Green Protocol for the Biginelli Three-Component Reaction: Ag 3PW12O40 as a Novel, Water-Tolerant Heteropolyacid for the Synthesis of 3,4-Dihydropyrimidinones

Article abstract of DOI:10.1002/ejoc.200300559

Biginelli three-component condensation of an aldehyde, β-keto ester, and urea proceeds smoothly on the surface of the silver salt of heteropolyacid (HPA), i.e. Ag₃PW₁₂O₄₀, in water to afford the corresponding 3,4-dihydropy

Full text of DOI:10.1002/ejoc.200300559

FULL PAPER
Green Protocol for the Biginelli Three-Component Reaction: Ag PW O as a
3
12 40
Novel, Water-Tolerant Heteropolyacid for the Synthesis of
3
,4-Dihydropyrimidinones
[
a]
[a]
[a]
[a]
Jhillu S. Yadav,* Basi V. Subba Reddy, Pamu Sridhar, Joolakanti S. S. Reddy,
[a]
[b]
[b]
Kommu Nagaiah, Nakka Lingaiah, and Potharaja S. Saiprasad
Keywords: Heteropolyacid / Multicomponent reactions / Polyoxometalates / Water media
Biginelli three-component condensation of an aldehyde, β-
keto ester, and urea proceeds smoothly on the surface of the
silver salt of heteropolyacid (HPA), i.e. Ag PW12O40, in water
3
to afford the corresponding 3,4-dihydropyrimidinones in
high-to-quantitative yields under mild conditions. The het-
erogeneous solid acid provides ease of separation of the cata-
lyst and isolation of the products. The recovered catalyst can
Compared to the classical Biginelli reaction conditions, this
new method has the advantages of improved yields, reus-
ability of the catalyst, an eco-friendly solvent, ease of isola-
tion of products, and simplicity in the experimental proced-
ure.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
be recycled in subsequent reactions with consistent activity. Germany, 2004)
Introduction
the Biginelli reaction has received renewed interest from re-
Aryl-3,4-dihydropyrimidinones have recently received
great attention because of their wide range of therapeutic
and pharmacological properties, such as antiviral, anti-
tumor, antibacterial, and antiinflammatory behaviour.
Furthermore, these compounds have emerged as the inte-
gral backbones of several calcium channel blockers, antihy-
searchers interested in discovering milder and more-efficient
procedures that are applicable to a wide range of substitu-
ents in all three components and proceed in better yields.
As a result, several improved procedures have been reported
[
1]
recently using Lewis acids, as well as protic acids, as pro-
[7,8]
moters.
Asymmetric versions of the Biginelli reaction
pertensives, α -adrenergic antagonists, and neuropeptide Y
1
a
have also been reported using Garner aldehyde or a sugar-
[
2]
(NPY) antagonists. Moreover, several alkaloids contain-
derived aldehyde, β-keto ester and urea to produce optically
ing the dihydropyrimidine core structure have been isolated
from marine sources and also exhibit interesting biological
properties. Most notably among these are the batzelladine
[9]
active 3,4-dihydropyrimidinones. Recently, environmen-
tally benign approaches have been developed using solvent-
[10]
free conditions.
Much attention, however, has been fo-
alkaloids, which are found to be potent HIV gp-120-CD
4
cussed on the use of water as a green solvent in organic
synthesis. In addition to its abundance, economy and safety,
water has become a natural substitute and an alternative
[
3]
inhibitors. Thus, the synthesis of this heterocyclic nucleus
is of much current importance. The simplest and the most
straightforward procedure, originally reported by Bigi-
[11]
environmentally benign solvent in organic synthesis. The
[
4]
nelli, involves the three-component, one-pot condensation
of an aldehyde, β-keto ester, and urea under strongly acidic
conditions. This so-called Biginelli reaction often suffers,
however, from low yields of products, particularly in case
use of an aqueous medium as solvent also reduces the
harmful effects of organic solvents on the environment.
These advantages become even more attractive if such reac-
tions can be performed using reusable catalysts.
[
5]
of substituted aromatic and aliphatic aldehydes. This
problem has led to the development of multi-step synthetic
strategies that produce relatively higher yields, but lack the
Heterogeneous solid acids are advantageous over conven-
tional homogeneous acid catalysts as they can be easily re-
covered from the reaction mixture by simple filtration and
can be reused after activation or without activation, thereby
[
6]
simplicity of the original one-pot-Biginelli protocol. Thus,
[
12]
making the process economically viable.
