Sulfonic acid-functionalized titanomagnetite nanoparticles as recyclable heterogeneous acid catalyst for one-pot solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones

Article abstract of DOI:10.1007/s13738-016-0920-0

Sulfonic acid-functionalized titanomagnetite (Fe_3?xTi_xO₄@SO₃H) nanoparticles were prepared by grafting sulfonic acid groups on Fe_3?xTi_xO₄ nanoparticles. This new heterogeneous ac

Full text of DOI:10.1007/s13738-016-0920-0

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0920-0
ORIGINAL PAPER
Sulfonic acid‑functionalized titanomagnetite nanoparticles
as recyclable heterogeneous acid catalyst for one‑pot solvent‑free
synthesis of 3,4‑dihydropyrimidin‑2(1H)‑ones/thiones
Davood Azarifar1 · Younes Abbasi1 · Omolbanin Badalkhani1
Received: 16 January 2016 / Accepted: 20 June 2016
© Iranian Chemical Society 2016
Abstract Sulfonic acid-functionalized titanomagnet-
ite (Fe3−xTixO4@SO3H) nanoparticles were prepared by
grafting sulfonic acid groups on Fe3−xTixO4 nanoparticles.
This new heterogeneous acid nanocatalyst demonstrated
an efficient catalytic performance in the one-pot synthesis
of dihydropyrimidin-2(1H)-one/thione derivatives under
solvent-free conditions with high yields. The nanocatalyst
could easily be separated from the reaction mixture sim-
ply by using an external magnet, recycled and reused for
several times with no significant loss of catalytic activity.
These nanoparticles were characterized by different phys-
icochemical techniques, such as Fourier transform infrared,
scanning electron microscopy, energy-dispersive X-ray
analysis, thermogravimetric and vibrating sample mag-
netometer (VSM) analyses.
medicinal properties as calcium channel blockers, α-1a-
antagonists [3], antiviral, antitumor, neuropeptide Y (NPY)
antagonists and anti-inflammatory activities [4–8]. Monas-
trol is one of the most important and widely used drugs
which acts as a specific inhibitor of mitotic kinesin Eg5 and
is considered as a lead compound for the development of
new anticancer drugs [9]. The most used methods for the
synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones are
originally based on the three-component Biginelli conden-
sation reaction between an aldehyde, urea/thiourea and an
easily enolizable carbonyl compound [10, 11]. However,
this method suffers from low yields in the case of substi-
tuted aromatic and aliphatic aldehydes [12]. So far, many
efficient and versatile catalytic approaches in the synthesis
of 3,4-dihydropyrimidin-2(1H)-ones have been developed
using different Lewis acids as well as protic acids as pro-
moters. Among these promoters which are effectively used
are conc. HCl [13], InCl3 [14], BF3·OEt2 [15], H2SO4 [16],
La(OTf)3 [17], Cd(NO3)2·4H2O [18], NH4OBr [19], ceric
ammonium nitrate (CAN) [20], 1-n-butyl-3-methyl imi-
dazolium tetrafluoroborate (BMImBF4) [21], FeCl3 [22],
InBr3 [23], SBA-15 sulfonic acid [24], silica sulfuric acid
[25], PEG-SO3 [26], etc. However, many of the methods
reported in the literature involve expensive and/or stoichi-
ometric amounts of catalysts, strongly acidic conditions,
low yields, long reaction times, incompatibility with other
functional groups and low selectivity. Therefore, the scope
of the Biginelli reaction for further developments toward
milder reaction conditions and better selection of the cata-
lyst and reaction components still exists [27].
Keywords Titanomagnetite · Fe3−xTixO4@SO3H
nanoparticles · Magnetic nanoparticle · Nanocatalyst ·
Dihydropyrimidin-2(1H)-one
Introduction
In the past few decades, dihydropyrimidinones (DHPMs),
as an important class of heterocyclic compounds, have
attracted great attention in medicinal and synthetic organic
chemistry owing to their pharmacological and therapeu-
tic properties such as antihypertensive and antibacterial
activities [1, 2]. In addition, these compounds exhibit vital
Among the catalysts used in organic transformations,
nanoparticles (NPs) have emerged as important catalysts
in organic synthesis owing to their interesting structures
and outstanding catalytic activities [1, 28, 29]. Develop-
ment of nanocatalysts has resulted in more economical and
* Davood Azarifar
azarifar@basu.ac.ir
1
Faculty of Chemistry, Bu-Ali Sina University, Zip Code
65178 Hamedan, Islamic Republic of Iran
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J IRAN CHEM SOC
Scheme 1 Titanomagnetite@SO3H-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones
environmentally friendly chemistry by replacing unstable,
nonselective or toxic catalysts [30, 31]. In particular, the
use of nanometal oxides has appeared as interesting chal-
lenge in several scientific and technological areas [32, 33].
