esting research challenge.
Keywords Dihydropyrimidinone Á Biginelli reaction Á
Magnetic nanoparticles Á Imidazole
At present, with awareness of environmental issues and
the biological importance of these compounds, several
general methods are known for the preparation of dihy-
dropyrimidinones using catalysts such as Brønsted acids
like p-toluenesulfonic acid [10], silica- sulfuric acid [11],
S. Nazari (&)
Department of Chemistry, Sousangerd Branch, Islamic Azad
University, Sousangerd, Iran
e-mail: simin.nazari57@gmail.com
KHSO [12], trifluoroacetic acid, trifluoromethanesulfonic
4
acid [13], Lewis acids such as BF ÁEt O/Cu(OAc) [14],
3
2
2
Yb(OTf) [15], FeCl [16], triphenylphosphine [17],
3
3
S. Saadat Á P. K. Fard
hexaaquaaluminium(III) tetrafluoroborate [18], microwave
heating [19], sonication [20], organocatalysts [21], and
ionic liquids [22].
Faculty of Science, Ahvaz Branch, Islamic Azad University,
Ahvaz, Iran
However, many of these methodologies suffer from
several drawbacks such as a long reaction times, low
product yields, an excess of organic solvent, harsh condi-
tions, occurrence of several side products, and difficulty in
recovery and reusability of the catalysts. Due to these
problems, the development of novel, efficient, and versatile
M. Gorjizadeh Á M. Afshari
Department of Chemistry, Shoushtar Branch, Islamic Azad
University, Shoushtar, Iran
E. R. Nezhad
Department of Chemistry, Payame Noor University,
PO BOX 19395-4697, Tehran, Iran
123

1
878
S. Nazari et al.
catalytic systems for the Biginelli reaction is an active
ongoing research area; thus, there is scope for further
improvement toward milder reaction conditions, variations
of substituents in all three components, and better yields.
Nowadays, magnetic catalysts have attracted enormous
interest because of their specific characteristics. These
types of catalysts, because of their high surface area, bio-
compatibility, and unique magnetic properties, have a
broad range of potential uses among the academic and
industrial scientific community [23–27]. In addition, they
can be easily separated by utilizing the magnetic interac-
tion between the magnetic nanoparticles and an externally
applied magnetic field. In view of this, in the present work,
imidazole functionalized on iron oxide magnetic nanopar-
ticles was successfully prepared, and its performance as a
catalyst for the Biginelli reaction was investigated.
Scheme 1
FeCl3·6H2O
(MeO) Si
3
+
HN
+
Cl
N
FeCl2·4H2O
OH
HO
HO
OH
OH
HO
MNP
HO
OH
OH
N
(MeO)3Si
NH
+
HO
HO
Cl
OH
I
Results and discussion
Synthesis of imidazole functionalized magnetic Fe O
3
4
O O
Si
nanoparticles (Im-MNPs) and its structural
and morphological analysis
O
O
O
O
Si
O
O
N
O
Fe3O4
NPs
NH
O
Si
Cl
MNP-supported systems have the potential to improve the
efficiency, selectivity, and yield of catalytic processes. The
higher surface-to-volume ratio means that much more of
the catalyst is actively participating in the reaction. When
the size of the support is decreased to the nanometer scale,
the surface area is substantially increased, and easy access
of reactants to the active sites can also be achieved [30]. A
study comparing the catalytic activity of immobilized
catalysts depending on support size indicated that nano-
scale supports gave the highest regioselectivities and
product yields [31]. In the present study, naked magnetic
Fe O nanoparticles were prepared through the chemical
Si
O
O
O
O
O
Si
O
Im-MNPs
.
3
4
2
?
3?
coprecipitation method from Fe and Fe ion solutions
in basic media. In the next step, the reaction of Cl groups of
(
3-chloropropyl)-trimethoxysilane with imidazole led to
product 1 (Si-Im). Ultimately, MNPs were coated with Si-
Im to achieve imidazole functionalized magnetic nano-
particles (Scheme 1).
The grafting of imidazole on the surface of magnetic
nanoparticles was verified by FT-IR studies. Figure 1
shows the FT-IR spectra of MNPs and Im-MNPs in the
-
1
5
00–4,000 cm wavenumber range. The IR spectrum of
the Im-MNPs shows characteristic adsorption bands at
-
,412 and 620 cm assigned to the stretching vibration of
1
3
Fig. 1 FT-IR spectra of a MNPs and b Im-MNPs
N–H groups [32] and characteristic peaks of the imidazole
fragment [33], respectively. The existence of linker to the
surface of MNPs is proved by the bands at 1,113 and
C–H stretching vibrations that appear at 2,800 and
-1
-
1
-1
2,900 cm . In addition, the infrared band at 574 cm
was associated with the stretching and torsional vibration
1
,008 cm assigned to the Si–O stretching vibrations [29].
