Secondary amines immobilized inside magnetic mesoporous materials as a recyclable basic and oxidative heterogeneous nanocatalyst for the synthesis of trisubstituted pyrimidine derivatives

Article abstract of DOI:10.1007/s11164-015-2284-y

A novel magnetic MCM-41 nanocomposite-based catalyst is reported for the first time in the multicomponent synthesis of trisubstituted pyrimidines in which piperazine is immobilized inside the mesochannels of magnetic MCM-41 as an organic base (α-Fe_2<

Full text of DOI:10.1007/s11164-015-2284-y

Res Chem Intermed
DOI 10.1007/s11164-015-2284-y
Secondary amines immobilized inside magnetic
mesoporous materials as a recyclable basic
and oxidative heterogeneous nanocatalyst
for the synthesis of trisubstituted pyrimidine derivatives
Reza Aryan1 Hamid Beyzaei1 Masoomeh Nojavan1
Tahereh Dianatipour1
•
•
•
Received: 25 July 2015 / Accepted: 12 September 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A novel magnetic MCM-41 nanocomposite-based catalyst is reported
for the first time in the multicomponent synthesis of trisubstituted pyrimidines in
which piperazine is immobilized inside the mesochannels of magnetic MCM-41 as
an organic base (a-Fe2O3-MCM-41-piperazine). This nanocatalyst was thoroughly
characterized by various techniques such as FT-IR, XRD, SEM, TEM, EDX and N2-
adsorption isotherms. Very uniform dispersion and ordered mesopores of a-Fe2O3-
MCM-41 causes piperazine molecules to be distributed very finely on the internal
surface of the pores, resulting in a very useful and robust magnetically recyclable
amine-based heterogeneous nanocatalyst. This catalytic system showed remarkable
activity in the solvent-free synthesis of 2,4,6-trisubstituted pyrimidine derivatives.
Keywords Magnetic mesoporous material Á Hybrid organic–inorganic catalyst Á
Piperazine Á Pyrimidine derivatives Á Multicomponent reaction
Introduction
The application of hybrid composite materials comprised of both organic and
inorganic compounds will lead to appropriate physical properties crucial for
catalytic purposes. The most obvious advantage of this inorganic–organic hybrid
catalyst is that it can act the role of a solution for the strict limitations of
homogeneous catalysts through easy catalyst separation, a high degree of reusability
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2284-
y) contains supplementary material, which is available to authorized users.
&
Reza Aryan
rezaaryanchemist@yahoo.com; rezaaryan@uoz.ac.ir
1
Department of Chemistry, Faculty of Science, University of Zabol,
Zabol, P. O. Box: 9861335856, Iran
123

R. Aryan et al.
and selectivity in organic processes [1–3]. The magnetic iron oxide nanoparticles
(NPs) are significantly attended to by researchers due to their distinctive properties
and potential applications in various fields [4–6]. Their paramagnetic nature enables
the separation of these NPs from the reaction mixture using an external magnetic
field. In general, the tendency of naked NPs to aggregate into large clusters causes
them to lose their specific properties. This problem can be overcome by coating the
NPs on silica, polymer or carbon shells [7–9]. These coatings prevent the magnetic
agglomerations in liquids and preserve their paramagnetic properties. MCM-41 has
been properly selected as a beneficial support for heterogeneous catalyst design
since the discovery of the M41S family of mesoporous materials. In fact, this is due
to its unique structural characteristics of having a narrow pore size distribution
between 2 and 15 nm, high surface areas up to 1500 m2 g-1, a large pore volume
and high chemical and thermal stabilities [10–13]. The integration of mesoporous
silica with magnetic NPs to form porous magnetic nanocomposites is, undoubtedly,
of great interest for practical applications. This type of magnetic nanocomposite has
the advantages of both mesoporous silica and magnetic NPs [14].
