H4SiW12O40·xH2O as a new catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-one

Article abstract of DOI:10.3987/COM-06-10905

H₄SiW₁₂O₄₀·xH₂O catalyzed the one-pot three component condensation reactions of aldehydes, 1,3-dicarbonyl compounds and urea in refluxing acetic acid leading to 3,4-dihydropyrimidin-2(1H)-one in high yields.

Full text of DOI:10.3987/COM-06-10905

HETEROCYCLES, Vol. 71, No. 2, 2007
373
HETEROCYCLES, Vol. 71, No. 2, 2007, pp. 373 - 378. © The Japan Institute of Heterocyclic Chemistry
Received, 6th October, 2006, Accepted, 15th December, 2006, Published online, 19th December, 2006. COM-06-10905
H4SiW12O40·xH2O AS A NEW CATALYST FOR THE SYNTHESIS OF
3,4-DIHYDROPYRIMIDIN-2(1H)-ONE
Khodabakhsh Niknam*,a and Nader Daneshvarb
aChemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr
75169, Iran, E-mail: niknam@pgu.ac.ir, Fax: (+98)771-4545188
bDepartment of Chemistry, Islamic Azad University, Gachsaran Branch, Iran
Abstract ― H4SiW12O40·xH2O catalyzed the one-pot three component
condensation reactions of aldehydes, 1,3-dicarbonyl compounds and urea in
refluxing acetic acid leading to 3,4-dihydropyrimidin-2(1H)-one in high yields.
One of the most important objectives now is to adapt classical processes so that pollution effects are kept
to a minimum, with both a reduction in energy and consumption of raw materials. In this respect,
heterogeneous systems are promising, and a new approach has been undertaken using solid acids
chemistry. Solid acids have many advantages such as simplicity in handling, decreased reactor and plant
corrosion problems, and more environmentally safe disposal in different chemical processes. Also, wastes
and by-products can be minimized or avoided by using solid acids in developing cleaner synthesis routes.
On the other hand, any reduction in the amount of liquid acid needed and/or any simplification in
handling procedures is required for risk reduction, economic advantage and environment protection,1 and
using an applicable industrial catalyst that is safe and eco-friendly, green and simply recycled in the
reaction mixtures has been under attention. In the past two decades, the broad utility of heteropoly acids
(HPAs) as acid and oxidation catalysts in solution as well as solid state for various industrial processes
has been demonstrated for a wide variety of synthetic transformation of organic substrates.1-3
Dihydropyrimidinone derivatives (DHPMs) have attached considerable interest in recent years because
these types of compounds exhibit attractive pharmacological profiles as calcium channel blockers,
antihypertensive agents, α1a-antagonists and neuropeptide Y (NPY) antagonists.4 In addition, several
marine alkaloids containing the dihydropyrimidinone-5-carboxylate motifs also showed interesting
biological properties.5
Biginelli synthesis involves reaction of ethyl acetoacetate, benzaldehyde and urea in alcohol solution in
the presence of a catalytic amount of hydrogen chloride to give 3,4-dihydropyrimidin-2(1H)-ones.6 A
major drawback of the classical Biginelli reaction is poor to moderate yields, particularly when
substituted aromatic aldehydes were employed. Therefore, several improved procedures for the
preparation of Biginelli compounds have been reported during the last two decades.7,8 Among the
improved synthetic methods is to use BF3·OEt2 as promoter as reported by Hu and Sidler.9 Later on,