In many cases,
[
a]
Division of Organic Chemistry, Indian Institute of Chemical
Technology,
heterogeneous catalysts can be recovered with only minor
changes in activity and selectivity so that they can be used
conveniently in continuous-flow reactions. Among various
heterogeneous catalysts, heteropolyacids are most attractive
because of their reusability, flexibility in modifying the acid
Hyderabad 500 007, India
Fax: (internat.) ϩ 91-40-27160512
E-mail: yadav@iict.ap.nic.in
Catalysis Division, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
[
b]
552
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300559
Eur. J. Org. Chem. 2004, 552Ϫ557

Synthesis of 3,4-Dihydropyrimidinones
FULL PAPER
Scheme 1
strength, ease of handling, environmental compatibility, action[4] can be increased from 20Ϫ60% to 82Ϫ96% while
non-toxicity and experimental simplicity.[
13]
the reaction times are shortened from 18 h to 3.0Ϫ4.5 h. To
optimize the conditions, we carried out the reactions using
different quantities of reactants. The best results were ob-
tained using a 0.1:1.0:1.0:2.0 ratio of Ag PW O , alde-
Results and Discussion
3
12 40
hyde, 1,3-dicarbonyl compound, and urea or thiourea. In
the absence of the heteropolyacid, the products were ob-
tained in low yields (20Ϫ30%) after long reaction times
In this report, we disclose an efficient and high-yielding
protocol for the synthesis of 3,4-dihydropyrimidinones in-
volving the three-component, one-pot condensation of an
aldehyde, β-dicarbonyl compounds and urea using hetero-
polyacids as novel and environmentally benign, hetero-
geneous, solid acid catalysts. Thus, treatment of benzal-
dehyde, ethyl acetoacetate and urea in the presence of the
silver salt of 12-tungustophosphoric acid[14] in water at 80
(
8Ϫ12 h) when the reactions were carried out in water at 80
C. The efficacy of other solid acids, such as KSF clay, acid
resin (Amberlyst-15) and acid-washed silica gel (H SO -
°
2
4
SiO ), were also studied for this reaction. Among these
2
catalysts, the silver() salt of heteropolyacid was found to be
superior in terms of conversion and reaction time. Compar-
able yields and reaction rates were also obtained when using
°
C resulted in the formation of 4-phenyl-3,4-dihydropyrimi-
dinone in 92% yield (Scheme 1).
30-wt% of silver heteropolyacid supported on silica. For ex-
In a similar fashion, a variety of aromatic, aliphatic, and
heterocyclic aldehydes underwent three-component conden-
sation smoothly to afford a wide range of substituted di-
hydropyrimidinones. Many of the pharmacologically rel-
evant substitution patterns on the aromatic ring could be
introduced with high efficiency by using this procedure
ample, treatment of a mixture of benzaldehyde and ethyl
acetoacetate with urea in the presence of 30-wt%
Ag PW O /SiO resulted in the formation of 4-phenyl-
3
12 40
2
3,4-dihydropyrimidinone in 93% yield after stirring in water
at 80 °C for 2.5 h. Thus, this procedure provides easy access
to the preparation of substituted pyrimidinones having a
wide range of substitution patterns on all three compo-
nents. The results obtained in the recycling experiments of
benzaldehyde, ethyl acetoacetate, and urea are presented in
Table 2.
The scope and generality of this process is illustrated with
respect to the various 1,3-diketones and aldehydes that are
tolerated; the results are presented in Table 1. Finally, the
catalyst was recovered by simple filtration and reused in
subsequent reactions with consistent activity.
(Table 1). Most importantly, aromatic aldehydes carrying
either electron-donating or -withdrawing substituents re-
acted well under the reaction conditions to give the corre-
sponding dihydropyrimidinones in high-to-quantitative
yields with high purity. Acid-sensitive furfural also worked
well without the formation of any side products (entry j,
Table 1). Another important feature of this method is sur-
vival of a variety of functional groups, such as olefin, nitro,
halide, ether, and ester groups, under the reaction con-
ditions. This method is even effective with aliphatic and α,β-
unsaturated aldehydes, which normally show extremely low
conversions in the Biginelli reaction (entries h and t,
Table 1). Unlike most of the reported methods, this pro-
cedure does not require any additives or activators or anhy-
drous conditions. Some other methods require the use of
Conclusion
In summary, we have found that heteropolyacids are ex-
toxic reagents in combination with Bronsted acids, such as tremely useful and highly efficient heterogeneous solid acids
hydrochloric acid and acetic acid, as additives.[ This pro- for the synthesis of biologically potent aryl 3,4-dihydropyri-
cedure not only preserves the simplicity of the Biginelli re- midinones by means of three-component condensations of
action, but also produces excellent yield of the products an aldehyde, 1,3-dicarbonyl compound, and urea or thio-
with high purity. Thiourea has been used with similar suc- urea in a one-pot operation. This method is applicable to a
cess to produce the corresponding thio derivatives of di- wide range of substrates, including aromatic, aliphatic, α,β-
hydropyrimidinones, which are also of much interest with unsaturated, and heterocyclic aldehydes, and provides a var-
respect to their biological activities (entries n, o, and p, iety of biologically relevant dihydropyrimidinones in high-
7e]
[
1]
Table 1). Decreased reaction times and improved yields to-quantitative yields after short reaction times. The combi-
are realised as a result of the increased reactivity of the nation of the water-tolerant heteropolyacid as a recyclable
substrates on the surface of heteropolyacid. By using heter- catalyst and water as a green solvent makes this method
opolyacid as catalyst, the yields of the one-pot Biginelli re- convenient, economic and environmentally friendly.
Eur. J. Org. Chem. 2004, 552Ϫ557
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
553

J. S. Yadav et al.
FULL PAPER
3
Table 1. Ag PW12O40-catalyzed synthesis of Biginelli 3,4-dihydropyrimidinones
554
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 552Ϫ557

Synthesis of 3,4-Dihydropyrimidinones
FULL PAPER
3
230, 3109, 2977, 1701, 1641, 1591, 1520 cmϪ1
(200 MHz, CDCl /[D ]DMSO): δ ϭ 9.10 (br. s, 1 H, NH), 8.20 (d,
J ϭ 8.5 Hz, 2 H, Ar), 7.60 (d, J ϭ 8.5 Hz, 2 H, Ar), 5.24 (br. s, 1
H, NH), 5.20 (s, 1 H, -CH-), 4.05 (q, J ϭ 7.0 Hz, 2 H, -OCH -),
) ppm.