The immobilization of homogeneous catalysts on a magnetic nanocomposite
facilitates easy catalyst recovery and recycling using external magnets. This magnetic
separation is also typically more efficient than filtration or centrifugation as it prevents
the loss of catalyst. One of the most significant methods for the preparation of hybrid
magnetic mesoporous catalysts is to introduce reactive organic molecules with known
chemical properties into the pores of mesoporous silica [15, 16]. The functionalization
or impregnation of amines onto porous supports has attracted much attention [17–20].
Amine groups can be grafted onto porous materials, either through impregnation, or by
post-synthetic methods as heterogeneous reusable bases. As an organic base,
piperazine is used as typical active catalyst for the synthesis of organic compounds
[21, 22]. Neutralization under acidic conditions requires the separation of piperazine
from homogeneous reaction mixtures, which results in the formation of worthless
ammonium salts. Immobilization of piperazine onto solid supports has been used to
obtain heterogeneous catalytic organic bases which do not need to be neutralized by an
acidic work-up [23–25]. Simple filtration can be used for successful separation of solid
base catalysts without any need for harmful acidic neutralization.
The search toward novel methodologies in organic synthesis according to green
(eco-friendly) chemistry principles has appeared as a privileged research field due to
environmental and economic concerns. Pyrimidine derivatives represent one of the
most prevalent heterocycles found in natural products, such as amino acid
derivatives (willardiine, tingitanine) [26], vitamins (vitamin B1) [27], antibiotics
(bacimethrin, sparsomycin, bleomycin) [28] and alkaloids (heteromines, crambes-
cins, manzacidins, variolins, meridianins, psammopemmins, etc.) [29]. A number of
2,4,6-trisubstituted pyrimidines were reported to possess diverse biological
activities like anticancer [30], antiviral [31], anti-leishmanial [32], anti-tubercular
[33], anti-HIV and antimalarial activities [34]. Due to the deep interest in
pyrimidine derivatives as potential drugs, much effort has been dedicated to the
study of new methodological approaches toward the synthesis of these derivatives.
There are several methods for the synthesis of 2,4,6-trisubstituted pyrimidines using
alkaline catalysts [35–37], Grignard reagents [38] and microwave irradiation [39].
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Secondary amines immobilized inside magnetic mesoporous…
However, some of these methods are plagued by the limitations of having a poor
yield, longer reaction times, using toxic solvents and difficult work-ups while have
their own benefits. Therefore, the development of a new, mild and efficient catalytic
methodology according to green chemistry principles still remains a challenge for
organic chemists to overcome these weaknesses. Therefore, the introduction of a
new heterogeneous solid catalyst for the solvent-free synthesis of 2,4,6-trisubsti-
tuted pyrimidines with high cost effectiveness and yields became one of our goals in
the field of green organic synthesis.
With a view of these considerations, and as part of a continuing effort in our
laboratory toward the synthesis of pyrimidine derivatives [40, 41], herein, we wish
to disclose the confinement of piperazine organocatalyst inside the mesochannels of
a-Fe2O3-MCM-41 leading to a reusable basic nanocatalyst a-Fe2O3-MCM-41-
piperazine (a-Fe2O3-MCM-41-P), which in turn showed excellent catalytic
performance in the synthesis of trisubstituted pyrimidine derivatives through
multicomponent reaction of benzaldehyde, acetophenone, and amidine derivatives
under solvent-free conditions (Scheme 1).
Experimental
The reagents and solvents applied in this work were obtained from Fluka or Merck
companies and used without further purification. Melting points of the products
were recorded on a Buchi B-540 apparatus. Fourier transform-infrared (FT-IR)
spectra were recorded on an ABB Bomem model FTLA 200-100 instrument. Proton
(1H) and carbon-13 (13C) nuclear magnetic resonance (NMR) spectra were
measured on a Bruker DRX-300 spectrometer, at 300 and 75 MHz, respectively,
using tetramethylsilane (TMS) as an internal standard. Chemical shifts (d) were
reported relative to TMS, and coupling constants (J) were reported in hertz (Hz).
Mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer with a
70-eV ionization potential. Elemental analyses of new compounds were performed
with a ‘‘vario EL III’’ instrument (serial no. 11024054). X-ray powder diffraction
(XRD) was carried out on a Philips X’Pert diffractometer with CoKa radiation. The
pore structure of the prepared catalyst was verified at 77 K by the nitrogen
absorption isotherms [(5.0.0.3) Belsorp, BEL Japan, Inc.]. The structure and
morphology of the products were characterized by transmission electron micro-
scopy (TEM) with a Philips CM-10 instrument at an accelerating voltage of 100 kV,
and scanning electron microscopy (SEM) analyses were performed using a
TESCAN VEGA II electron microscope (Czech Republic) operating at an
Ar1
N
Y
O
Scheme 1 a-Fe2O3-MCM-41-P
as a magnetic nanocatalyst for
the synthesis of trisubstituted
pyrimidine derivatives
H2N
NH
Ar1
H
α-Fe2O3-MCM-41-P
N
+
Y
Solvent-free
Ar2
O
80°C
Ar2
Y = NH2 , Ph
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R. Aryan et al.
accelerating voltage of 15 kV. The chemical compositions of the samples were
evaluated by SEM (using SAMx microanalysis application software) equipped with
an energy-dispersive X-ray (EDX).
Catalyst preparation
Preparation of a-Fe2O3-MCM-41
The (a-Fe2O3)-MCM-41 nanocomposite was prepared using a published method
[3]. A mixture with a molar ratio of 3.2 FeCl3:1.6 FeCl2:1 CTABr:39 NH4OH:2300
H2O was used for the preparation of naked Fe3O4 NPs at room temperature.
Typically, 2 g of iron (III) chloride (FeCl3Á6H2O) and 0.8 g of iron (II) chloride
(FeCl2Á4H2O) were dissolved in 10 mL of distilled water under nitrogen
atmosphere. The resulting solution was added drop wise to a 100-mL solution of
1.0-M NH4OH solution containing 0.4 g of cetyltrimethylammonium bromide
(CTABr) to construct a colloidal suspension of magnetic iron oxide NPs.
The magnetic MCM-41 was prepared by adding 20 mL of the magnetic colloid to
a 1.0-L solution with the molar ratio of 292 NH4OH:1 CTABr:2773 H2O under
vigorous mixing and sonication. Then, sodium silicate (16 mL) was added, and the
mixture was allowed to stir at room temperature for 24 h under well-mixed
conditions. The magnetic MCM-41 [Fe3O4-MCM-41] was collected by an external
magnetic field and washed with alcoholic ammonium nitrate. The surfactant
template was then removed from the synthesized material by calcination at 450 °C
for 4 h to give the a-Fe2O3-MCM-41. It is worth mentioning that in the absence of
nitrogen atmosphere, the magnetic property of Fe3O4 is decreased.
Preparation of (a-Fe2O3)-MCM-41-P
The magnetic mesoporous silica a-Fe2O3-MCM-41 (1 gr) was then poured into an
acetone solution of piperazine (0.86 g, 10 mmol in 5 mL of dried acetone). After
3 h stirring at room temperature, the solvent was evaporated under vacuum to afford
the corresponding piperazine-confined a-Fe2O3-MCM-41 which is named briefly
here as a-Fe2O3-MCM-41-P (Scheme 2).