Moreover, they have attracted much interest in synthetic
chemistry due to their extraordinary physical and chemi-
cal properties [34, 35]. Usually, many nanometal oxides,
especially TiO2, Al2O3, ZnO, etc., exhibit both Lewis acid
and base characters on their surfaces [36], and are also
excellent adsorbents or supports for a variety of organic
and inorganic catalysts with enhanced catalytic reactivity.
The advantages allocated to these nanometal oxides stem
from their strong oxidizing power, non-toxicity, selectiv-
ity, reusability, long-term stability and high activity owing
to their high number of surface atoms [37–39]. The high
surface area-to-volume ratio of metal oxide nanoparticles
is mainly responsible for their high catalytic activities [40].
In this context, magnetic nanoparticles are quite outstand-
ing because of their versatility as nanocatalysts in various
organic reactions including epoxidation [41], benzylation
[42], in biotechnology and medicine [43, 44], in industry
as absorbents for gases and also in destruction of hazard-
ous chemicals [45]. These magnetic nano-oxides can also
act as excellent supports for a wide variety of organic mol-
ecules and catalysts to enhance their reactivity in organic
reactions. High yield, selectivity and easy recyclability
are well-known characteristics of a variety of magnetic
nanocatalyst-based organic reactions [39, 46, 47]. Among
the magnetic nanometal oxide-supported catalysts, various
nano-oxide particles functionalized with different acidic
groups such as phosphotungstic acid (H3PW12O40), Prey-
ssler-type heteropolyacid, sulfamic and sulfonic acids have
been grafted on the surface of magnetic nanoparticles and
successively used to selectively catalyze chemical reactions
[48–51].
In this report, we describe the application of our previ-
ously synthesized titanomagnetite-supported sulfonic acid
(Fe3−xTixO4@SO3H) as a recyclable, heterogeneous, solid
acid nanocatalyst [52] in the Biginelli and Biginelli-like
reactions. The reactions proceed smoothly under solvent-
free conditions to afford a variety of 3,4-dihydropyrimidin-
2(1H)-ones/thiones in relatively low reaction times with
excellent yields (Scheme 1).
Experimental setup
Materials and instrumentation
Chemicals were purchased from Merck chemical company.
1H and 13C NMR spectra were measured for samples in
CDCl3 or DSMO-d6 with a Bruker Avance DRX-90 instru-
ment at 90, 250 and 400 MHz, using Me4Si as internal stand-
ard. Fourier transform infrared (FTIR) spectra were recorded
on a Shimadzu 435-U-04 FT spectrophotometer from KBr
pellets. Melting points were measured on a BUCHI 510
apparatus in open capillary tubes. Scanning electron micros-
copy (SEM) was performed on a KYKY-EM3200 instru-
ment operated at 26 kV accelerating voltage. Qualitative
analysis of the Fe3−xTixO4@SO3H sample was performed by
using energy-dispersive X-ray fluorescence (EDXRF) spec-
troscopy (Brand: Link analytical XR300). Energy-dispersive
X-ray analysis of the prepared catalyst was performed on a
SEM-TESCAN MIRA3-FEG instrument. Ultrasonication
was performed in a 2200 ETH-SONICA ultrasound cleaner
with a frequency of 45 kHz. The magnetic measurements
were taken in a vibrating sample magnetometer (VSM,
MDKFT, Iran) at room temperature. The thermal gravimetric
analysis (TGA) curves were recorded under air atmosphere
using Linseis-181a1750 (Germany) instrument.
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J IRAN CHEM SOC
Fig. 1 FTIR spectra of
(a) Fe3−xTixO4 MNPs; (b)
Fe3−xTixO4@SO3H MNPs
Preparation of the catalyst Fe3−xTixO4@SO3H MNPs
respectively, added to the reaction mixture. The resulted
mixture was refluxed at 90 °C under N2 atmosphere for
30 min followed by dropwise addition of an aqueous solu-
tion of NaOH (1.6 g) and NaNO3 (0.77 g) in deionized
water (10 mL) under vigorous stirring at a rate of 500 rpm
for 1 h. Finally, the resulting mixture was cooled to room
temperature. The precipitated titanomagnetite nanoparticles
were isolated in an external magnetic field simply by using
a magnet bar, then washed with water several times and
dried in air.
