Efficient Ce(NO3)3·6H2O-catalyzed solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.3390/11080649

Cerium(III) nitrate hexahydrate efficiently catalyzes the three-component Biginelli reaction under solvent-free conditions of an aldehyde, a β-keto ester or β-diketone and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones or -th

Full text of DOI:10.3390/11080649

Molecules 2006, 11, 649-654
molecules
ISSN 1420-3049
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Full Paper
Efficient Ce(NO3)3·6H2O-Catalyzed Solvent-Free Synthesis of
3,4-Dihydropyrimidin-2(1H)-ones
Mehdi Adib,* Khadijeh Ghanbary, Manizheh Mostofi and Mohammad Reza Ganjali
School of Chemistry, University College of Science, University of Tehran, P. O. Box 14155-6455,
Tehran, Iran
* Author to whom correspondence should be addressed; Tel/fax: +98(21)66495291; E-mail:
madib@khayam.ut.ac.ir
Received: 27 October 2005; in revised form: 9 May 2006/ Accepted: 23 August 2006 / Published: 23
August 2006
Abstract: Cerium(III) nitrate hexahydrate efficiently catalyzes the three-component
Biginelli reaction under solvent-free conditions of an aldehyde, a β-keto ester or β-
diketone and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-2(1H)-
ones or –thiones in excellent yields.
Keywords: Dihydropyrimidinones; cerium(III) nitrate; Biginelli reaction; solvent-free
synthesis.
Introduction
3,4-Dihydropyrimidin-2(1H)-ones (DHPM) and their sulfur analogs have been reported to possess
remarkable pharmacological properties. Some of which have antiviral, antitumor, antibacterial,
antiinflammatory, and antihypertensive activities [1-5], some are calcium channel modulators [6], and
α1a adrenoceptor-selective antagonists [7]. The structurally rather simple DHPM monastrol (Figure 1)
specifically inhibits the mitotic kinesin Eg5 motor protein and can be considered as a new lead for the
development of anticancer drugs [8]. The batzelladine alkaloids A and B (Figure 1) inhibit the binding
of HIV envelope protein gp-120 to human CD4 cells and, therefore, are potential new leads for AIDS
therapy [9]. As a result new synthetic methods for the efficient preparation of these heterocyclic
compounds are of great importance. Very recently, several modified and improved procedures for the

Molecules 2006, 11
650
one-pot synthesis of dihydropyrimidinones have been reported [10], but many of reported methods
have drawbacks such long reaction times, harsh reaction conditions, the use of stoichiometric reagents
or of toxic and inflammable solvents, difficult work-ups or low yields of products and incompatibility
with other functional groups in the molecules. Consequently, there is a need to develop new methods
using less hazardous reagents and solvents, or even better, ones that can be carried out under solvent-
free conditions.
Figure 1. Examples of biologically active DHPMs.
HO
NH
O
H
H
+
N
NH
O
O
N
O
(CH2)6
H3C
N
N
(CH2)6CH3
H
H
C2H5O
H3C
NH
H
H2N
N
O
N
S
+
NH2
H
monastrol
batzelladine B
Results and Discussion
In recent years lanthanide salts have been used as catalysts in the Biginelli reaction, for example:
LaCl3·7H2O in refluxing EtOH [11a] or Yb(OTf)3 under solvent-free conditions [11b]. Bose and co-
workers have reported the CeCl3·7H2O-catalyzed synthesis of DHPMs in moderate to good yields (65-
80%) under solvent-free conditions, but their procedure suffers from some drawbacks such as the very
long reaction times needed (up to 10 h) and the use of fairly high amounts of the catalyst (25 mol %)
[11c]. In this paper, we wish to report a simple and efficient method for the synthesis of DHPMs using
cerium(III) nitrate under solvent-free conditions. Thus, the reactions of several activated and
deactivated aromatic and aliphatic aldehydes with a β-keto ester (or β-diketone) and urea using a
catalytic amount of Ce(NO3)3·6H2O produced a range of DHPMs in excellent yields under solvent-free
conditions at 80 ºC (Scheme 1).
Scheme 1.
R
O
O
O
X
Ce(NO3)3.6H2O (cat.)
80o C
R'
H3C
NH
RCHO +
+
H3C
R'
H2N
NH2
N
H
X
1
4
3
2
R' = OEt, OMe, Me
R =
X = O, S
aromatic,
heteroaromatic,
unsaturated,
aliphatic
Thiourea was also used as one of the ingredients with similar success to provide the corresponding
3,4-dihydropyrimidin-2(1H)-thiones, which are also of interest for their biological activities [8]. In all

