TiO2 as a reusable catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions

Article abstract of DOI:10.1002/hlca.200900197

An efficient solvent-free method for the synthesis of various 3,4-dihydropyrimidin-2(1H)-ones using TiO₂ as a recyclable heterogeneous catalyst is described. Compared to known methods, satisfactory results are obtained with excellent yields, sh

Full text of DOI:10.1002/hlca.200900197

Helvetica Chimica Acta – Vol. 93 (2010)
261
TiO2 as a Reusable Catalyst for the One-Pot Synthesis of
3,4-Dihydropyrimidin-2(1H)-ones under Solvent-Free Conditions
by Mohammad Zaman Kassaee*, Hassan Masrouri, Farnaz Movahedi, and Reza Mohammadi
Department of Chemistry, Tarbiat Modares University, P. O. Box 14155-4838, Tehran, Iran
(phone: þ 98-912-1000392; fax: þ 98-21-88006544; e-mail: kassaeem@modares.ac.ir,
drkassaee@yahoo.com)
An efficient solvent-free method for the synthesis of various 3,4-dihydropyrimidin-2(1H)-ones using
TiO2 as a recyclable heterogeneous catalyst is described. Compared to known methods, satisfactory
results are obtained with excellent yields, short reaction times, and simplicity in the experimental
procedure.
Introduction. – The Biginelli reaction [1] offers an efficient way to access
multifunctionalized 3,4-dihydropyrimidin-2(1H)-ones and related heterocyclic com-
pounds.
Results and Discussions. – We wish to report an efficient and simple method for the
synthesis of 3,4-dihydropyrimidin-2(1H)-ones through a three-component condensa-
tion of 1,3-dicarbonyl compounds, aldehydes, and urea, using commercially available
titania (TiO2) as an inexpensive heterogeneous and recyclable catalyst under neutral
and solvent-free conditions (Scheme).
Scheme
In a typical general experimental procedure, we probed cyclocondensation of
benzaldehyde, urea, and ethyl acetoacetate (¼ethyl 3-oxobutanoate) in the presence of
TiO2 (10 mol-%) at 708 under solvent-free conditions. The mixture of reactants
solidified within 20 min. It was diluted with AcOEt, and the catalyst was separated by
filtration. The filtrate was washed with H2O (two times) and dried over anhydrous
MgSO4. Then, it was evaporated under reduced pressure to yield the crude product,
which was further purified by recrystallization from EtOH to afford pure ethyl 6-
methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate in 98% yield. A
wide range of structurally varied b-dicarbonyl compounds, aldehydes, and urea are
coupled by this procedure to produce the corresponding dihydropyrimidinones
(Table 1). Both b-keto ester and b-diketone readily participated in this reaction.
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

