Yttria-zirconia-based Lewis acid catalysis of the Biginelli reaction: An efficient one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones

Article abstract of DOI:10.1080/00397910802519174

Yttria-zirconia-based Lewis acid efficiently catalyzes the three-component cyclocondensation reaction of aldehyde, β-keto ester, and urea or thiourea in refluxing acetonitrile to produce the corresponding dihydropyrimidones in high yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802519174

This article was downloaded by: [University of Chicago Library]
On: 22 May 2013, At: 14:12
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Yttria-Zirconia–Based Lewis
Acid Catalysis of the Biginelli
Reaction: An Efficient
One-Pot Synthesis of 3,4-
Dihydropyrimidin-2-(1H)-ones
S. Ramalingam a & Pradeep Kumar a
a Division of Organic Chemistry, National Chemical
Laboratory, Pune, India
Published online: 04 Mar 2009.
To cite this article: S. Ramalingam & Pradeep Kumar (2009): Yttria-Zirconia–Based
Lewis Acid Catalysis of the Biginelli Reaction: An Efficient One-Pot Synthesis of 3,4-
Dihydropyrimidin-2-(1H)-ones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:7, 1299-1309
To link to this article: http://dx.doi.org/10.1080/00397910802519174
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.

The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communications1, 39: 1299–1309, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802519174
Yttria-Zirconia–Based Lewis Acid Catalysis of
the Biginelli Reaction: An Efficient One-Pot
Synthesis of 3,4-Dihydropyrimidin-2-(1H)-ones
S. Ramalingam and Pradeep Kumar
Division of Organic Chemistry, National Chemical Laboratory,
Pune, India
Abstract: Yttria-zirconia–based Lewis acid efficiently catalyzes the three-
component cyclocondensation reaction of aldehyde, b-keto ester, and urea or
thiourea in refluxing acetonitrile to produce the corresponding dihydropyrimi-
dones in high yields.
Keywords: Biginelli reaction, dihydropyrimidone, yttria-zirconia–based Lewis acid
One-pot coupling of three or more compounds, often called multicompo-
nent reaction, has attracted a great deal of attention in recent years for
the synthesis of complex organic molecules.[1] The Biginelli reaction is
constituted by a one-pot, acid-catalyzed cyclocondensation of an
aldehyde, a b-keto ester, and urea, leading to 3,4-dihydropyrimidin-2-
(1H)-one (DHPM) (Scheme 1). DHPM derivatives have attracted consid-
erable interest in recent times because of their promising therapeutic[2a]
and biological activities[2b] such as antiviral, antitumor, antibacterial,
and anti-inflammatory activities. In addition, 4-aryldihydropyrimidones
have emerged as potent calcium channel blockers, antihypertensive
agents, a1a-adrenergic antagonists, and neuropeptide antagonists.[3]
Furthermore, the dihydropyrimidinone-5-carboxylate core unit is found
in many marine natural products including batzelladine alkaloids, which
are potent HIV gp-120-CD4 inhibitors.[4]
Received June 30, 2008.
Address correspondence to Pradeep Kumar, Division of Organic Chemistry,
National Chemical Laboratory, Pune 411008, India. E-mail: pk.tripathi@ncl.res.in
1299

1300
S. Ramalingam and P. Kumar
Scheme 1. Synthesis of dihydropyrimidones (DHPM) by Biginelli cycloconden-
sation reaction using yttria-zirconia–based Lewis acid.
The most simple and straightforward procedure, reported by Biginelli in
1893, involves a one-pot condensation of ethylacetoacetate, benzaldehyde,
and urea under strong acidic conditions.[5] However, low yields in the case
of substituted aromatic and aliphatic aldehydes[3a,5] led to the development
of multistep strategies that produce somewhat higher overall yields but lack
the simplicity of the one-pot, one-step synthesis.[3a,6] Several methods
for the Biginelli DHPM synthesis have been documented in the literature.
These involve the use of protic acids and Lewis acid catalysts such as AcOH
and BF3 ꢀ OEt2.[7a] HCl and FeCl3
and LaCl3 ꢀ 7H2O,[7c] YbOTf,[7d]
[7b]
polyphosphate-ester,[7e] InCl3,[7f] InBr3,[7g] LiClO4,[7h] FeCl3 ꢀ 6H2O,[7i] zirco-
nium(IV) chloride,[7j] Mn(OAc)3 ꢀ 2H2O.[7k] In addition to the zeolites,[8a]
ionic liquids,[8b] microwave irradiation,[8c,8d] ultrasound,[8e] and KSF clay[8f]
have also been employed for Biginelli’s condensation reaction.
Recently, NH4Cl,[9a] N-butyl-N,N-dimethyl-a-phenylethylammo-
niumbromide,[9b] boric acid,[9c] triflates of Bi[9d(i)] and Cu,[9d(ii)] chlorides
of Cd[9e(i)] and Zn[9e(ii)] combination of TMSCl=NaI,[9f] Ag3PW12O10 (as
water-tolerant catalyst),[9g] and polyaniline-bismoclite[9h] have been
reported to catalyze the Biginelli reaction to give DHPMs.
However, in spite of their potential utility, many of these methods
involve expensive reagents, stoichiometric amounts of catalysts, strongly
acidic conditions, longer reaction times, high temperatures, unsatisfactory
yields, and incompatibility with other functional groups. Therefore, the
development of new methods would extend the scope of the useful Biginelli
reaction. Yittria-zirconia-based Lewis acid catalyst was widely used as
solid acid catalyst for varied organic transformations, for example, for
the Diel–Alder reaction,[10a] acylation of alcohols, thiols, and amines[10b]
in our group. Herein, we report an efficient synthesis of 3,4-dihydropyrimi-
din-2-(1H)-ones catalyzed by yttria-zirconia-based Lewis acid catalyst.
In a general experimental procedure, when b-keto ester (1 equiv.),
aldehyde (1 equiv.), and urea (1.3 equiv.) were refluxed together in the
presence of 10 mol% of yttria-zirconia catalyst in 10% aq. acetonitrile
at 60 ꢁC, the mixture underwent cyclocondensation to afford the corre-
sponding dihydropyrimidones in good to excellent yields. A wide range
of structurally varied b-dicarbonyl compound, aldehyde, and urea were
condensed by this procedure to produce the corresponding dihydropyri-
midones. The results are reported in Table 1. Both b-keto ester and