Preparation of the magnetic Fe3−xTixO4 MNPs
Titanomagnetite nanoparticles were prepared as previ-
ously reported procedure [52] based on the similar proce-
dure reported by Yang et al. [53]. FeSO4·7H2O (1.903 g)
was dissolved in deionized water (10 mL). The pH of the
solution was changed to <1 by adding HCl solution. Then,
hydrazine monohydrate (2 mL) and TiCl4 (0.75 mL) were,
6000
TiKα
5000
4000
3000
2000
TiLα
O Kα
FeKα
S Kβ
S Kα
1000
FeLα
β
TiK
FeK
β
keV
0
0
5
10
Fig. 3 SEM micrograph of titanomagnetite@SO3H nanoparticles
Fig. 2 EDX spectrum of Fe3−xTixO4@SO3H nanoparticles
1 3

J IRAN CHEM SOC
Fig. 4 TGA/DTG curves of
Fe3−xTixO4@SO3H MNPs
Preparation of sulfonic acid‑functionalized Fe3−xTixO4
MNPs
Typical procedure for the synthesis
of 3,4‑dihydropyrimidin‑2(1H)‑ones/thiones
The above-prepared Fe3−xTixO4 MNPs (1 g) were dispersed
in CH2Cl2 (15 mL) under ultrasonication for 30 min. Then,
chlorosulfonic acid (1.5 mL) was added dropwise over
a period of 2 h at room temperature under vigorous stir-
ring at a rate of 500 rpm. After addition was completed,
the resulting mixture was shaken for 1 h. The precipitated
Fe3−xTixO4@SO3H MNPs were magnetically isolated from
the reaction mixture by a magnet bar. The isolated nanopar-
ticles were consecutively washed with CH2Cl2 (3 × 5 mL)
and EtOH (3 × 5 mL) and dried in air. The number of SO3H
acid sites per one gram of the support was determined to be
(4.1–5.5 mmol) via titration with 0.025 M NaOH solution.
A mixture of aromatic aldehyde 1 (1 mmol), methyl (or
ethyl) acetoacetate (or acetophenone) (1 mmol) and urea
(or thiourea) (1.5 mmol) was added Fe3−xTixO4@SO3H
(0.03 g), and the resulted mixture was stirred at 100 °C
for an appropriate time (Table 2). After completion of
the reaction as monitored by thin-layer chromatography
(TLC), the resulted reaction mixture was cooled to room
temperature, diluted with ethanol (10 mL) and stirred
for 10 min. Then, the catalyst was isolated in a magnetic
field, the solvent was evaporated, and the resulted solid
was washed with cool water carefully. Crystallization of
the crude product from ethanol provided pure products.
All the synthesized products 5a–r and 6a–b are known
compounds which were characterized based on their
1
melting points and spectral (FTIR, H and 13C NMR)
data and compared with the reported corresponding data
(Table 2).
Selected data
5‑Methoxycarbonyl‑6‑methyl‑4‑phenyl‑3,4‑dihydropy‑
rimidin‑2(1H)‑one (5a) White solid, m.p. 212–214 °C;
IR (KBr) ν: 3457, 3334, 3227, 3110, 2952, 1697, 1668,
1651, 1600, 1415, 1341, 1276, 1240, 1189, 1095, 794,
1
698 cm−1; H NMR (400 MHz, DMSO-d6) δ: 2.26 (s,
3H, CH3), 3.53 (s, 3H, CH3), 5.15–5.16 (d, 1H, CH),
7.24–7.33 (m, 5H, H-Ar), 7.79 (s, 1H, NH), 9.26 (s, 1H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6) δ: 17.8, 50.7,
Fig. 5 VSM curves of (a) Fe3−xTixO4 MNPs; (b) Fe3−xTixO4@SO3H
MNPs
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J IRAN CHEM SOC
Table 1 Screening the reaction parameters for the model synthesis of 5-methoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one
Entry
Catalyst (g)
Solvent
Temperature (°C)
Time (min)
Yield (%)a
1
0.01
No solvent
H2O
r.t.
60
60
60
60
60
40
40
50
90
80
42
2
0.01
r.t.