The presence of the anchored propyl group is confirmed by
1
23

Imidazole functionalized magnetic Fe
3
O
4
nanoparticles as a novel
1879
imidazole moieties [29]. Thus, the TGA curves also convey
the obvious information that the imidazole molecules are
successfully grafted onto the magnetic nanoparticles.
The structural and morphological characterization of the
Im-MNPs nanostructure was performed by measuring SEM
using a Philips XL30 scanning electron microscope
(Fig. 3). FESEM observations show that nanoparticles in all
the samples have a spherical shape, indicating the Im-MNPs
has a large surface area. The fabricated nanocatalyst has
homogeneous distributions of nanoparticles, and the mag-
netite particle size distribution has an average of 37 nm.
Application of Im-MNPs as nanomagnetic catalyst
for synthesis of dihydropyrimidinones by Biginelli
reaction
In continuation of our investigation on the use of magnetic
nanocatalysts for chemical transformations [24, 25], herein,
we report the one-pot condensation of different dicarbonyl
compounds with various aldehydes and urea in the pre-
sence of catalytic amounts of Im-MNPs as an efficient and
recyclable catalyst (Scheme 2). In order to optimize the
reaction conditions, the reaction of benzaldehyde, ethy-
lacetoacetate, and urea was conducted under different
conditions in both the absence and presence of Im-MNPs.
Results are given in Table 1.
Fig. 2 TGA curve of Im-MNPs
modes of the magnetite Fe–O bonds in tetrahedral sites
34]. Thus, all the above results indicate that imidazole has
[
been grafted successfully on MNPs.
Figure 2 shows the TGA analysis of Im-MNPs. The
TGA thermogram exhibits the first weight loss of 6 %
below 130 °C, which might be due to the loss of physically
adsorbed water adhering to the sample surface and surface
hydroxyl groups. The second weight loss step of about 1 %
in the region of 230-315 °C may be related to the thermal
crystal phase transformation from Fe O to c-Fe O [29,
Building upon this result, further studies were con-
ducted, and it was found that with 0.15 g of Im-MNPs was
optimum for this reaction and gave product in 91 % yield
in just 30 min (Table 1, entry 4). The reaction temperature
was also optimized; below 80 °C, the reaction proceeded
slowly giving relatively low yield, and no improvement
was observed above 80 °C. Moreover, to see the
3
4
2 3
3
5]. The latest weight loss between 380 and 475 °C
(
*5 %) was due to the breakdown and decomposition of
Fig. 3 SEM images of Im-MNPs
123

1
880
S. Nazari et al.
R1
Scheme 2
O
CHO
O
O
O
R2
Im-MNPs (0.15 g)
Solvent free, 80 °C
NH
+
R2
+
Me
H N
NH2
2
N
R1
O
H
.
After optimizing the conditions, the scope and general-
ity of this protocol were examined by subjecting a broad
range of building block combinations such as aromatic
aldehydes carrying either electron-donating or -withdraw-
ing substituents, different b-ketoesters, and urea using Im-
MNPs as a catalyst under solvent-free conditions. All the
building block combinations reacted very well, giving
moderate to excellent yields with high purity of the desired
products under optimized reaction conditions (Table 2). In
addition, the condensation protocol was fairly general, and
several functionalities, including nitro, chloro, methoxy,
and hydroxy, survived during the course of the reaction.
In a proposed mechanism that is supported by the literature
Table 1 Optimization of reaction conditions for the synthesis of
DHPMs
Entry
Im-MNPs/g
Temp./°C
Time
Yield/%
1
2
3
4
5
6
7
8
–
80
80
80
80
80
25
60
90
6 h
Trace
65
0.05
0.1
85 min
60 min
30 min
30 min
2 h
88
0.15
0.2
91
88
0.15
0.15
0.15
Trace
70
65 min
30 min
89
[36–38], Im-MNPs promoted this heterocyclization reaction
Table 2 One-pot synthesis of substituted 3,4-DHPMs catalyzed by
Im-MNP under solvent-free conditions
by virtue of their inherent Brønsted acidity conferred by the
most acidic N–H hydrogen. This makes the Im-MNPs capable
of bonding with the carbonyl oxygen, increasing the reactiv-
ities of the parent carbonyl compounds. Then nucleophilic
attack of the nitrogen of urea on the activated carbonyl group
resulted in the formation of acylimine, followed by the addi-
tion of b-ketoester to the imine bond, and consequently the
ring was closed by the nucleophilic attack by the amine on the
carbonyl group (Scheme 3) [36, 39, 40].