]DMSO): δ ϭ 164.9, 151.7, 149.3, 146.6,
.
1H NMR
Table 2. Recycling experiments of benzaldehyde, ethyl acetoacetate,
and urea
3
6
2
Recycle
no.
Solvent
Reaction
temp. [°C]
Reaction
Time [h]
Yield
[%]
2
.27 (s, 3 H, -CH
3
), 1.09 (t, J ϭ 7.0 Hz, 3 H, -OCH
C NMR (50 MHz, [D
27.5, 123.7, 59.3, 53.6, 17.8, 13.9 ppm. EIMS: m/z (%) ϭ 276 [M ]
2 3
CH
1
3
6
ϩ
1
1
2
3
4
5
1
2
3
4
EtOH
EtOH
EtOH
EtOH
EtOH
water
water
water
water
80
80
80
80
80
80
80
80
80
3.0
3.0
3.0
3.0
3.0
4.0
4.0
4.0
4.0
95
93
95
94
93
92
92
91
90
(
75), 183 (100), 169 (30), 155 (40), 137 (18).
Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-oxo-3,4-dihydropyrimidine-
-carboxylate (2d): Colorless crystals, m.p. 203Ϫ205 °C. IR (KBr):
5
Ϫ1
ν
˜
ϭ 3225, 3098, 2928, 2835, 1710, 1651, 1613, 1583, 1513 cm .
1
H NMR (200 MHz, CDCl
NH), 7.22 (d, J ϭ 8.7 Hz, 2 H, Ar), 6.80 (d, J ϭ 8.7 Hz, 2 H, Ar),
.60 (br. s, 1 H, NH), 5.30 (s, 1 H, -CH-), 4.01 (q, J ϭ 7.1 Hz, 2
H, -OCH -), 3.80 (s, 3H, -OCH ), 2.36 (s, 3 H, CH ), 1.20 (t, J ϭ
.1 Hz, 3 H, -OCH CH
) ppm. 13C NMR (50 MHz, CDCl
]DMSO): δ ϭ 165.3, 158.0, 152.0, 147.5, 136.9, 127.3, 113.6,
3 6
/[D ]DMSO): δ ϭ 8.40 (br. s, 1 H,
5
2
3
3
7
2
3
3
/
[D
6
Experimental Section
ϩ
9
2
9.9, 59.0, 53.2, 17.0, 14.0 ppm. EIMS: m/z (%) ϭ 261 [M ] (100),
17 (70), 183 (52), 155 (50), 137 (25).
General Remarks: Melting points are uncorrected. IR spectra were
1
recorded on a refractive spectrophotometer using KBr optics. H
Ethyl 4-(4-Flurophenyl)-6-methyl-2-oxo-4-3,4-dihydropyrimidine-5-
carboxylate (2e): Colorless crystals, m.p. 175Ϫ177 °C. IR (KBr):
and 13C NMR spectra were recorded in CDCl
3 6
/[D ]DMSO using
TMS as the internal standard. Mass spectra were recorded using a
mass spectrometer operating at 70 eV. TLC was conducted on 0.25-
mm pre-coated silica gel plates (60F-254). The catalyst was pre-
pared according to the procedure reported in literature.[
Ϫ1
1
ν˜ ϭ 3243, 1698, 1638 cm
]DMSO): δ ϭ 9.0 (br. s, 1 H, NH), 7.80 (br. s, 1 H, NH), 7.20
m, 2 H, Ar), 6.98 (m, 2 H, Ar), 5.21 (s, 1 H, -CH-), 4.05 (q, J ϭ
.
3
H NMR (200 MHz, CDCl /
[D
6
(
14]
7
.1 Hz, 2 H, -OCH
CH
) ppm. 13C NMR (50 MHz, CDCl
δ ϭ 165.3, 162.9, 159.8, 152.0, 148.6, 141.1, 128.3, 115.1, 99.2, 59.3,
2
-), 2.25 (s, 3 H, -CH
3
), 1.15 (t, J ϭ 7.1 Hz, 3
H, -OCH
2
3
3
/[D ]DMSO):
6
General Procedure: A mixture of aldehyde (5 mmol), ethyl ace-
toacetate (5 mmol), urea (10 mmol), and Ag PW12O40 (10% w/w of
3
ϩ
5
3.3, 17.8, 14.1 ppm. EIMS: m/z (%) ϭ 278 [M ] (12), 249 (100).