28
3
0.01
EtOH
r.t.
34
4
0.03
No solvent
No solvent
No solvent
No solvent
No solvent
No solvent
EtOH
r.t.
75
5
0.03
50
80
6
0.03
100
100
100
100
50
98
7
0.05
92
8
0.1
90
9
10b
No catalyst
0.03
Trace
19
Conditions: benzaldehyde (1 mmol), urea (1.5 mmol), methyl acetoacetate (1 mmol), solvent (6 mL)
a
Isolated pure yield
b
Under ultrasound irradiation
53.7, 98.9, 126.1, 127.2, 128.4, 144.6, 148.6, 152.1,
165.8 ppm.
1465, 1418, 1384, 1340, 1313, 1290, 1222, 1090, 758, 698,
1
517 cm−1; H NMR (300 MHz, DMSO-d6) δ: 1.09 (s, 3H,
CH3), 2.25 (s, 3H, CH3), 3.96–4.01 (q, 4H, CH2), 5.14–5.15
(d, 1H, CH), 7.23–7.34 (m, 5H, H-Ar), 7.76 (s, 1H, NH),
9.21 (s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6) δ:
14.0, 17.7, 53.9, 59.1, 99.1, 126.2, 127.2, 128.3, 144.8,
148.3, 152.1, 165.2 ppm.
4‑(4‑Hydroxyphenyl)‑5‑methoxycarbonyl‑6‑methyl‑3,4‑di‑
hydropyrimidin‑2(1H)‑one (5e) White solid, m.p. 237–
240 °C; IR (KBr) ν: 3585, 3368, 3271, 3236, 3120, 2953,
1701, 1684, 1639, 1615, 1602, 1459, 1381, 1231, 1088,
1
760, 659 cm−1; H NMR (90 MHz, DMSO-d6) δ: 2.22 (s,
5‑Ethoxycarbonyl‑6‑methyl‑4‑(4‑methylphenyl)‑3,4‑di‑
hydropyrimidin‑2(1H)‑one (5l) White solid, m.p. 217–
220 °C; IR (KBr) ν: 3427, 3248, 3119, 2980, 1724, 1705,
1650, 1461, 1384, 1328, 1310, 1286, 1224, 1171, 1090,
3H, CH3), 3.50 (s, 3H, CH3), 5.02 (s, 1H, CH), 6.70 (s, 2H,
H-Ar), 6.97 (s, 2H, H-Ar), 7.62 (s, 1H, NH), 9.12 (s, 1H,
NH), 9.32 (s, 1H, OH) ppm; 13C NMR (22.5 MHz, DMSO-
d6) δ: 17.7, 50.5, 53.3, 99.6, 115.0, 127.2, 135.2, 147.8,
152.2, 156.5, 165.9 ppm.
1
785, 605, 478 cm−1; H NMR (300 MHz, DMSO-d6) δ:
1.08–1.12 (t, 3H, CH3), 2.24 (s, 3H, CH3), 2.26 (s, 3H,
CH3), 3.95–4.00 (q, 2H, CH2), 5.10 (s, 1H, CH), 7.12 (s,
4H, H-Ar), 7.70 (s, 1H, NH), 9.17 (s, 1H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6) δ: 14.0, 17.7, 20.6, 53.5, 59.1,
99.3, 126.1, 128.8, 136.3, 141.8, 148.1, 152.1, 165.3 ppm.
5‑Methoxycarbonyl‑6‑methyl‑4‑(4‑methylphenyl)‑3,4‑di‑
hydropyrimidin‑2(1H)‑one (5g) White solid, m.p. 207–
211 °C; IR (KBr) ν: 3335, 3219, 3108, 2955, 1698, 1668,
1652, 1455, 1415, 1343, 1323, 1301, 1241, 1186, 1092,
937, 800, 774, 663, 512 cm−1; 1H NMR (90 MHz, DMSO-
d6) δ: 2.24 (s, 6H, CH3), 3.51 (s, 3H, CH3), 5.08 (s, 1H,
CH), 7.10 (s, 4H, H-Ar), 7.69 (s, 1H, NH), 9.17 (s, 1H,
NH) ppm; 13C NMR (22.5 MHz, DMSO-d6) δ: 17.6, 20.4,
50.4, 53.5, 99.3, 126.0, 128.8, 136.2, 141.7, 148.1, 152.2,
165.7 ppm.