262
Helvetica Chimica Acta – Vol. 93 (2010)
Table 1. TiO2-Catalyzed Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones/thionesa)
Entry Product
R
R’
X
Time [min] Yield [%]b) M.p. [8] (lit. m.p.)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
Ph
Ph
Ph
Ph
EtO
Me
MeO
MeO
EtO
Me
MeO
EtO
Me
MeO
EtO
EtO
MeO
MeO
EtO
EtO
MeO
EtO
Me
MeO
EtO
MeO
EtO
MeO
EtO
MeO
EtO
MeO
EtO
EtO
O
O
O
S
20
20
30
20
30
20
25
20
20
35
30
40
25
25
25
35
35
30
25
35
35
40
40
30
30
45
45
60
60
50
55
60
50
60
98
96
98
91
92
89
91
92
96
97
97
93
94
92
93
90
93
95
89
91
92
88
90
93
95
90
92
87
89
91
86
83
86
82
203 – 204 (201 – 203) [2]
235 – 237 (233 – 236) [2]
209 – 211 (207 – 210) [2]
228 – 230 (221 – 222) [3]
204 – 205 (202 – 204) [3]
216 – 219
221 – 223
220 – 222
228 – 230
212 – 214 (204 – 206) [4]
213 – 215 (213 – 216) [3]
184 – 187 (192 – 194) [4]
210 – 212 (209 – 211) [5]
193 – 195 (191 – 193) [2]
201 – 203 (199 – 201) [2]
150 – 152 (150 – 152) [4]
205 – 208 (207 – 208) [3]
210 – 212 (210 – 212) [2]
205 – 208
224 – 225
194 – 196 (193 – 195) [4]
235 – 237
221 – 223 (222 – 224) [4]
247 – 249 (245 – 246) [6]
230 – 233 (230 – 232) [4]
230 – 232
234 – 237 (232 – 235) [2]
184 – 186
Ph
S
4-BrꢀC6H4
4-BrꢀC6H4
4-BrꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
4-MeꢀC6H4
3-MeꢀC6H4
4-MeOꢀC6H4
4-MeOꢀC6H4
4-MeOꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
3-ClꢀC6H4
3-ClꢀC6H4
3-ClꢀC6H4
2-ClꢀC6H4
2-ClꢀC6H4
4-OHꢀC6H4
4-OHꢀC6H4
PhꢀCH¼CH
PhꢀCH¼CH
Thien-2-yl
Thien-2-yl
Furan-2-yl
O
O
O
O
O
O
S
O
O
O
S
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
4y
4z
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
209 – 211 (207 – 208) [7]
228 – 230
245 – 247
157 – 158 (157 – 158) [2]
194 – 195 (194 – 195) [2]
242 – 244 (242 – 244) [4]
3-NO2, 4-ClꢀC6H4 EtO
Bu
iPr
H
EtO
EtO
EtO
a) Reaction conditions: aldehyde (1.5 mmol), urea/thiourea (2 mmol), b-dicarbonyl compound
(1.5 mmol), catalyst (10 mol-%), at 708 under solvent-free conditions. b) Yield of isolated material.
The reaction can tolerate a wide range of heterocyclic, aliphatic, or aromatic
aldehydes carrying either electron-donating or electron-withdrawing substituents in
ortho, meta, or para position. Acid sensitive aldehydes such as furfuraldehyde (¼ furan-
2-carbaldehyde) worked well without the formation of any side products and gave the
3,4-dihydropyrimidin-2(1H)-one derivative in 91% yield (Table 1, Entry 30). Thiourea
has been used with similar success to provide the corresponding dihydropyrimidin-
2(1H)-thiones which are also of interest with regard to their biological activity. Thus,
variations in all three components have been accommodated very comfortably. All
1
products were characterized on the basis of their spectroscopic data such as H- and
13C-NMR, and physical data.

Helvetica Chimica Acta – Vol. 93 (2010)
263
To investigate the effects of media, we carried out the condensation of
benzaldehyde, urea, and ethyl acetoacetate in various organic solvents under refluxing
condition while using 10 mol-% of TiO2 as the catalyst (Table 2). The use of solvents
such as MeCN, THF, EtOH, or H2O decreased the product yields (Table 2, Entries 1 –
4). In evaluating the effects of catalyst concentration, we found the use of 10 mol-% of
TiO2 sufficient to push the reaction forward. A higher amount of TiO2 (20 mol-%) did
not improve the result to an appreciable extent (Table 2, Entry 9).
Table 2. Optimization of the TiO2-Catalyzed Model Reaction for the Synthesis of 3,4-Dihydropyrimidin-
2(1H)-ones/thionesa)
Entry
Solvent
Catalyst
Time [min]
Yield [%]b)
1
2
3
4
5
6
7
8
9
MeCN
THF
H2O
EtOH
neat
neat
neat
neat
neat
TiO2 (10 mol-%)
TiO2 (10 mol-%)
TiO2 (10 mol-%)
TiO2 (10 mol-%)
No catalyst
TiO2 (5 mol-%)
TiO2 (10 mol-%)
TiO2 (10 mol-%)
TiO2 (20 mol-%)
120
90
180
120
180
50
240
20
20
68
86
45
80
0
78
30c)
98
98
a) Reaction conditions: aldehyde (1.5 mmol), urea/thiourea (2 mmol), b-dicarbonyl compound
(1.5 mmol), catalyst (10 mol-%) under reflux or solvent-free conditions at 708. b) Yield of isolated
material. c) Reaction carried out at room temperature.
To appraise the effect of the temperature, the reaction of benzaldehyde, urea, and
ethyl acetoacetate in the presence of a catalytic amount of TiO2 was carried out at
different temperatures under similar experimental conditions. The reaction rate was
very slow at ambient temperature, but improved with increasing the temperature. The
optimum temperature was found to be 708 and no improvement was realized at higher
temperatures. Biginelli reaction of benzaldehyde, ethyl acetoacetate, and urea under
the described reaction conditions did not proceed in the absence of catalyst. No
additive or protic/Lewis acid is necessary in this method. Another important aspect of
this procedure is the survival of a variety of functional groups such as Br, Cl, NO2, OH,
MeO, and a conjugated C¼C bond under the reaction conditions.
The possibility to recycle and reuse TiO2 has also been studied (Table 3). The
catalyst was separated by filtration from the mixture after dilution with AcOEt, and
was reused as such for subsequent experiments under similar reaction conditions. The
yields of 4a only decreased a little after the fifth reuse of TiO2.
Conclusion. – In conclusion, the present three-component, one-pot condensation
for the synthesis of dihydropyrimidin-2(1H)-ones/thiones by TiO2 catalysis provides an
efficient, facile, and environmentally acceptable modification of Biginelliꢂs reaction.
This method offers several advantages including high yields, short reaction times, a
simple work-up procedure under solvent-free conditions, ease of separation, and
recyclability of the catalyst, as well as the ability to tolerate a wide variety of
substituents in all the three components.