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HETEROCYCLES, Vol. 71, No. 2, 2007
Kappe and co-workers further improved this reaction by employing microwave irradiation in the presence
of polyphosphate ether to give higher chemical yields of dihydropyrimidinone products.10 Recently, the
use of lanthanide compounds,11 Lewis acids,12-14 silica sulfuric acid,15 N-bromosuccinimide,16 alkali
hydrogen sulfate,17,18 RuCl3,19 12-molybdatophosphoric acid,20 H3PW12O40,21 L-prolin methyl ester
hydrochloride,22 Dowex-50W,23 K5CoW12O40,24 and uronium hydrogen sulfates25 also gave improved
yield.
Due to the importance of Biginelli reaction products, the discovery and introduction of better and milder
conditions using new catalysts has been under attention. Along this line, using HPAs, which are low in
toxicity, highly stable towards humidity, recyclable and air stable have found more attention. Among
these heteropoly acids, we chose silicotungestic acid which recently was used as a catalyst for the
cyclodehydration of 1,4-butandiol to tetrahydrofuran,26 and large soret effect for silicotungestic acid in a
supporting electrode.27 In this paper, we describe a one-pot method for the Biginelli reaction using
silicotungstic acid, H4SiW12O40·xH2O, a recyclable catalyst from the Keggin-type heteroploy acids
(Scheme 1).
O
Ar
H
Ar
O
R2
NH
H4SiW12O40 (2 mol%)
AcOH/reflux
O
2
R2
NH2
Me
N
H
O
+
Me
H2N
O
O
4
1
3
R2= OEt, Me
Scheme 1
Table 1. H4SiW12O40 Catalyzed Reaction of Aldehydes, Urea and 1,3-Dicarbonyl Compounds
Entry
ArCHO
R2
Time (h) Yield (%)a
Mp ( ˚C)
Found
Reported
4a
4b
4b
4c
4d
4e
4f
4g
4h
4i
C6H5CHO
4-Cl-C6H4CHO
4-Cl-C6H4CHO
4-NO2-C6H4CHO OEt
4-CN-C6H4CHO
2-Cl-C6H4CHO
3-NO2-C6H4CHO OEt
4-Me-C6H4CHO OEt
2-MeO-C6H4CHO OEt
4-MeO-C6H4CHO OEt
OEt
OEt
OEt
6
7
22
8
8
7
7
5
5
4
80
90
203-205 202-2049
210-212 213-2159
-
<10b
90
209-212 208-2119
OEt
OEt
82
90
90
91
90
91
127-129
-
215-217 215-21810
227-229 226-22710
172-174 1729
259-260 259-26015
204-206 201-2039
204-205 203-20512
4j
4k
Furfural
2-thiophen-
carbaldehyde
C6H5CHO
OEt
OEt
4
4
80
83
195-197
-
4l
4m
4n
Me
6
4
8
84
85
88
229-231 233-2368
169-171 170-17215
229 (dec) 230(dec)11
4-MeO-C6H4CHO Me
4-NO2-C6H4CHO Me
aIsolated yield. bThe reaction was performed in acetic acid solution and in the absence of H4SiW12O40.