4‑(2‑Chlorophenyl)‑5‑ethoxycarbonyl‑6‑methyl‑3,4‑di‑
hydropyrimidin‑2(1H)‑one (5j) White solid, m.p. 224–
227 °C; IR (KBr) ν: 3431, 3242, 3104, 2955, 1701, 1643,
1
1602, 1574, 1384, 1290, 1222, 1081, 761, 678 cm−1; H
NMR (300 MHz, DMSO-d6) δ: 0.97–1.01 (t, 3H, CH3),
2.30 (s, 3H, CH3), 3.86–3.92 (q, 2H, CH2), 5.63 (s, 1H,
CH), 7.25–7.41 (m, 4H, H-Ar), 7.73 (s, 1H, NH), 9.30 (s,
1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6) δ: 13.8,
17.6, 51.4, 59.0, 97.8, 127.7, 128.7, 129.0, 129.3, 131.6,
141.6, 149.2, 151.3, 164.9 ppm.
5‑Ethoxycarbonyl‑6‑methyl‑4‑phenyl‑3,4‑dihydropyrimi‑
din‑2(1H)‑one (5h) White solid, m.p. 209–212 °C; IR
(KBr) ν: 3434, 3246, 3121, 2979, 1725, 1701, 1649, 1600,
1 3

J IRAN CHEM SOC
Table 2 Synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones catalyzed by sulfonic acid-functionalized titanomagnetite MNPs Fe3−xTixO4@
SiO3H under solvent-free condition at 100 °C
Entry
Ar
R
X
Product
Time (min)
Yielda (%)
Mp (°C)
Found
Reported
1
C6H5
Me
Me
Me
Me
Me
Me
Me
Et
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
5a
5b
5c
5d
5e
5f
40
35
40
40
35
40
30
40
40
35
40
30
35
45
35
45
45
30
35
45
98
90
85
94
92
96
98
96
86
92
94
98
95
94
89
90
91
96
88
87
212–214
206–208
182–185
197–201
237–240
283–286
207–211
209–212
198–202
224–227
183–187
217–220
264–268
206–209
206–208
182–187
201–204
181–185
199–201
260–265
210–213 [59]
205–207 [60]
181–183 [61]
193–196 [62]
235–237 [63]
284–286 [63]
204–206 [64]
207–211 [65]
202–204 [66]
222–224 [64]
181–185 [65]
216–219 [65]
262–263 [63]
207–209 [61]
208–210 [67]
–
2
4-ClC6H4
2-ClC6H4
4-FC6H4
3
4
5
4-HOC6H4
2-MeOC6H4
4-MeC6H4
C6H5
6
7
5g
5h
5i
8
9
4-ClC6H4
2-ClC6H4
4-FC6H4
Et
10
11
12
13
14
15
16
17
18
19
20
Et
5j
Et
5k
5l
4-MeC6H4
2-MeOC6H4
4-NO2C6H4
C6H5
Et
Et
5m
5n
5o
5p
5q
5r
6a
6b
Et
Et
4-FC6H4
Et
S
3-NO2C6H4
4-HOC6H4
4-MeC6H4
4-ClC6H4
Et
S
203–205 [68]
183–184 [68]
229–230 [69]
265–266 [69]
Et
S
–
O
O
–
Conditions: aldehyde 1 (1 mmol), urea 2 (1.5 mmol), methyl (or ethyl) acetylacetate (1 mmol), catalyst (0.03 g), temperature 100 °C
a
Isolated pure yield
5‑Ethoxycarbonyl‑6‑methyl‑4‑phenyl‑3,4‑dihydropy‑
rimidin‑2(1H)‑thione (5o) Cream solid, m.p. 206–
208 °C; IR (KBr) ν: 3329, 3176, 3107, 2979, 1670,
1574, 14.65, 1371, 1327, 1283, 1195, 1176, 1118, 1028,
NMR (250 MHz, DMSO-d6) δ: 1.06 (t, 3H, CH3), 2.27 (s,
3H, CH3), 3.94–3.99 (q, 2H, CH2), 5.16 (s, 1H, CH), 7.11–
7.22 (m, 4H, Ar-H), 9.62 (s, 1H, NH), 10.33 (s, 1H, NH)
ppm; 13C NMR (62 MHz, DMSO-d6) δ: 14.3, 17.5, 18.1,
53.8, 60.0, 101.0, 115.5, 115.9, 128.8, 128.9, 140.2, 145.6,
160.0, 163.9, 165.4, 174.6 ppm.