Scheme 2 The preparation of novel hybrid organic–inorganic magnetic nanocatalyst a-Fe2O3-MCM-41-
P
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Secondary amines immobilized inside magnetic mesoporous…
Procedure for the solvent-free synthesis of trisubstituted pyrimidines
in the presence of a-Fe2O3-MCM-41-P
A mixture of benzaldehyde derivatives (1 mmol), acetophenone or 4-methylace-
tophenone (1 mmol), and benzamidine hydrochloride (1 mmol) or guanidinium
carbonate (0.75 mmol) along with the catalyst (0.05 g) was thoroughly ground and
then transferred into a reaction vessel where this mixture was stirred at 80 °C for
appropriate times. The reactions were monitored by thin-layer chromatography
[TLC; ethyl acetate (EtOAc):petroleum ether, 1:4]. After completion of the reaction,
the mixture was allowed to cool to room temperature, then chloroform (3 mL) was
added and the mixture was stirred for an extra 30 min. After collecting the magnetic
catalyst with an external magnet, the solvent was removed in vacuo and the
precipitates were recrystallized from ethanol to furnish the desired trisubstituted
pyrimidine derivatives.
Selected physical and spectroscopic data for the new 2,4,6-trisubstituted
pyrimidine derivatives
4-(4-Cyanophenyl)-6-phenylpyrimidin-2-amine (4d)
IR (KBr): 3467, 3363, 3112, 3059, 2301, 1598 cm-1 1H NMR [300 MHz,
.
deuterated chloroform (CDCl3)]: d 6.89 (s, 2H), 7.52–7.56 (m, 3H), 7.82 (s, 1H),
8.01 (d, J = 6.3 Hz, 2H), 8.22–8.27 (m, 2H), 8.42 (d, J = 6.3 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d 104.7, 110.6, 118.4, 125.8, 128.0, 128.3, 131.2, 131.9, 132.6,
133.9, 153.9, 154.8, 157.1. MS: m/z = 272 (M?), 230, 168, 143, 42. Elemental
analysis: C17H12N4 Calculated: C, 74.98; H, 4.44; N, 20.58; Found: C, 74.54; H,
4.76; N, 20.91.
4-(4-Acetamidoophenyl)-6-phenylpyrimidin-2-amine (4e)
IR (KBr) 3491, 3392, 3177, 3081, 1661, 1609 cm-1. 1H NMR (300 MHz, CDCl3):
d 2.22 (s, 3H), 7.45 (s, 2H), 7.50–7.55 (m, 7H), 7.67 (d, J = 6.3 Hz, 2H), 8.06 (d,
J = 6.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 24.8, 103.8, 119.5, 127.1, 127.9,
128.7, 130.4, 133.2, 137.7, 140.1, 163.6, 165.3, 166.2, 168.6. MS: m/z = 304 (M?),
262, 261, 200, 161, 143, 43, 42. Elemental analysis: C18H16N4O Calculated: C,
71.04; H, 5.30; N, 18.41; O, 5.26. Found: C, 70.73; H, 5.63; N, 18.69.
4-(4-Acetamidophenyl)-6-(4-methylphenyl)pyrimidin-2-amine (4g)
IR (KBr): 3489, 3341, 3177, 3092, 1669, 1598 cm-1. 1H NMR (300 MHz, CDCl3):
d 2.09 (s, 3H), 2.39 (s, 3H), 6.63 (s, 2H), 7.33 (d, J = 6.3 Hz, 3H), 7.63 (s, 1H),
7.72 (d, J = 6.6 Hz, 2H), 8.12 (d, J = 6.3 Hz, 2H), 8.17 (d, J = 6.6 Hz, 2H). 13C
NMR: (75 MHz, CDCl3): d 20.9, 24.1, 100.8, 118.5, 126.8, 127.5, 129.2, 131.7,
134.6, 140.1, 141.2, 163.8, 164.1, 164.5, 168.6. MS: m/z = 318 (M?), 200, 175,
174, 158, 44, 43. Elemental analysis: C19H18N4O Calculated: C, 71.68; H, 5.70; N,
17.60; O, 5.03; Found: C, 71.22; H, 5.98; N 17.23.
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R. Aryan et al.