aldehyde) in water or ethanol (10 mL) was stirred at 80 °C for the
appropriate time (Table 1). On completion of the reaction, as indi-
cated by TLC, the reaction mixture was lyophilized to remove the
water. The resulting product was separated from the catalyst by
washing with methanol. The product thus obtained was recrys-
tallized from methanol to yield pure dihydropyrimidinone. The re-
covered catalyst was dried in an oven at 120 °C for 3Ϫ5 h and
reused in subsequent reactions. The products obtained were ident-
ified by comparison of their NMR, IR, and mass spectra and
physical data, and analysis by TLC and mixed TLC, with authentic
samples. The spectroscopic data of all the products were identical
with those of authentic samples.[
Ethyl 4-(4-Hydroxyphenyl)-6-methyl-2-oxo-3,4-dihydropyrimidine-5-
carboxylate (2f): Colorless solid, m.p. 198Ϫ200 °C. IR (KBr): ν˜ ϭ
Ϫ1
1
3
[D
6
520, 3230, 3150, 1705, 1690 cm . H NMR (200 MHz, CDCl
]DMSO): δ ϭ 8.80 (br. s, 1 H, NH), 7.09 (d, J ϭ 8.5 Hz, 2 H,
Ar), 7.0Ϫ7.05 (br. s, 1 H, NH), 6.60 (d, J ϭ 8.5 Hz, 2 H, Ar), 5.09
br. s, 1 H, NH), 3.90 (q, J ϭ 7.0 Hz, 2 H, -OCH -), 2.20 (s, 3 H, -
CH ), 2.50 (br. s, 1 H, OH), 1.18 (t, J ϭ 7.0 Hz, 3 H, -OCH CH
ppm. EIMS: m/z (%) ϭ 276 [M ] (10), 248 (100), 231 (28), 204
80), 168 (87), 136 (48).
3
/
(
2
3
2
3
)
ϩ
(
7,8,15]
Ethyl 6-Methyl-2-oxo-4-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrim-
idine-5-carboxylate (2g): Colorless crystals, m.p. 217Ϫ219 °C. IR
Ethyl 6-Methyl-2-oxo-4-phenyl-3,4-dihydropyrimidine-5-carboxylate
Ϫ1
1
(
KBr): ν˜ ϭ 3300, 1735, 1705 cm . H NMR (200 MHz, CDCl
3
/
(
2a): Colorless crystals, m.p. 201Ϫ203 °C. IR (KBr): ν˜ ϭ 3520,
6
[D ]DMSO): δ ϭ 8.85 (br. s, 1 H, NH), 7.25 (s, 2 H, Ar), 5.21 (br.
Ϫ1
1
3
230, 3150, 1705, 1690 cm
]DMSO): δ ϭ 8.05 (br. s, 1 H, NH), 7.22Ϫ7.30 (m, 5 H, Ar),
.50 (br. s, 1 H, NH), 5.35 (s, 1 H, -CH-), 4.03 (q, J ϭ 7.1 Hz, 2
-) 2.36 (s, 3 H, CH ), 1.09 (t, J ϭ 7.1 Hz, 3 H, CH
ppm. 13C NMR (50 MHz, [D
]DMSO): δ ϭ 163.5, 150.4, 143.3,
26.4, 125.5, 124.5, 97.6, 57.3, 52.2, 16.0, 12.2 ppm. EIMS: m/z
.
3
H NMR (200 MHz, CDCl /
s, 1 H, NH), 5.19 (s, 1 H, -CH-), 4.10 (q, J ϭ 7.0 Hz, 2 H, -OCH
, 3.75 (s, 6 H, -OCH ), 3.70 (s, 3 H, -OCH ), 2.10 (s, 3 H, -CH
.09 (t, J ϭ 7.0 Hz, 3 H, -OCH
CDCl /[D ]DMSO): δ ϭ 165.6, 153.7, 153.2, 146.2, 139.3, 103.5,
01.1, 60.6, 59.9, 56.0, 55.6, 18.4, 14.1 ppm. EIMS: m/z (%) ϭ 350
2
-
[
D
6
5
)
1
3
3
3
),
2 3
CH ) ppm. C NMR (50 MHz,
1
3
H, -OCH
2
3
3
)
3
6
6
1
1
ϩ
(
68) [M ], 335 (9), 321 (50), 304 (23), 277 (41), 261 (22), 238 (69),
22 (22), 195 (100), 183 (72), 168 (23), 155 (45), 137 (75), 125 (52),
ϩ
(%) ϭ 261 [M ] (100), 243 (52), 213 (15), 217 (15), 148 (32).
2
Ethyl 4-(4-Cholorophenyl)-6-methyl-2-oxo-3,4-dihydropyrimidine-5- 110 (40), 77 (32), 66 (41).
carboxylate (2b): Colorless crystals, m.p. 213Ϫ215 °C. IR (KBr):
Ϫ1
1
Ethyl
6-Methyl-2-oxo-4-(4-styryl)-3,4-dihydropyrimidine-5-car-
ν˜ ϭ 3233, 3093, 2976, 2933, 1701, 1643 cm . H NMR (200 MHz,
CDCl /[D ]DMSO): δ ϭ 8.01 (br. s, 1 H, NH), 7.25 (m, 4 H, Ar),
.60 (br. s, 1 H, NH), 5.35 (s, 1 H, -CH-), 4.10 (q, J ϭ 7.1 Hz, 2
boxylate (2h): Colorless crystals, m.p. 232Ϫ235 °C. IR (KBr): ν˜ ϭ
3
6
Ϫ1
1
3 6
3241, 1704, 1650 cm . H NMR (200 MHz, CDCl /[D ]DMSO):
5
δ ϭ 8.90 (br. s, 1 H, NH), 7.85 (br. s, 1 H, NH), 7.27 (m, 5 H, Ar),
6.45 (d, J ϭ 14.4 Hz, 1 H, -CHϭCH-Ph), 6.15 (dd, J ϭ 14.5,
2 3
H, -OCH -), 2.35 (s, 3 H,-CH ), 1.19 (t, J ϭ 7.1 Hz, 3 H, -
) ppm. 13C NMR (50 MHz, CDCl
OCH
2
CH
3
/[D ]DMSO): δ ϭ
3 6
4
.1 Hz, 1 H, -CHϭCH), 5.30 (d, J ϭ 4.1 Hz, 1 H, -CH-), 4.10 (q,
J ϭ 7.0 Hz, 2 H, -OCH -), 2.23 (s, 3 H, -CH ), 1.13 (t, J ϭ 7.0 Hz,
) ppm. C NMR (50 MHz, CDCl /[D ]DMSO): δ ϭ
65.1, 152.6, 148.5, 136.2, 130.0, 128.6, 128.1, 127.5, 126.2, 97.8,
1
51.8, 143.7, 128.2, 128.1, 98.7, 59.1, 53.3, 17.7, 13.9 ppm. EIMS:
m/z (%) ϭ 265 [M ] (60), 221 (35), 183 (100), 155 (42), 137 (35),
36 (48).