1
761, 693, 597, 543 cm−1; H NMR (250 MHz, DMSO-
d6) δ: 1.06 (t, 3H, CH3), 2.26 (s, 3H, CH3), 3.93–4.02 (q,
2H, CH2), 5.15 (s, 1H, CH), 7.17–7.34 (m, 5H, Ar-H),
9.61 (s, 1H, NH), 10.29 (s, 1H, NH) ppm; 13C NMR
(62 MHz, DMSO-d6) δ: 14.4, 17.5, 18.2, 54.4, 60.0,
101.1, 126.8, 128.1, 128.9, 130.5, 143.9, 145.4, 165.5,
174.7 ppm.
4‑Phenyl‑6‑(p‑tolyl)‑3,4‑dihydropyrimidin‑2(1H)‑one
(6a) White solid, m.p. 199–201 °C; IR (KBr) ν: 3462,
3407, 3305, 3163, 3032, 2971, 1664, 1650, 1613, 1598,
1537, 1367, 1202, 1184, 1146, 864, 815, 783, 708,
1
589 cm−1; H NMR (250 MHz, DMSO-d6) δ: 2.26 (s, 3H,
5‑Ethoxycarbonyl‑4‑(4‑fluorophenyl)‑6‑methyl‑3,4‑di‑
hydropyrimidin‑2(1H)‑thione (5p) Cream solid, m.p.
182–187 °C; IR (KBr) ν: 3325, 3176, 3104, 2986, 1682,
1657, 1576, 1506, 1467, 1283, 1195, 1177, 1119 cm−1; 1H
CH3), 5.64 (s, 4H, CH and NH), 6.05–6.09 (m, 1H, Ar-H),
6.63–6.66 (d, 2H, Ar-H), 7.10–7.20 (m, 6H, Ar-H) ppm;
13C NMR (62 MHz, DMSO-d6) δ: 21.0, 59.3, 126.1, 126.3,
129.0, 136.6, 140.0, 158.1 ppm.
1 3

J IRAN CHEM SOC
Table 4 Catalytic reusability of Fe3−xTixO4@SiO3H MNPs for the
Results and discussion
model reaction between benzaldehyde, urea and methyl acetylacetate
Characterization of the catalyst Fe3−xTixO4@SO3H
MNPs
Run
Time (min)
Yield (%)a
1
2
3
4
5
40
40
45
50
60
98
96
95
94
92
In continuation of our efforts to develop clean and green
recovery of the heterogeneous catalyst, herein, we are
encouraged to examine the catalytic potential of our pre-
viously synthesized sulfonic acid-functionalized titano-
magnetite (Fe3−xTixO4@SO3H) nanoparticles [52] as a
nanomagnetic heterogeneous system for the synthesis of
3,4-dihydropyrimidin-2(1H)-ones/thiones. It is a known
fact that the presence of Ti+4 cations in the structure of nan-
oparticles can increase the number of superficial hydroxyl
groups [54]. Such an structural quality can improve the
loading capacity of sulfonic acid groups on the surface of
the titanomagnetite nanoparticles (4.0–5.5 mmol/g) com-
pared to the magnetite Fe3O4 NPs (1.76 mmol/g) [55] and
magnetite silica-coated Fe3O4 NPs (0.32 mmol/g) [56].
Firstly, Fe3−xTixO4 MNPs were prepared using our
reported procedure [52] by treatment of the mixture of
equimolar amounts of FeSO4·7H2O and TiCl4 in acidic
solution with hydrazine hydrochloride in deionized water
with refluxing under nitrogen atmosphere. The result-
ing titanomagnetite nanoparticles were separated from the
reaction mixture simply by using a magnetic bar. Then, a
dispersion of Fe3−xTixO4 MNPs in CH2Cl2 was ultrasoni-
cated for 30 min followed by treatment with chlorosul-
fonic acid with stirring at room temperature. The resulting
Fe3−xTixO4@SO3H MNPs were isolated by using a mag-
netic bar. The number of SO3H groups per gram of the sup-
port NPs determined by acid–base titration was found to be
in the range of 4.1–5.5 mmol.
a
Isolated yield
735 cm−1 [57, 58]. In both of these IR spectra, the broad
sharp peaks appearing at 578 and 534 cm−1, respectively,
are ascribed to Fe–O stretching vibration.