HETEROCYCLES, Vol. 71, No. 2, 2007
375
In the present communication, urea, ethyl acetoacetate, and aldehydes were converted to the
corresponding pyrimidinones in a three-component one-pot Biginelli-type reaction in the presence of a
catalytic amount of H4SiW12O40. The best condition to prepare the dihydropyrimidinones were achieved
when 2 mol% of HPA, 1.5 equivalent of urea and 1 equivalent of both ethyl acetoacetate and aldehyde
were heated under reflux for 4-8 h, affording the desired product in good yields (Table 1). It's well known
that Biginelli reaction is an acid promoted reaction, so to validate the effect of catalyst (H4SiW12O40), we
accomplished the reaction of 4-chlorobenzaldehyde, ethyl acetoacetate and urea in acetic acid solution
and without catalyst. As shown in Table 1, the conversion of this reaction into desired product was less
than 10% after 22 h refluxing in AcOH. We found that this method is effective with a variety of
substituted aromatic aldehydes independently of the nature of the substituents on the aromatic ring,
representing an improvement to the classical Biginelli’s methodologies.
In conclusion, we reported here a catalytic method for synthesis of Biginelli-type 3,4-dihydropyrimidin-
2(1H)-ones using H4SiW12O40 as an efficient, recyclable and eco-friendly heterogeneous inorganic
catalyst. H4SiW12O40 is non-corrosive and environmentally benign and presents fewer disposal problems.
EXPERIMENTAL
General: Chemicals were purchased from Fluka, Merck and Aldrich chemical companies. IR spectra
were run on a Shimadzu Infra Red Spectroscopy IR-435. The 1H NMR was run on Avance Bruker AQS
300 MHz and 400 MHz. With TLC using silica gel SILG/UV 254 plates the progress of reaction was
followed. All the products (except 4d and 4k) are known compounds and were characterized by IR and
1H NMR spectroscopic data and their mps. compared with reported literature values.
General procedure:
A solution of aldehyde (10 mmol), β-ketoester (10 mmol) and urea (0.9 g, 15 mmol) in acetic acid (5 mL)
was treated with H4SiW12O40·xH2O (2 mol%, 0.05 g). The reaction mixture was heated at reflux
temperature and the progress of the reaction was monitored by TLC using petroleum ether: ethyl acetate
as eluent. Upon completion of the reaction pured into ice-water (30 mL). The resulting solid product was
then removed by filtration and recrystallized from ethanol to afford the pure product.
5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (4a):21 1H NMR (DMSO-d6,
300 MHz): δ 1.09 (t, 3H, J= 6.9 Hz), 2.24 (s, 3H), 3.97 (q, 2H, J= 6.8 Hz), 5.13 (s, 1H), 7.15-7.27 (m, 3H),
7.31 (d, 2H, J= 6.0 Hz), 7.74 (s, 1H), 9.20 (s, 1H).
5-Ethoxycarbonyl-6-methyl-4-(4-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (4b): 1H NMR
(DMSO-d6, 400 MHz): δ 1.08 (t, 3H, J= 7.0 Hz), 2.25 (s, 3H), 3.97 (q, 2H, J= 7.0 Hz), 5.14 (d, 1H, J= 2.6
Hz), 7.25 (d, 2H, J= 8.2 Hz), 7.39 (d, 2H, J= 8.2 Hz), 7.78 (s, 1H), 9.26 (s, 1H).