4-(4-Acetamidophenyl)-2,6-diphenylpyrimidine (4k)
1
IR (KBr): 3376, 3135, 3101, 3073, 2921, 1665, 1591 cm-1. H NMR (300 MHz,
CDCl3): d 2.21 (s, 3H), 7.31 (d, J = 6.6 Hz, 2H), 7.44–7.47 (m, 4H), 7.62 (s, 1H),
7.85 (d, J = 6.6 Hz, 2H) 7.91–7.95 (m, 3H), 8.32–8.35 (m, 4H). 13C NMR:
(75 MHz, CDCl3): d 24.4, 98.7, 115.8, 125.5, 126.1, 127.0, 127.6, 128.9, 129.1,
129.6, 130.1, 132.1, 132.9, 143.4, 157.9, 163.4, 166.1, 168.9. MS: m/z = 365 (M?),
261, 204, 161, 104. Elemental analysis: C24H19N3O Calculated: C, 78.88; H, 5.24;
N, 11.50; O, 4.38; Found: C, 78.53; H, 5.51; N, 11.19.
4-(4-Acetamidophenyl)-6-(4-methylphenyl)-2-phenylpyrimidine (4l)
1
IR (KBr): 3389, 3111, 3092, 3073, 2973, 1673, 1589 cm-1. H NMR (300 MHz,
CDCl3): d 2.11 (s, 3H), 2.44 (s, 3H), 7.43 (d, J = 6.3 Hz, 2H), 7.59 (s, 3H), 7.82 (d,
J = 6.3 Hz, 2H), 8.4 (d, J = 6.3 Hz, 2H), 8.45–8.49 (m, 2H), 8.64–8.67 (m, 2H),
8.74–8.78 (m, 2H). 13C NMR (75 MHz, CDCl3): d 21.0, 24.1, 118.7, 127.2, 127.9,
128.0, 128.2, 128.6, 128.9, 129.2, 129.5, 130.8, 133.8, 137.6, 141.1, 163.1, 163.5,
163.9, 168.7. MS: m/z = 379 (M?), 275, 261, 218, 161, 118, 104. Elemental
analysis: C25H21N3O Calculated: C, 79.13; H, 5.58; N, 11.07; O, 4.22; Found: C,
78.88; H, 5.84; N, 10.81.
Results and discussion
The obtained basic nanocatalyst a-Fe2O3-MCM-41-P was characterized by XRD,
FT-IR, SEM, TEM, N2-adsorption isotherms and EDX (refer to electronic
supporting information, ESI).
The XRD pattern of the a-Fe2O3-MCM-41-P is shown in Fig. 1. The XRD
analysis was performed from 2.0° (2h) to 80.0° (2h). The observed diffraction
patterns clarified that the magnetic a-Fe2O3 substances present in the MCM-41
structure and the change of the sample’s color from black to brick-red after the
Fig. 1 Catalytic reusability of a-Fe2O3-MCM-41-P for the synthesis of trisubstituted pyrimidines
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Secondary amines immobilized inside magnetic mesoporous…
calcination of the catalyst is also due to the oxidation of embedded Fe3O4 to a-
Fe2O3 NPs [42]. The XRD pattern of a-Fe2O3-MCM-41-P (ESI, Fig. S1a) displays
all the characteristic peaks of MCM-41 at 2.0° (2h) to 10.0° (2h; low-angle region),
indicating a high degree of pore symmetry of MCM-41. The XRD spectra patterns
at 20.0° (2h) to 80.0° (2h) of a-Fe2O3-MCM-41-P material displayed diffraction
peaks at about 2h = *23.0°, *33.0°, *45.0°, *60.0°, *70.0°, which is
attributed to characteristic peaks of a-Fe2O3 (ESI, Fig. S1b).