ϩ
2
3
1
3
3
1
H, -CH
3
3
6
1
ϩ
Ethyl
6-Methyl-4-(4-nitrophenyl)-2-oxo-3,4-dihydropyrimidine-5-
59.2, 51.8, 17.7, 14.2 ppm. EIMS: m/z (%) ϭ 286 [M ] (17), 259
carboxylate (2c): Colorless solid, m.p. 208Ϫ211 °C. IR (KBr): ν˜ ϭ (100).
Eur. J. Org. Chem. 2004, 552Ϫ557
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
555

J. S. Yadav et al.
FULL PAPER
Ethyl 6-Methyl-4-(2-naphthyl)-2-oxo-3,4-dihydropyrimidine-5-car-
boxylate (2i): Solid, m.p. 247Ϫ248 °C. IR (KBr): ν˜ ϭ 3245, 3118,
), 2.41 (s, 3 H, CH
C NMR (50 MHz, [D ]DMSO): δ ϭ 174.3, 165.0, 145.3, 142.4,
3
), 1.13 (t, J ϭ 7.1 Hz, 3 H, -OCH
2 3
CH ) ppm.
1
3
6
Ϫ1
1
2
(
(
977, 1698, 1647, 1431, 1231, 1088, 790 cm
[D ]DMSO): δ ϭ 9.10 (br. s, NH), 8.30 (d, J ϭ 8.2 Hz, 1 H), 7.85 (%) ϭ 310 [M ] (99), 281 (82), 199 (100).
d, J ϭ 8.2 Hz, 1 H), 7.80 (t, J ϭ 8.2 Hz, 1 H), 7.40Ϫ7.55 (m, 5
.
H NMR 132.3, 128.6, 128.4, 100.4, 59.7, 53.5, 17.2, 14.0 ppm. EIMS: m/z
ϩ
6
5-Acetyl-6-methyl-4-phenyl-2-thioxo-3,4-dihydropyrimidine
(2p):
H), 6.10 (s, 1 H), 3.90 (q, J ϭ 7.0 Hz, 2 H), 2.40 (s, 3 H), 0.90 (t,
ϩ
Colorless crystals, m.p. 220Ϫ222 °C. IR (KBr): ν˜ ϭ 3282, 1615,
J ϭ 7.0 Hz, 3 H) ppm. EIMS: m/z (%) ϭ 310 [M ] (30), 217 (15),
Ϫ1
1
1
575 cm . H NMR (200 MHz, CDCl
3 6
/[D ]DMSO): δ ϭ 8.40 (br.
176 (100), 133 (65), 119 (20), 91 (100), 69 (70).
s, 1 H, NH), 7.35 (m, 5 H, Ar), 6.09 (br. s, 1 H, NH), 4.98 (s, 1
H, -CH-), 2.60 (s, 3 H, -COCH ), 2.38 (s, 3 H, -CH ) ppm.
1
3
Ethyl 4-(2-Furyl)-6-methyl-2-oxo-3,4-dihydropyrimidine-5-car-
C
3
3
boxylate (2j): Colorless solid, m.p. 209Ϫ211 °C. IR (KBr): ν˜ ϭ NMR (50 MHz, CDCl /[D ]DMSO): δ ϭ 195.1, 174.1, 144.9,
3
6
Ϫ1
1
3
(
280, 3126, 2920, 1720, 1650, 1580, 1265, 1130 cm
200 MHz, CDCl /[D ]DMSO): δ ϭ 9.0 (br. s, 1 H, NH), 7.80 (br. (%) ϭ 246 [M ] (10), 233 (15), 168 (30), 141 (20), 94 (100), 76 (80),
s, 1 H, NH), 6.25 (m, 2 H, Ar), 6.10 (s, 1 H, Ar), 5.25 (br. s, 1 H,
.
H NMR
143.2, 129.0, 128.0, 126.9, 110.8, 54.1, 30.8, 18.0 ppm. EIMS: m/z
ϩ
3
6
43 (95).