Molecules 2006, 11
651
cases, 3,4-dihydropyrimidin-2(1H)-ones (and -thiones) were the sole products and no by-products
were observed. The experimental procedure is very simple and convenient, and under the reaction
conditions used, can tolerate a variety of other functional groups such as methoxy, nitro, hydroxy,
halides and olefins. The results are summarized in Table 1, which clearly indicates the generality and
scope of the reaction with respect to various aromatic, heteroaromatic, unsaturated, and aliphatic
aldehydes.
According to the mechanism suggested by Kappe [12], we propose a mechanism for the Ce(III)-
catalyzed Biginelli reaction as shown in Scheme 2. The aldehyde may react with urea to form an acyl
imine intermediate 5, which is activated by Ce(III). Subsequent nucleophilic addition of the activated
β-dicarbonyl compound 6 followed by cyclization and dehydration affords the 3,4-dihydropyrimidin-
2(1H)-one 4.
Scheme 2.
3+
Ce
O
O
H3C
R'
R
OH
R
6
X
_
H2O
N
NH2
RCHO
+
H2N
NH2
HN
NH2
X
Ce(III)
X
5
R
R
O
R'OC
H3C
NH
_
R'
H3C
NH
H2O
X
N
H
X
O
H2N
4
Table 1. Ce(NO3)3·6H2O-Catalyzed Synthesis of Dihydropyrimidinones
and Dihydropyrimidinethiones under Solvent-Free Conditions a.
Entry
R
R' X time (min) Yield (%)b
1
2
3
4
5
6
7
8
C6H5
OEt O
OEt O
OEt O
OEt O
OEt O
OEt O
OEt O
OEt O
10
15
20
15
10
10
25
20
98
95
93
97
97
98
90
92
2-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4

Molecules 2006, 11
652
Table 1. Cont.
R' X time (min) Yield (%)b
Entry
9
R
4-ClC6H4
4-BrC6H4
4-FC6H4
3-O2NC6H4
4-O2NC6H4
OEt O
OEt O
OEt O
OEt O
OEt O
25
25
25
25
25
10
30
15
25
35
40
10
20
10
10
30
10
10
10
10
30
10
10
10
94
93
95
89
91
97
91
93
84
87
84
96
93
97
96
90
97
96
90
97
96
95
96
94
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
2,4-(MeO)2C6H3 OEt O
1-Naphthyl
2-Furyl
OEt O
OEt O
OEt O
OEt O
OEt O
OMe O
OMe O
OMe O
Me O
Me O
Me O
OEt S
OEt S
OEt S
OEt S
OMe S
OMe S
PhCH=CH
n-Pentyl
n-Hexyl
C6H5
4-O2NC6H4
4-MeOC6H4
C6H5
4-O2NC6H4
4-MeOC6H4
C6H5
4-O2NC6H4
4-MeOC6H4
3-HOC6H4
C6H5
4-MeOC6H4
C6H5
32
Me
S
a
All products are known compounds and were characterized by
comparison of their spectral data and m.p. values with those of
authentic samples.
b
Isolated yields
Conclusions
In summary, we have developed a new and efficient synthetic methodology for the synthesis of
3,4-dihydropyrimidin-2(1H)-ones and their thio analogs under solvent-free conditions using a catalytic
amount of Ce(III) nitrate. Moreover, the mild reaction conditions, short reaction times, high yields of
the products, ease of work-up, compatibility with various functional groups, and the environmentally
friendly nature of the procedure should make the present method a useful and important addition to the
known methodologies for the Biginelli reaction.

Molecules 2006, 11
653
Acknowledgements
This research was supported by the Research Council of University of Tehran as a research project
(6102036/1/02).
Experimental
General
All chemicals were obtained from Merck (Germany) and were used without further purification.
1
Melting points were measured on an Electrothermal 9100 apparatus, and are uncorrected. H-NMR
spectra were recorded for deuterioacetone solutions using tetramethylsilane as the internal standard on
a Bruker DRX-500 AVANCE spectrometer at 500.1 MHz operating at ambient temperature (δ in ppm
and J in Hz).
Typical Procedure: 5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (Entry 1)
A mixture of benzaldehyde (0.106 g, 1 mmol), ethyl acetoacetate (0.130 g, 1 mmol), urea (0.090 g,
1.5 mmol), and Ce(NO3)3·6H2O (5 mol%) was heated with stirring at 80°C for 10 min. The progress of
the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room
temperature, and the precipitate was washed with cold water (3
× 5 mL). The pure product was
obtained as colorless crystals by recrystallization from 95% EtOH, mp 200-201°C (Lit. [11b] 201-
203°C); 1H-NMR (acetone-d6): δ 1.15 (3 H, t, J = 7.1 Hz, OCH2CH3), 2.39 (3 H, s, CH3), 4.05 (2 H, q,
J = 7.1 Hz, OCH2CH3), 5.38 (1 H, d, J = 3.0 Hz, NHCH), 6.88 (1 H, br. s, NH), 7.24 (1 H, t, J = 7.3
Hz, CHpara), 7.30 (2 H, t, J = 7.5 Hz, 2 CHmeta), 7.36 (2 H, t, J = 7.5 Hz, 2 CHortho) and 8.29 (1 H, br. s,
NH). The catalyst remaining in the aqueous phase can be recovered by removing the water by heating
and then drying under vacuum at 100 °C for 2 h.
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Molecules 2006, 11
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Sample Availability: Samples are available from authors.
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