The FT-IR spectrum of piperazine shows a peak at 3125 cm-1 attributed to N–H
vibration, and peaks in the 2800–3000 region are attributed to aliphatic C–H
vibrations of CH2CH2 (ESI, Fig. S2a). The FT-IR spectrum of a-Fe2O3-MCM-41
shows a band in the region of 500–650 cm-1 , attributed to the stretching vibrations
of the (Fe–O) bond in a-Fe2O3 , and the band at about 1100–1220 cm-1 belongs to
(Si–O) stretching vibrations (ESI, Fig S2b,). In the FT-IR spectrum of a-Fe2O3-
MCM-41-P (ESI Fig. S2c), the stretching vibrations of C–H and N–H bonds of the
piperazine structure are visible and the red-shift of N–H bonds to 3189 cm-1 could
be due to the hydrogen bond formation between a piperazine nitrogen atom and
oxygen atom on the surfaces of the silica pores. The FT-IR of recovered a-Fe2O3-
MCM-41-P catalyst (ESI, Fig. S2d) showed a characteristic pattern similar to the
fresh catalyst (compare ESI Fig. S2c and Fig. S2d).
The N2 adsorption isotherms of (a-Fe2O3)-MCM-41 filled with piperazine shown
in Fig. S3 (ESI) which is characteristic of highly ordered two-dimensional
hexagonal mesostructure material with uniform open cylindrical channels (ESI,
Fig. S3a, b). The specific surface area and total pore volume obtained by the N2
adsorption isotherms calculated by the Brunauer–Emmett–Teller (BET) method
[43] were 1242 m2 g-1 and 1.67 cm3 g-1 , respectively, before addition of
piperazine, and 177 m2 g-1 and 0.21 cm3 g-1 , respectively, after loading
piperazine into the catalyst pores. This clearly improves the loading of piperazine
into the pores of magnetic MCM-41. The pore diameter of the a-Fe2O3-MCM-41-P
was 3.6 nm, as derived from the adsorption and desorption branches by the
Broekhoff and deBoer model [44].
The SEM image of a-Fe2O3-MCM-41-P showed the uniformity and spherical
morphology of the nanocatalyst, and the diameter of resulting microspheres was
*100 nm (ESI, Fig. S4a). The HRTEM images clearly showed the ordered
mesoporous channels of a-Fe2O3-MCM-41-P catalyst (ESI, Fig. S4b, c, d).
Also, energy dispersive X-ray analysis (EDX) spectra of the fresh and recovered
catalysts confirmed the presence and weight percent of C, N, O, and Fe (ESI,
Fig. S5). This observation also proved evidently the stability of the catalyst structure
during pyrimidine synthesis and the existence of piperazine inside the nanocatalyst
pore after catalyst recycling (compare ESI Fig. S5a and S5b).
Synthesis of 2,4,6-trisubstituted pyrimidines catalyzed by a-Fe2O3-MCM-
41-P
As part of our ongoing efforts directed toward the development of new, safe and
versatile methodologies for the synthesis of pyrimidine derivatives [39, 40], we
began to study the application of a-Fe2O3-MCM-41-P as a magnetically recyclable
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R. Aryan et al.
heterogeneous basic catalyst for the solvent-free synthesis of 2,4,6-trisubstituted
pyrimidines.
In order to optimize the reaction conditions, various amounts of the catalyst were
applied in the model reaction of acetophenone 1, 4-chlorophenylbenzaldehyde 2,
and guanidinium carbonate 3a (Scheme 3) under different reaction temperatures
and the results are summarized in Table 1.
As indicated in Table 1, the best result was obtained when 0.05 g of the catalyst
was used at 80 °C (Table 1, entry 6). Further increasing the amount of catalyst
affected neither the yield nor the reaction time (Table 1, entry 8). Also, increasing
the reaction temperature to 120 °C did not have a remarkable effect on the yield or
the reaction time (Table 1, entry 7).
In order to assess the efficiency of this hybrid organic–inorganic catalyst in
comparison with its building components, MCM-41, a-Fe2O3-MCM-41, MCM-41-
Piperazine, a-Fe2O3-MCM-41-piperazine, and piperazine were separately examined
under the optimized condition (Table 2).