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5-Ethoxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one (4c):18 1H NMR
(DMSO-d6, 300 MHz): δ 1.08 (t, 3H, J= 7.2 Hz), 2.27 (s, 3H), 3.98 (q, 2H, J= 7.2 Hz), 5.29 (d, 1H, J= 2.9
Hz), 7.51 (d, 2H, J= 8.5 Hz), 7.78 (s, 1H), 8.19 (d, 2H, J= 8.5 Hz), 9.29 (s, 1H).
5-Ethoxycarbonyl-6-methyl-4-(4-cyanophenyl)-3,4-dihydropyrimidin-2(1H)-one (4d): IR (KBr):
1
3235, 3110, 2221, 1700, 1635 cm-1. H NMR (DMSO-d6, 300 MHz): δ 1.07 (t, 3H, J= 7.1 Hz), 2.25 (s,
3H), 3.97 (q, 2H, J= 7.1 Hz), 5.21 (s, 1H), 7.42 (d, 2H, J= 8.2 Hz), 7.80 (d, 2H, J= 8.2 Hz), 7.88 (s, 1H),
9.33 (s, 1H). 13C NMR (DMSO-d6, 75 MHz): δ 14.48, 18.29, 54.28, 59.79, 98.69, 110.55, 119.20, 127.81,
133.00, 149.77, 150.47, 152.28, 165.55.
5-Ethoxycarbonyl-6-methyl-4-(2-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (4e): 1H NMR
(DMSO-d6, 300 MHz): δ 0.98 (t, 3H, J= 6.9 Hz), 2.29 (s, 3H), 3.88 (q, 2H, J= 6.8 Hz), 5.62 (s, 1H), 7.18-
7.34 (m, 3H), 7.40 (d, 1H, J= 7.3 Hz), 7.72 (s, 1H), 9.28 (s, 1H).
5-Ethoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one (4f): 1H NMR
(DMSO-d6, 400 MHz): δ 1.09 (t, 3H, J= 7.0 Hz), 2.26 (s, 3H), 3.99 (q, 2H, J= 7.0 Hz), 5.30 (d, 1H, J= 3.5
Hz), 7.64-7.69 (m, 2H), 7.91 (d, 1H), 8.08 (s, 1H), 8.13 (d, 1H, J= 7.8 Hz), 9.38 (s, 1H).
5-Ethoxycarbonyl-6-methyl-4-(4-methylphenyl)-3,4-dihydropyrimidin-2(1H)-one (4g): 1H NMR
(DMSO-d6, 400 MHz): δ 1.10 (t, 3H, J= 7.0 Hz), 2.25 (s, 3H), 3.97 (q, 2H, J= 7.0 Hz), 5.10 (d, 1H, J= 3.1
Hz), 7.10 (d, 4H, J= 3.2 Hz), 7.69 (s, 1H), 9.16 (s, 1H).
1
5-Ethoxycarbonyl-6-methyl-4-(2-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4h): H NMR
(DMSO-d6, 400 MHz): δ 1.02 (t, 3H, J= 7.0 Hz), 2.26 (s, 3H), 3.78 (s, 3H), 3.90 (q, 2H, J= 7.0 Hz), 5.48
(s, 1H), 6.80-7.05 (m, 3H), 7.22 (d, 1H, J= 7.8 Hz), 7.27 (s, 1H), 9.11 (s, 1H).
5-Ethoxycarbonyl-6-methyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4i):19 1H NMR
(DMSO-d6, 300 MHz): δ 1.16 (t, 3H, J= 7.2 Hz), 2.24(s, 3H), 3.76 (s, 3H), 3.98 (q, 2H, J= 7.2 Hz), 5.10
(d, 1H, J= 3.2 Hz), 6.79 (d, 2H, J= 8.7 Hz), 7.17 (d, 2H, J= 8.7 Hz), 7.25 (s, 1H), 8.94 (s, 1H).
5-Ethoxycarbonyl-6-methyl-4-(furyl)-3,4-dihydropyrimidin-2(1H)-one (4j):17 1H NMR (DMSO-d6,
300 MHz): δ 1.13 (t, 3H, J= 7.0 Hz), 2.22 (s, 3H), 4.02 (q, 2H, J= 6.9 Hz), 5.20 (d, 1H, J= 2.5 Hz), 6.09
(d, 1H, J= 2.3 Hz), 6.35 (s, 1H), 7.55 (s, 1H), 7.79 (s, 1H), 9.30 (s, 1H).
5-Ethoxycarbonyl-6-methyl-4-(thionyl)-3,4-dihydropyrimidin-2(1H)-one (4k):
1
IR (KBr): 3228, 3116, 1700, 1640 cm-1. H NMR (DMSO-d6, 300 MHz): δ 1.15 (t, 3H, J= 7.0 Hz), 2.21
(s, 3H), 4.05 (q, 2H, J= 7.0 Hz), 5.40 (s, 1H), 6.88-6.93 (m, 2H), 7.34 (d, 1H, J= 4.5 Hz), 7.90 (s, 1H),
9.30 (s, 1H). 13C NMR (DMSO-d6, 75 MHz): δ 14.59, 18.12, 49.79, 59.84, 100.26, 123.98, 125.09,

HETEROCYCLES, Vol. 71, No. 2, 2007
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127.14, 149.09, 149.20, 152.71, 165.49.
1
5-Acetyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (4l): H NMR (DMSO-d6, 300 MHz): δ
2.10 (s, 3H), 2.28 (s, 3H), 5.25 (s, 1H), 7.17-7.27 (m, 3H), 7.31 (d, 2H, J= 6.5 Hz), 7.83 (s, 1H), 9.19 (s,
1H).
5-Acetyl-6-methyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4m): 1H NMR (DMSO-d6,
400 MHz): δ 2.01 (s, 3H), 2.30 (s, 3H), 3.82 (s, 3H), 5.21 (d, 1H, J= 3.2 Hz), 6.88 (d, 2H, J= 7.5 Hz), 7.04
(d, 2H, J= 7.5 Hz), 7.42 (s, 1H), 9.11 (s, 1H).
1
5-Acetyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one (4n): H NMR (DMSO-d6, 300
MHz): δ 2.11 (s, 3H), 2.29 (s, 3H), 5.32 (s, 1H), 7.51 (d, 2H, J= 8.2 Hz), 7.79 (s, 1H), 8.20 (d, 2H, J= 8.2
Hz), 9.27 (s, 1H).
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