As shown in Fig. 2, the energy-dispersive X-ray spec-
trum (EDX) obtained from the synthesized Fe3−xTixO4@
SO3H MNPs clearly indicates the expected elemental com-
position (O, S, Ti, Fe).
The morphology and particle size of Fe3−xTixO4@SO3H
MNPs were observed by scanning electron microscopy
(SEM) analysis as shown in Fig. 3. From SEM image, it
can be seen that Fe3−xTixO4@SO3H MNPs are spherical in
shape and their average size is estimated to be in the range
of 30–50 nm.
For further analysis, we studied the stability of the
Fe3−xTixO4@SO3H nanoparticles using thermal gravimetric
(TGA) and derivative thermal gravimetric (DTG) analy-
ses and their corresponding thermal decomposition curves
are obtained as shown in Fig. 4. The weight loss occurred
upon heating in the temperature range of 25–160 °C can
be assigned to the desorbed water or other organic solvents
which were used in the preparation steps of the catalyst.
Moreover, the weight loss occurred by further heating to
300 °C can be ascribed to the loss of sulfonic acid groups.
Finally, the weight loss from 579 to 680 °C is likely due to
the variation in composition of the nanoparticles.
The synthesized catalyst was characterized by different
methods such as Fourier transform infrared (FTIR) spec-
tral, energy-dispersive X-ray (EDX), scanning electron
microscopy (SEM), thermal gravimetric (TGA) and vibrat-
ing sample magnetometry (VSM) analyses.
The magnetic properties of Fe3−xTixO4 and Fe3−xTixO4@
SO3H nanoparticles were measured by using vibrating sam-
ple magnetometer (VSM) at room temperature as presented
in Fig. 5. It has been reported that the saturation magneti-
zation (Ms) value of the bared Fe3−xTixO4 nanoparticles is
33.853 emu/g and the Ms value of the Fe3−xTixO4@SO3H
nanoparticles is 18.848 emu/g. These data confirm the suc-
cessful synthesis of the Fe3−xTixO4@SO3H nanocatalyst,
which are consistent with the expected data.
The FTIR spectra of Fe3−xTixO4 and Fe3−xTixO4@SO3H
NPs are shown in Fig. 1a, b, respectively. The spectrum
of the Fe3−xTixO4@SO3H NPs performs the characteris-
tic peaks for SO3H-functionalized nanoparticles which
are clearly different from those of the unfunctionalized
Fe3−xTixO4 NPs (Fig. 1a), namely indicating the successful
conjugation of sulfonic acid groups onto the surface of the
Fe3−xTixO4 MNPs. The broad absorption band centered at
3416 cm−1 in the IR spectrum of the Fe3−xTixO4 (Fig. 1a)
is assigned to the incorporation of symmetrical and asym-
metrical modes of the O–H bonds which are attached to the
surface metal atoms. The broad band appearing at 3000–
3500 cm−1 along with the peaks at 1195 and 1132 cm−1
is attributed to the O–H bond of the sulfonic acid group
(Fig. 1b). The absorption band for Ti–O bond appears at
Catalytic activity of Fe3−xTixO4@SO3H MNPs in the
synthesis of dihydropyrimidin‑2(1H)‑ones/thiones
In order to evaluate the merits and catalytic capability of
the synthesized heterogeneous catalyst Fe3−xTixO4@SO3H
MNPs in organic transformations, we chose to investigate
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J IRAN CHEM SOC
Scheme 2 A possible reaction pathway for the Fe3−xTixO4@SiO3H-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones
Table 3 Comparison of the
results using Fe3−xTixO4@
SiO3H MNPs with results
obtained by other reported
catalysts for the synthesis of
3,4-dihydropyrimidin-2(1H)-
ones from Biginelli reaction
Entry Catalyst
Condition
Temperature (°C) Time (h) Yield (%) References
1
2
Fe3−xTixO4@SiO3H MNPs Solvent-free
100
120
80
0.5
48
10
8
98
80
86
90
91
92
75
81
91
89
Current
[21]
[70]
[71]
[68]
[61]
[66]
[72]
[73]
[74]
Yb(III)-resin
PS-PEG-SO3H
SiO2-R-SO3H
SSA
Solvent-free
Reflux
3
4
Reflux
80
5
Reflux
80
6
6
MCM-41-R-SO3H
[Et3NH][HSO4]
SBSSA
Reflux
80
6
7
Solvent free
100
1
8
Glacial HOAc 110
1
9
[Cbmim]Cl
SA-MNPs
Solvent free
Solvent free
80
1
10
100
–
its catalytic activity in one-pot three-component Biginelli
and Biginelli-like reactions for the synthesis of dihydro-
pyrimidin-2(1H)-ones/thiones. Initially, we examined the
three-component one-pot reaction between benzaldehyde,
urea and methyl acetoacetate as a model reaction to exam-
ine the catalytic potential of the Fe3−xTixO4@SO3H MNPs.