The crucial role of a-Fe2O3 was revealed by taking into account the results of
Table 2 and a significant distinction in the catalytic activities was clearly
ascertained. When piperazine, MCM-41, MCM-41-piperazine were used as
catalysts separately in the model reaction, no product was obtained (Table 2,
O
Cl
Conditions of different
catalysts and
NH2
NH2
+H2N
temperatures
CO3
+
N
N
O
1
2
NH2
3a
H
4b
Cl
2
Scheme 3 The model reaction for the synthesis of 2-amino-4-(4-chlorophenyl)-6-phenyl pyrimidine
Table 1 Optimization of solvent-free synthesis of 2-amino-4-(4-chlorophenyl)-6-phenyl pyrimidine (4b)
in the presence of a-Fe2O3-MCM- 41-piperazine as catalyst
Entry
Catalyst (grams)
T (°C)
Time (h)
Yield of 4b (%)a
1
2
3
4
5
6
7
8
0.01
0.01
0.01
0.01
0.03
0.05
0.05
0.06
r.t
5
5
5
5
5
1
1
1
0
0
40
60
80
80
80
120
80
23
42
86
93
95
93
Equimolar amounts of reactants were used in the model reaction
T temperature
a
Isolated yield
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Secondary amines immobilized inside magnetic mesoporous…
Table 2 Comparison of catalytic activity of different catalysts in the model reaction
Entry
Catalysta
Yield (%)b
1
2
3
4
5
6
a
Piperazine
0
(a-Fe2O3)-MCM-41
MCM-41-piperazine
(a-Fe2O3)-MCM-41-P
MCM-41
60
0
93
0
62c
(a-Fe2O3)-MCM-41?P
The model reaction was performed at 80 °C for 1 h and 0.05 g of catalyst was used
Isolated yields
b
c
In this case, the model reaction was performed in the presence of (a-Fe2O3)-MCM-41 (0.025 g) and
fresh piperazine (0.022 g) at 80 °C for 1 h
entries 1, 3 and 5). These results indicated that basic media or high surface area
alone are not sufficient for promoting the model reaction.
Comparison of magnetic MCM-41-P with non-magnetic MCM-41-P (Table 2,
entries 2 and 5) showed that the presence of ferric oxide in the solid catalyst as an
oxidant resulted in aromatization of the product, while in the absence of ferric
oxide, the aromatization did not occur and the 1-phenyl-3-(4-chlorophenyl)-2-
propenone was formed instead (Table 2, entry 5). Notably, no product formation in
the case of piperazine as the catalyst indicated that a basic catalyst was insufficient
for reaction promotion (Table 2, entry 1), demonstrating the significance of
supporting piperazine on a magnetic MCM-41 nanocomposite as a hybrid organic–
inorganic material to reach high catalytic activity (Table 2, entry 4). The
introduction of piperazine into a-Fe2O3-MCM-41 pores led to the formation of a
highly basic media inside the magnetic MCM-41 material. On the other hand, the
high basicity of secondary amine sites along with high surface area of the magnetic
mesoporous material and an oxidative complement of the catalyst (Fe3? ions) act
synergistically with each other in this process. This means that a very well-
distributed, highly oxidative and basic medium develops inside the pores of
magnetic MCM-41 with the advantage of a high probability for the starting
materials to react, which causes the reaction to proceed most efficiently, leading to
the best yield (Table 2, entry 4). These observations clearly highlight the
cooperation between the basic strength and oxidative role of various components
incorporated in the catalyst structure in promoting the reaction toward the synthesis
of desired trisubstituted pyrimidines.
The most interesting point in Table 2 was that we poured separately the magnetic
MCM-41 and fresh solid piperazine in the reaction medium in order to find out
whether or not the presence of piperazine inside MCM-41 mesopores has a
notable impact on the catalytic activity. Surprisingly, we observed a reactivity in
this case similar to entry no. 2 (magnetic MCM-41 used solely), proving that the
presence of piperazine molecules inside magnetic MCM-41 mesopores is critical for
the present process (Table 2, entry 4).