1
2
R
Entry R
X Yield/% M.p./°C Lit. m.p./°C
1
2
3
4
5
6
7
8
9
1
1
1
1
1
C
6
H
5
Me O 93
Me O 84
Me O 85
Me O 95
Me O 89
OEt O 93
OEt O 91
OEt O 85
OEt O 88
OEt O 82
OMe O 92
OMe O 78
OMe O 83
231–234 233–236 [15]
229–230 230 (dec) [15]
224–225 226–227 [41]
180–182 178–180 [15]
228–230 230–231 [42]
200–202 203–205 [6]
203–205 202–204 [6]
226–228 210–211 [42]
232–234 236–237 [42]
214–216 213–215 [14]
211–213 210–213 [43]
179–182 181–183 [43]
201–204 203–205 [43]
149–150 151–153 [44]
4–NO
2
–C
6
H
4
4–Cl–C
6 4
H
4–CH
3
O–C
–C
6
H
4
4
4–CH
3
6
H
4
6 5
C H
In view of environmentally friendly methodologies,
recovery and reuse of the Im-MNPs is highly preferable.
Im-MNPs did not suffer from extensive mechanical deg-
radation and were quantitatively recovered simply by
adding ethanol to the stirred reaction mixture followed by
application of an external magnet and washing with water
and acetone. It could be reused for subsequent reactions.
Recycled Im-MNPs showed no significant loss of effi-
ciency with regard to yield after four successive runs;
hence, this procedure can be regarded as a novel, facile,
convenient, and environmentally benign method for the
synthesis of 3,4-dihydropyrimidine-2(1H)-one derivatives.
4–CH
3
O–C
–C
4–OH–C
6
H
4–NO
2
6 4
H
6
H
4
0
1
2
3
4
4–Cl–C
6
H
4
6 5
C H
2–Cl–C
4–Cl–C
6
H
H
4
4
6
4–CH O–C
3
6
H
4
OEt
S 90
effectiveness of the imidazolium ion on this catalysis
reaction, we also examined bare MNPs in separate exper-
iments under optimized conditions. The obtained result
showed that in the absence of imidazole support, the
reaction proceeded sluggishly, and after a prolonged
reaction time, a considerable amount of starting material
remained. Therefore, the imidazole groups were strong
promoters of the reaction.
Conclusion
In this work, imidazole functionalized magnetic Fe O
3 4
nanoparticles were successfully prepared, and their per-
formance as a nanomagnetic catalyst for the Biginelli
1
23

Imidazole functionalized magnetic Fe
3
O
4
nanoparticles as a novel
1881
R
Scheme 3
R
O
O
NH2
CO2Et
R
H
H
H
HN
N
+
+
Me
OEt
-
H O
COCH3
NH2
H N
O
2
H
O
2
O
H N
O
2
R
R
CO Et
CO Et
2
2
HN
HN
-
H O
2
O
N
CH3
O
N
H
CH3
.
reaction was investigated. The most interesting features of
the present work include the durability as well as efficient
catalytic activity for one-pot synthesis of dihydropyrimid-
inone derivatives via three-component coupling reactions
of aldehydes, b-ketoesters, and urea under solvent-free
conditions at 80 °C. The attractive features of this method
are high yield, short reaction time, clean reaction profiles,
simple workup procedure, ease of separation, and recy-
clability of the magnetic catalyst, as well as the ability to
tolerate a wide variety of substitutions in the reagents.
method, 3.17 g FeCl Á4H O (1.6 mmol) and 7.57 g
3
2
2
FeCl Á6H O (2.8 mmol) were dissolved in 320 cm of
3
2
2
?
deionized water, such that Fe /Fe = 1/1.75. The mixed
3?
3
solution was stirred under N at 80 °C for 1 h; 40 cm of
2
NH ÁH O was injected into the reaction mixture in one
3
2
portion, stirred under N for another 1 h, and then cooled to
2
room temperature. The black precipitated particles were
washed with doubly distilled water and 0.02 M solution of
NaCl through magnetic decantation. Practically, the NaCl
solution helped delete the excess amount of ammonia,
providing a better and faster decantation of suspended
Fe O nanoparticles in water when an external magnet was
3
4
Experimental
used. Finally, Fe O magnetic nanoparticles were dried
3 4
under vacuum at 70 °C.