2
NH), 5.30 (s, 1 H, -CH-), 4.10 (q, J ϭ 7.1 Hz, 2 H, -OCH -), 2.23
) ppm. 13
C
Methyl
4-(2,4-Dichlorophenyl)-6-methyl-2-oxo-3,4-dihydropyrim-
(
s, 3 H, -CH
NMR (50 MHz, CDCl
49.2, 142.1, 110.3, 105.2, 96.8, 59.2, 47.7, 17.7, 14.1 ppm. EIMS:
3
), 1.12 (t, J ϭ 7.1 Hz, 3 H, -OCH
2
CH
3
idine-5-carboxylate (2q): Solid, m.p: 241Ϫ243 °C. IR (KBr): ν˜ ϭ
3
/[D ]DMSO): δ ϭ 165.0, 155.9, 152.4,
6
Ϫ1
1
3
384, 3232, 3105, 2960, 1700, 1640, 1612 cm
(200 MHz, CDCl /[D ]DMSO): δ ϭ 9.10 (br. s, 1 H, NH), 7.30 (s,
H, Ar), 7.15Ϫ7.25 (m, 2 H, Ar), 6.98 (br. s, 1 H, NH), 5.62 (s, 1
H, -CH-), 3.55 (s, 3 H, -COOCH ), 2.33 (s, 3 H, -CH ) ppm. EIMS:
.
H NMR
1
ϩ
ϩ
3
6
m/z (%) ϭ 250 [M ] (80), 221 [M Ϫ C
2 5
H ] (99), 177 (100).
1
Ethyl 6-Methyl-2-oxo-4-(2-thienyl)-3,4-dihydropyrimidine-5-car-
3
3
ϩ
boxylate (2k): Colorless crystals, m.p. 215Ϫ217 °C. IR (KBr): ν˜ ϭ
m/z (%) ϭ 314 [M ] (26), 299 (85), 279 (100), 255 (98), 219 (8), 183
Ϫ1
1
3
165, 1680, 1633 cm . H NMR (200 MHz, CDCl
3
/[D
6
]DMSO): (66), 170 (100), 137 (93), 110 (32), 67 (11), 42 (50).
δ ϭ 9.0 (br. s, 1 H, NH), 7.50 (br. s, 1 H, NH), 7.13 (d, J ϭ 8.1 Hz,
Ethyl
4-Cyclohexyl-6-methyl-2-oxo-3,4-dihydropyrimidine-5-car-
2
7
H, Ar), 6.85Ϫ6.90 (m, 2 H, Ar), 5.55 (s, 1 H, -CH-), 4.15 (q, J ϭ
.1 Hz, 2 H, -OCH -), 2.30 (s, 3 H, -CH ), 1.13 (t, J ϭ 7.1 Hz, -
CH ) ppm. EIMS: m/z (%) ϭ 266 [M ] (84), 237 (100), 193
boxylate (2r): Solid, m.p. 235Ϫ236 °C, IR (KBr): ν˜ ϭ 3236, 3118,
2
3
Ϫ1
1
ϩ
2920, 2850, 1726, 1702, 1647, 1450, 1230, 1095, 789 cm
NMR ([D ]DMSO): δ ϭ 8.45 (br. s, NH), 6.15 (br. s, NH), 4.15
m, 3 H), 2.30 (s, 3 H), 1.75 (m, 4 H), 1.45 (m, 3 H), 1.25 (t, J ϭ
. H
OCH
91).
2
3
6
(
(
ϩ
Ethyl 2-Oxo-4,6-diphenyl-3,4-dihydropyrimidine-5-carboxylate (2l): 6.8 Hz, 3 H), 1.05 (m, 4 H) ppm. EIMS: m/z (%) ϭ 266 [M ] (40),
Colorless crystals, m.p. 157Ϫ159 °C. IR (KBr): ν˜ ϭ 3214, 3086,
183 (35), 137 (100), 155 (70), 40 (55).
Ϫ1
1
2
980, 1699, 1651 cm . H NMR (200 MHz, CDCl
δ ϭ 7.92 (br. s, 1 H, NH), 7.15Ϫ7.30 (m, 10 H, Ar), 5.53 (br. s, 1
H, NH), 5.13 (s, 1 H, -CH-), 4.05 (q, J ϭ 7.1 Hz, 2 H, -OCH -),
3 6
/[D ]DMSO):
Ethyl 6-Methyl-2-oxo-4-(3-phenoxyphenyl)-3,4-dihydropyrimidine-5-
carboxylate (2s): Solid, m.p. 193Ϫ194 °C. IR (KBr): ν˜ ϭ 3243,
2
Ϫ1
1
1
3
3113, 2981, 1712, 1654, 1582, 1487, 1245, 1097, 785 cm
NMR ([D ]DMSO): δ ϭ 8.40 (br. s, NH), 7.45 (m, 3 H), 7.05 (m,
H), 6.85 (m, 1 H), 5.80 (br. s, NH), 5.35 (s, 1 H), 4.10 (q, J ϭ
. H
2
.30 (s, 3 H, CH
NMR (50 MHz, [D
29.5, 128.8, 128.2, 128.1, 128.0, 126.6, 102.4, 60.0, 55.8, 13.6 ppm.
3
), 1.20 (t, J ϭ 7.1 Hz, -OCH
2
CH
3
) ppm.
C
6
6
]DMSO): δ ϭ 165.3, 153.2, 147.1, 143.5, 135.1,
5
1
ϩ
6.8 Hz, 2 H), 2.35 (s, 3 H), 1.15 (t, J ϭ 6.8 Hz, 3 H) ppm. EIMS:
EIMS: m/z (%) ϭ 322 [M ] (45), 294 (20), 278 (50), 249 (35), 185
60), 157 (15), 138 (70), 91 (85), 77 (65), 69 (100).