To establish the reaction conditions, we studied the effects
of green solvents like H2O and EtOH, catalyst loading and
reaction temperature on the reaction. Based on the experi-
mental results as summarized in Table 1, the optimal results
for the reaction are obtained under solvent-free condition
with using the catalyst loading of 0.03 g at 100 °C (entry
6). Further increasing the amount of the catalyst exhibited
no improving effect on the yield (entries 7, 8). The impor-
tant role of the catalyst in the reaction was substantiated by
conducting the reaction in the absence of the catalyst that
resulted in no detectable amount of the expected product
and ended with almost full recovery of the starting materi-
als (entry 9). It is interesting to note that under ultrasound
irradiation in EtOH the reaction resulted in only very low
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J IRAN CHEM SOC
yield of the product with using optimal amount of the cata-
lyst (entry 10).
for five consecutive times without a noticeable loss of
its activity. The integrity of the recovered catalyst was
examined and proved to be as active as the originally used
catalyst.
In order to develop the scope of the reactions, the reac-
tion was carried out using a diverse series of variously
substituted aldehydes, methyl and ethyl acetoacetates
(or acetophenone) 3 under the optimized conditions, i.e.,
the catalyst loading of 0.03 g at 100 °C under solvent-
free condition for the synthesis of the corresponding
3,4-dihydropyrimidin-2(1H)-ones/thiones (5a‑r and 6a‑
b) (Scheme 1). The results summarized in Table 2 indi-
cate that all the reactions proceed smoothly within short
reaction times to provide the respected products in high
yields irrespective of the nature of substituent groups. All
the products are known compounds which are character-
ized on the basis of their physical properties and spectral
Conclusion
In summary, a highly efficient, green and straightforward
procedure has been developed for the one-pot synthesis
of dihydropyrimidinones using Fe3−xTixO4@SO3H MNPs
as an efficient and recyclable heterogeneous magnetic
nanocatalyst. It is important to note that the catalytic per-
formance of this nanocatalyst is greatly enhanced under
solvent-free conditions, which is important from the green
chemistry point of view. In addition, the reactions proceed
smoothly under solvent-free conditions with relatively low
reaction times and excellent yields. Therefore, this protocol
can be considered as a suitable, inexpensive and green alter-
native method for the synthesis of dihydropyrimidinones/
thiones.
1
(FTIR, H-NMR, 13C-NMR) data which were in accord
with those reported in the literature. The characteristic
data for some selected products are given in the experi-
mental section.
In order to evaluate the catalytic efficiency of the pre-
pared nanocatalyst Fe3−xTixO4@SiO3H, we compared the
advantages of this nanocatalyst with some other previously
reported catalysts for the synthesis of 5-methoxycarbonyl-
6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one deriva-
tives from Biginelli reaction. The results summarized in
Table 3 indicate that the present catalyst possesses higher
activity compared to other catalysts as listed in this Table. It
can be seen that simplicity in preparation of the present cat-
alyst, efficient recyclability and reusability of the catalyst,
use of green solvent-free condition, short reaction times and
high yields of the products can be considered as outstanding
characteristics of the present protocol (entry 10).
Based on the mechanism previously proposed for the
Biginelli reaction by Kappe [75], a plausible mechanism
for the formation of 3,4-dihydropyrimidin-2(1H)-ones/
thiones is depicted in Scheme 2. It is likely that the initial
step to involve the rate-limiting nucleophilic addition of
urea to catalyst-activated aldehyde to produce the N-alky-
lidene urea intermediate (A) after dehydration. The inter-
ception of the intermediate imine (A) by the enolized ace-
toacetate resulted in the formation of the intermediate (B)
which undergoes consecutive cyclization and dehydration
under the catalytic effect to furnish the expected dihydro-
pyrimidinones/thiones 5.
Acknowledgments The authors wish to acknowledge the financial
support of the Research Council of the Bu-Ali Sina University (Iran)
to carry out this research.
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