3,4-Dihydropyrimidin-2-(1H)-ones
1301
Table 1. Synthesis of dihydropyrimidones (DHPM)a by Biginelli cyclocondensa-
tion reaction using yttria-zirconia–based Lewis acid
Time Yieldb
Entry
R1
R2
R
X
(h)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
C6H5
O
O
O
O
O
O
O
O
O
O
7
6
6
4
6
10
5
7
5
5
94
95
92
91
81
80
92
80
86
93
70
90
72
80
95
67
4-(CH3)-C6H4
4-(OMe)-C6H4
3-(OMe)-C6H4
2,4-(OMe)2-C6H3
3,4-(OMe)2-C6H3
3,4,5-(OMe)2-C6H2
2-(OMe)-6-(Me)-C6H3
4-(OH)-3-(OMe)-C6H3
2-(OH)-C6H4
2,6-(OH)2-3-(CO2Me)-4-(Me)-C6H O 15
4-(CI)-C6H4
2-(CI)-C6H4
=
C6H4-CH CH (E)
4-[N(Me)2]-C6H4
O
O
O
O
O
6
9
7
8
16
17
18
19
20
21
Me
Me
Me
Me
Me
OMe
O’Bu
C6H5CH2 C6H5
4-(Me)-C6H
C6H5
O
O
O
O
O
5
7
8
5
7
80
94
56
88
86
OEt
OMe
4-(OH)-C6H5
22
23
24
25
Me
O’Bu
OMe
OEt
4-(OH)-3-(OMe)-C6H3
C6H5
C6H5
O
O
S
7
16
4
80
82
96
69
C6H5CH2
Me
C6H5CH2
OMe
S
16
26
27
28
29
30
31
32
33
C6H5
C6H5
Me
Me
Me
Me
Me
Me
OEt
OEt
Me
Me
Me
Me
Me
Me
C6H5
S
S
S
O
O
O
O
O
12
9
15
6
8
10
5
62
72
75
92
67
84
71
71
3,4-(OMe)2C6H4
4-(NO2)-C6H4
4-(OMe)-C6H4
3,4-(OMe)2-C6H3
3,4,5-(OMe)3-C6H2
4-(OH)-3-(OMe)-C6H3
2-(Cl)-C6H4
9
(Continued )