ϩ
m/z (%) ϭ 352 [M ] (35), 323 (60), 279 (15), 183 (100), 155 (90),
(
137 (45), 91 (70), 69 (30).
5
-Acetyl-4-(4-methoxyphenyl)-6-methyl-2-oxo-3,4-dihydropyrimidine
Ethyl 6-Methyl-2-oxo-4-pentyl-3,4-dihydropyrimidine-5-carboxylate
(
2m): Colorless crystals, m.p. 166Ϫ168 °C. IR (KBr): ν˜ ϭ 3242,
Ϫ1
1
(2t): Solid, m.p. 151Ϫ153 °C. IR (KBr): ν˜ ϭ 3249, 2933, 1730,
1
714, 1624 cm . H NMR (200 MHz, CDCl
3 6
/[D ]DMSO): δ ϭ
Ϫ1
1
1
6
646, 1433, 1331, 1288, 1086, 779 cm . H NMR ([D ]DMSO):
9.03 (br. s, 1 H, NH), 7.45 (br. s, 1 H, NH), 7.18 (d, J ϭ 8.7 Hz, 2
δ ϭ 8.55 (br. s, NH), 6.05 (br. s, NH), 4.25 (m, 1 H), 4.15 (m, 2
H, Ar), 6.85 (d, J ϭ 8.7 Hz, 2 H, Ar), 5.20 (s, 1 H, -CH-), 3.75 (s,
1
3
H), 2.30 (s, 3 H), 1.55 (m, 2 H), 1.25Ϫ1.40 (m, 9 H), 0.95 (t, J ϭ
3
H, -COCH
3
), 2.23 (s, 3 H, -OCH
]DMSO): δ ϭ 194.4, 158.5, 152.1, 147.8, 136.4,
27.7, 113.9, 109.6, 55.1, 53.3, 30.2, 18.8 ppm. EIMS: m/z (%) ϭ
3
), 1.90 (s, 3 H, -CH
3
) ppm.
C
ϩ
6
.8 Hz, 3 H) ppm. EIMS: m/z (%) ϭ 254 [M ] (25), 209 (30), 183
NMR (50 MHz, [D
1
2
6
(
45) 155 (100), 137 (15), 91 (65), 40 (70).
ϩ
60 [M ] (44), 259 (100).
Ethyl
4-(4-Methoxyphenyl)-6-methyl-2-thioxo-3,4-dihydropyrim- Acknowledgments
idine-5-carboxylate (2n): Colorless crystals, m.p. 150Ϫ152 °C. IR
(
B. V. S., P. S., and J. S. S. R. thank CSIR, New Delhi, for awarding
their fellowships.
Ϫ1
1
KBr): ν˜ ϭ 3250, 1651, 1598, 1561 cm
CDCl /[D ]DMSO): δ ϭ 9.90 (br. s, 1 H, NH), 9.21 (br. s, 1 H,
NH), 7.15 (d, J ϭ 8.1 Hz, 2 H, Ar), 6.67 (d, J ϭ 8.1 Hz, 2 H, Ar),
.15 (s, 1 H, -CH-), 4.03 (q, J ϭ 7.1 Hz, 2 H, -OCH -), 2.23 (s, 3
H, -CH ), 1.15 (t, J ϭ 7.1 Hz, 3 H, -OCH CH
) ppm. 13C NMR
50 MHz, CDCl /[D ]DMSO): δ ϭ 173.7, 174.0, 165.2, 158.8,
44.7, 135.8, 127.7, 113.9, 101.1, 59.6, 55.1, 53.5, 17.2, 14.1 ppm.
. H NMR (200 MHz,
3
6
[
[
1]
C. O. Kappe, Tetrahedron 1993, 49, 6937Ϫ6963 and references
5
2
cited therein.
3
2
3
2] [2a]
K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S.
(
1
3
6
Moreland, A. Hedberg, B. C. O’Reilly, J. Med. Chem. 1991,
[2b]
34, 806Ϫ811.
C. O. Kappe, W. M. F. Fabian, Tetrahedron
ϩ
EIMS: m/z (%) ϭ 306 [M ] (82), 277 (80), 32 (100).
[2c]
1
997, 53, 2803Ϫ2816.
K. S. Atwal, G. C. Roonyak, B. C.
O’Reilly, J. Schwartz, J. Org. Chem. 1989, 54, 5898Ϫ5907.
Ethyl 4-(4-Chlorophenyl)-6-methyl-2-thioxo-3,4-dihydropyrimidine-
-carboxylate (2o): Colorless crystals, m.p. 192Ϫ194 °C. IR (KBr):
H NMR (200 MHz, CDCl
]DMSO): δ ϭ 10.0 (br. s, 1 H, NH), 9.30 (br. s, 1 H, NH), 7.15
m, 4 H, Ar), 5.25 (s, 1 H, -CH-), 4.10 (q, J ϭ 7.1 Hz, 2 H, -OCH
[3] [3a]
A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Bean, A. J.
Freyer, C. De Brosse, S. Mai, A. Truneh, D. J. Faulkner, J. Org.