264
Helvetica Chimica Acta – Vol. 93 (2010)
Table 3. Reusability of the TiO2 Catalysta)
Number of use
Yield [%]
Recovery of TiO2 [%]
1
2
3
4
5
98
98
96
93
89
99
98
98
96
95
a) Formation of 4e under the standard conditions.
Experimental Part
General. The reagents and solvents used in this work were obtained from Fluka (Buchs, Switzerland)
and used without further purification. M.p.: Electrothermal 9100 apparatus. 1H- and 13C-NMR spectra: at
500.1, and 125.7 MHz, resp., on a Bruker DRX 500-Avance FT-NMR instrument with (D6)DMSO as the
solvent.
General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones (exemplified for 4a). To a
stirred mixture of benzaldehyde (1.5 mmol, 159.2 mg), urea (2 mmol, 120.1 mg), and ethyl acetoacetate
(¼ethyl 3-oxobutanoate; 1.5 mmol, 195.2 mg) was added the TiO2 catalyst (10 mol-%, 8 mg) at 708.
Solidification occurred within 20 min. The resulting solid was diluted with AcOEt (2 ml), and the catalyst
was separated by filtration through a Bꢀchner funnel. The filtrate obtained was washed with H2O (two
times) and dried (MgSO4). Evaporation of the solvent under reduced pressure yielded a crude product
which was purified by recrystallization from EtOH to afford pure ethyl 1,2,3,4-tetrahydro-6-methyl-2-
oxo-4-phenylpyrimidine-5-carboxylate (4a) in 98% yield, M.p. 203 – 2048. Similarly, other aldehydes were
reacted with urea/thiourea and b-dicarbonyl compounds to obtain the corresponding 3,4-dihydropyr-
imidin-2(1H)-ones/thiones (Table 1).
REFERENCES
[1] P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360.
[2] Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem. 2000, 65, 3864.
[3] Y. Yu, D. Liu, C. Liu, G. Luo, Bioorg. Med. Chem. Lett. 2007, 17, 3508.
[4] N.-Y. Fu, Y.-F. Yuan, Z. Cao, S.-W. Wang, J.-T. Wang, C. Peppe, Tetrahedron 2002, 58, 4801.
[5] C. O. Kappe, W. M. F. Fabian, M. A. Semones, Tetrahedron 1997, 53, 2803.
[6] A. Kumar, R. A. Maurya, Tetrahedron Lett. 2007, 48, 4569.
[7] G. Sabitha, G. S. K. K. Reddy, C. S. Reddy, J. S. Yadav, Synlett 2003, 858.
Received May 27, 2009