In order to examine the scope and generality of the process, various
benzaldehyde, acetophenone and amidine derivatives were employed under the
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Secondary amines immobilized inside magnetic mesoporous…
optimized reaction conditions. The results are summarized in Table 3. These results
indicate the fact that the use of as low as 0.05 g of a-Fe2O3-MCM-41-P exhibits
noticeable efficiency for all of the reactants tested under the optimized reaction
conditions (Scheme 4, Table 3).
As shown in Table 3, this reaction was fairly general, clean, rapid and efficient
under the optimized reaction conditions in the presence of (a-Fe2O3)-MCM-41-P.
The very significant feature of the catalyst used in the present protocol is that
benzaldehyde derivatives with various electron demands were used effectively. The
products were obtained from electron-rich (Table 3, entries 5, 7, 11 and 12) or
electron-poor benzaldehydes (Table 3, entries 3, 4 and 10) as reactants with
similarity in reaction times and yields. Also, it is important to note that the magnetic
property of this catalyst facilitates its efficient recovery from the reaction mixture
during the work-up procedure. Thus, in order to examine catalyst reusability as a
crucial factor, the catalyst was effectively collected and used in subsequent runs in
the model reaction (Scheme 3) without observation of any significant decrease in
activity even after three runs (Fig. 1).
A reasonable mechanism is proposed in Scheme 5. The presence of piperazine
inside nanochannels of magnetic MCM-41-P catalyst activates the formation of
chalcone intermediate 5 through deprotonation of acetophenone derivative by
piperazine. This intermediate undergoes cyclization-oxidation after nucleophilic
attack by amidine derivatives 3 as the result of dual Lewis acid character of Fe3?
and oxidative-Lewis base character of O2- ions. So, the synergistic cooperation
between piperazine, Fe3? and O2- ion leads to the formation of the desired product.
Conclusion
A novel hybrid organic–inorganic magnetic nanocatalyst was designed and used in
the synthesis of important pyrimidine heterocyclic building blocks through the
multicomponent reaction of acetophenone, benzaldehyde and amidine derivatives.
The reactions did not proceed well in the presence of the chemical components of
the catalyst but performed very effectively in the presence of prepared nanocatalyst,
carefully highlighting the efficiency and significance of the presently reported
catalytic system. Multicomponent and solvent-free reaction conditions, the ability to
NH2
+H2N
Ar1
N
Y
CO3
O
NH2
α-Fe2O3-MCM-41-P
Ar1
Ar2
N
2
(0.05 gr)
(1)
O
(3a)
or
Ar2
+
Solvent-free
80°C
Ph
Y = NH2 , Ph
H
H2N NH2Cl
(4)
(2)
(3b)
Scheme 4 Synthesis of trisubstituted pyrimidine derivatives under optimized reaction conditions
123

R. Aryan et al.
Ar2
Ar1
Ar2
O
H
Ar1
+
O
O
2
5
1
H2N
R
HO
OH
Fe2O3
NH
3
OH
OH
O
HN
H
H
O
N
H
Ar1
R
N
OH
HO
N
Ar2
4
Scheme 5 The plausible mechanism for the synthesis of pyrimidine derivatives catalyzed by a-Fe2O3-
MCM-41-P
use reactants with various electron demands without remarkable difference in
reactivity in terms of reaction times and yields, a high degree of catalyst reusability
and the preparation of some novel trisubstituted pyrimidine derivatives were the
other most significant aspects of the newly introduced nanocatalyst.
Acknowledgments The authors gratefully acknowledge Prof. Rostamizadeh from K. N. Toosi
University of Technology, and Dr. Jadidi from Shahid Beheshti University G. C. for their helpful
consultations. The partial financial support of the present study by the Research Council of the University
of Zabol is also gratefully acknowledged.
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