5
ν˜ ϭ 3255, 1657, 1560 cmϪ1
.
1
/
[3b]
3
Chem. 1995, 60, 1182Ϫ1188.
B. B. Snider, J. Chen, A. D.
[D
6
Patil, A. Freyer, Tetrahedron Lett. 1996, 37, 6977Ϫ6980.
P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360Ϫ416.
[4]
(
2
-
556
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 552Ϫ557

Synthesis of 3,4-Dihydropyrimidinones
FULL PAPER
Massi, S. Sabbatini, V. Bertolasi, J. Org. Chem. 2002, 67,
6979Ϫ6994.
[
[
[
5] [5a]
K. Folkers, T. B. Johnson, J. Am. Chem. Soc. 1934, 56,
[
5b]
1
180Ϫ1185.
K. Folkers, H. J. Harwood, T. B. Johnson, J.
[
5c]
[10] [10a]
Am. Chem. Soc. 1932, 54, 3751Ϫ3758.
K Folkers, T. B.
A. Dondoni, A. Massi, Tetrahedron Lett. 2001, 42,
Johnson, J. Am. Chem. Soc. 1933, 55, 3361Ϫ3368. [ P. Wipf,
5d]
7975Ϫ7978.
Res. Dev. 2002, 6, 817Ϫ818.
[10b]
B. C. Ranu, A. Hajra, S. S. Dey, Org. Process
[10c]
A. Cunningham, Tetrahedron Lett. 1995, 36, 7819Ϫ7822.
V. R. Choudhary, V. H. Tillu,
6] [6a]
B. C. O’Reilly, K. S. Atwal, Heterocycles 1987, 26,
V. S. Narkhede, H. B. Borate, R. D. Wakharkar, Catal. Com-
mun. 2003, 4, 449Ϫ453.
[11] [11a]
[
6b]
1
185Ϫ1188.
M. F. Malley, Heterocycles 1987, 26, 1189Ϫ1192.
talev, E. A. Kishko, N. Sivova, A. Y. Kuznetsov, Molecules
998, 3, 100Ϫ106.
K. S. Atwal, B. C. O’Reilly, J. Z. Gougoutas,
[6c]
A. D. Shu-
P. A. Grieco, Organic Synthesis in Water, Blackie Academic
and Professional, London, 1998. [
11b]
C. J. Li, T. H. Chan, Or-
1
ganic Reactions in Aqueous Media, John Wiley & Sons, New
York, 1997, p. 159.
[12] [12a]
7] [7a]
E. H. Hu, D. R. Sidler, U.-H. Dolling, J. Org. Chem. 1998,
[
7b]
6
7
2
3, 3454Ϫ3457.
C. O. Kappe, S. F. Falsone, Synlett 1998,
N. Mizuno, M. Misono, Chem. Rev. 1998, 98, 199Ϫ217.
I. V. Kozhevnikov, Catal. Rev. Sci. Eng. 1995, 37, 311Ϫ352.
[
7c]
[12b]
18Ϫ720.
B. C. Ranu, A. Hajra, U. Jana, J. Org. Chem.
000, 65, 6270Ϫ6272. [ Y. Ma, C. Qian, L. Wang, M. Yang,
7d]
[13] [13a]
T. Okuhara, N. Mizuno, M. Misono, Applied Catal., A
[7e]
[13b]
J. Org. Chem. 2000, 65, 3864Ϫ3868.
2
J. Lu, H. Ma, Synlett
2001, 222, 63Ϫ77.
I. V. Kozhevnikov, Chem. Rev. 1998,
[
7f]
000, 63Ϫ64.
F. Bigi, S. Carloni, B. Frullanti, R. Maggi, G.
98, 171Ϫ198.
[14]
Sartori, Tetrahedron Lett. 1999, 40, 3465Ϫ3468.
J. Haber, K. Pamin, L. Matachowski, B. Napruszewska, J. Pol-
[
[
8] [8a]
Ch. V. Reddy, M. Mahesh, P. V. K. Raju, T. R. Babu, V. V.
N. Reddy, Tetrahedron Lett. 2002, 43, 2657Ϫ2659. [ A. S.
Paraskar, G. K. Dewkar, A. Sudalai, Tetrahedron Lett. 2003,
towicz, J. Catal. 2002, 207, 296Ϫ306.
8b]
[15] [15a]
N.-Y. Fu, Y.-F. Yuan, Z. Cao, S.-W. Wang, J.-T. Wang, C.
Peppe, Tetrahedron 2002, 58, 4801Ϫ4807. [
15b]
J. S. Yadav, B. V.
[
8c]
4
4, 3305Ϫ3308.
A. Shaabani, A. Bazgir, F. Teimouri, Tetra-
S. Reddy, R. Srinivas, Ch. Venugopal, T. Ramalingam, Syn-
thesis 2001, 1341Ϫ1345. [
Singh, Tetrahedron 1999, 55, 12873Ϫ12880.
Received August 30, 2003
15c]
K. Singh, J. Singh, P. K. Deb, H.
hedron Lett. 2003, 44, 857Ϫ859.
9] [9a]
A. Dondoni, A. Massi, E. Minghini, S. Sabbatini, V. Bertol-
asi, J. Org. Chem. 2003, 68, 6172Ϫ6183. [9b] A. Dondoni, A.
Eur. J. Org. Chem. 2004, 552Ϫ557
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
557