Iron(II) chloride tetrahydrate (99 %), iron(III) chloride
hexahydrate (98 %), imidazole, aldehydes, and other
chemical materials were purchased from Fluka and Merck
and used without further purification. Products were char-
Preparation of imidazole functionalized magnetic
Fe O nanoparticles (Im-MNPs)
3
4
1
acterized by comparison of their physical data, IR and H
In the first step, a mixture of 2.00 g 3-chloromethoxy-
propylsilane (10.0 mmol) and 0.68 g imidazole
(10.0 mmol) was heated at 110 °C for 17 h with continu-
1
NMR, and C NMR spectra with known samples. NMR
3
spectra were recorded in CDCl on a Bruker Avance DPX
3
4
00 MHz spectrometer using TMS as internal standard.
ous stirring under N atmosphere. The product of this step
2
3
(Si-Im) was dissolved in 100 cm ethanol/water (volume
The purity determination of the products and reaction
monitoring were accomplished by TLC on silica gel
polygram SILG/UV 254 plates. The FT-IR spectra were
measured on a BOMEM MB-Series 1998 FT-IR spectro-
photometer using the potassium bromide pressed disc
method. The particle morphology was examined by mea-
suring SEM using a Philips XL30 scanning electron
microscope operating at 20 kV. The TGA curve of the
imidazole functionalized on Fe O magnetic nanoparticles
ratio 1:1) solution. The obtained MNP powder (1.5 g) was
3
also dispersed in 200 cm ethanol/water solution by soni-
cation for 30 min and then was added to the ethanolic
solution of Si-Im. After mechanical agitation under N2
atmosphere at 40 °C for 4 h [29], the expected final
product, imidazole functionalized MNPs, was separated by
magnetic decantation, washed with acetonitrile and
dichloromethane, and left to dry in a desiccator.
3
4
was recorded on a BAHR SPA 503 at heating rates of
-
1
1
1
0 °C min . The thermal behavior was studied by heating
–3 mg of samples in aluminum-crimped pans under
General procedure for the synthesis
of dihydropyrimidinones
nitrogen gas flow over a temperature range of 25–600 °C.
A mixture of aldehyde (10 mmol), ethyl acetoacetate
(10 mmol), urea (15 mmol), and 0.15 g Im-MNPs was
stirred at 80 °C for the appropriate time (Table 2). Progress
of the reaction was monitored by TLC using n-hexane -
ethyl acetate as eluent. Upon completion of the reaction
Preparation of the magnetic Fe O nanoparticles
3
4
(
MNPs)
Naked Fe O nanoparticles were prepared via an improved
3
4
3
chemical coprecipitation method [28]. According to this
(20–55 min), the reaction mixture was diluted with 20 cm
123

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S. Nazari et al.
ethanol, the reaction mass was stirred and allowed to cool,
and the catalyst was concentrated on the sidewall of the
reaction vessel using an external magnet and washed with
ethanol. Then the solvent was evaporated under reduced
pressure to obtain a solid residue. The crude product was
14. Hu EH, Sidler DR, Dolling UH (1998) J Org Chem 63:3454
1
1
1
5. Ma Y, Qian C, Wang L, Yang M (2000) J Org Chem 65:3864
6. Lu J, Bai Y (2002) Synthesis 466
7. Debache A, Amimour M, Belfaitah A, Rhouati S, Carboni B
(2008) Tetrahedron Lett 49:6119
18. Litvic M, Vecenaj I, Ladisic ZM, Lovric M, Vinkovic V, Litvic
MF (2010) Tetrahedron 66:3463
washed with cold water and a mixture of EtOH:H O (1:1).
2
1
2
9. Khrustalev DP (2009) Russ J Gen Chem 79:164
0. Yadav JS, Reddy BVS, Reddy KB, Raj KS, Prasad AR (2001) J
Chem Soc Perkin Trans 1:1939
Finally, the solid was recrystallized from hot ethanol to
afford pure product. All products are known compounds
1
and were characterized by IR and H NMR spectroscopic
21. Ding D, Zhao C (2010) Eur J Org Chem 20:3802
2
2
2. Fang D, Zhang D, Liu Z (2010) Monatsh Chem 141:419
3. Sheykhan M, Mamani L, Ebrahimi A, Heydari A (2011) J Mol
Catal A: Chem 335:253
4. Kiasat AR, Nazari S (2012) J Mol Catal A: Chem 365:80
5. Kiasat AR, Nazari S (2013) J Incl Phenom Macrocycl Chem
data and melting points and compared with reported values.
Acknowledgments We are grateful to the Islamic Azad University
Sousangerd Branch for supporting this work.
2
2
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6. Pfeifer A, Zimmermann K, Plank C (2012) Pharm Res 29:1161
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