1302
S. Ramalingam and P. Kumar
Table 1. Continued
Time Yieldb
Entry
R1
R2
R
X
(h)
(%)
34
35
36
37
38
Me
Me
Me
Me
Me
Me
Me
OEt
OEt
Me
2,6-(OH)2-3-(CO2Me)-4-(Me)-C6H O 10
56
88
86
75
73
=
C6H5-CH CH (E)
O
O
O
O
6
C6H5CH2
C2H5
(CH3)2CH
10
14
17
aProducts were characterized by spectral data and also by comparison with
authentic samples.
bIsolated yield.
b-diketone participated in this reaction readily. A wide variation in alkyl
groups of b-dicarbonyl compounds was tolerated in this procedure. A
variety of substituted aromatic, aliphatic and heterocyclic aldehydes were
subjected to the condensation reaction efficiently. Aromatic aldehydes
carrying either electron-withdrawing or donating groups afforded high
yields of products. Acid-sensitive aldehydes such as furfural, phenylace-
taldehyde, and cinnamaldehyde worked well without the formation of
any side product, which are normally observed in the presence of either
protic or Lewis acids. In addition to its simplicity and milder reaction
conditions, the method was found to be effective even with aliphatic
and a,b-unsaturated aldehydes, which normally give poor yields in the
presence of either protic or Lewis acids because of their decomposition
or polymerization under acidic conditions. Another important feature
of this procedure is the survival of a variety of functional groups such
as olefins, ethers, esters, nitro, and halides under the reaction conditions.
Thiourea has been used with similar success to provide the corresponding
dihydropyrimidin-2-(1H)-thiones, which are also of great interest with
regard to biological activity.[2] Thus, variations in all three components
have been accommodated very comfortably.
In summary, the present procedure demonstrates an efficient
yttria-zirconia-based Lewis acid catalysis of the cyclocondensation of
1,3-dicarbonyl compound, aldehyde, and urea or thiourea and is a much
improved modification of Biginelli reaction. In addition to its simplicity
and milder reaction conditions, this method has the ability to tolerate a
wide variety of substitutions in all three components, which is lacking
in many of the existing procedures. Thus, this procedure offers easy
access to the substituted dihydropyrimidin-2-(1H)-ones and thiones
with varied substitution patterns in very high yields. Additionally, the
other advantages of this method are simple operation, easy workup,

3,4-Dihydropyrimidin-2-(1H)-ones
1303
and recyclability of the catalyst. We believe our procedure will find
important applications in the synthesis of dihydropyrimidones to cater
the needs of academia as well as pharmaceutical industries.
EXPERIMENTAL
Materials and Equipment
All reactions were run under an air atmosphere. Chromatographic
separations were done using EM SiO2-60 (300–400 mesh) as the
stationary phase. The IR spectra were recorded on a Perkin-Elmer
spectrophotometer 683B or 1605FT-IR and adsorptions are expressed
1
in centimetersꢂ1. H and 13C NMR spectra were recorded on Brucker
AC-200 instruments using tetramethylsilane (TMS) as the internal stan-
dard. Mass spectra were obtained with a Finningen MAT mass spectro-
meter. Elemental analyses were carried out with a Carlo Erba CHNS-O
analyzer. The diffractogram of x-ray powder diffraction pattern
was recorded on a Rigaku diffractometer model D=Max. IIIVC with
N-filtered Cu-Ka radiation. Fourier transform infrared (FTIR) spectrum
of pyridine adsorbed on the yttrium-based catalyst was recorded on a
Nicolet 60 SXB FTIR spectrometer. The temperature programmed
description (TPD) profile (ammonia) of the yttrium-based catalyst was
recorded on a Sorbstar apparatus. Determination of specific surface area
was carried out by BET (Brunner–Emmett–Teller) N2 adsorbtion using
a Omnisorp 100CX apparatus. Solvents were purified and dried by
standard procedures before use according to reported procedure.[11]
Petroleum ether refers to the fraction collected in boiling range 60–80 ꢁC.
The catalyst was prepared and characterized following the literature
procedure.[10a] The catalyst was calcined at 573 K before use.
Synthesis of Catalyst
The catalyst was prepared by mixing aqueous solutions of yttrium nitrate
and zirconyl nitrate in the molar ratio 16:84, to which aqueous ammonia
(28%) was added under vigorous stirring until a pH of 8.5 was achieved
and precipitate was formed. Washing with deionized water, drying at
110 ꢁC for 24 h, treating with sulfuric acid (4M), drying at 120 ꢁC, and
subsequent programmed calcinations at 500 ꢁC for 3 h at a heating
rate of 2 ꢁC minꢂ1 resulted in a highly acidic material. The chemical com-
position of the final catalyst [determined by X-ray fluorescence (XRF)
technique] was found to be 82.6 mol% Zr, 15.6mol% Y, and 1.8 mol% S.

1304
S. Ramalingam and P. Kumar
The physicochemical characterization of the catalyst was carried out by
titration, TPD, scanning electron microscopy (SEM), and N2 adsorption
techniques.
General Procedure
Benzaldehyde (1 equiv), ethyl acetoacetate (1 equiv), and urea (1.3 equiv)
in aqueous CH3CN were refluxed together at 60–65 ꢁC in the presence of
yttria-zirconia (10 mol%) for 7 h (Table 1). After completion of the
reaction as indicated by thin-layer chromatography (TLC), the reaction
mixture was filtered under hot condition for catalyst recovery and
washed with aq. acetonitrile. The filtrate, after cooling to room tempera-
ture, was poured into crushed ice, and the resulting solid was filtered to
give the crude product, which was recrystallized from hot methanol to
afford the pure product in 94% yield.
Spectral Data for Selected Products
Ethyl-6-methyl-2-oxo-4-(2-methyl-6-methoxy)-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (Entry 8, Table 1)
IR (CHCl3, cmꢂ1): nmax 3432, 3257, 1650, 1574, 1439. 1H NMR
(200 MHz, CDCl3): 1.13 (t, 3H, J ¼ 4 Hz), 2.33 (s, 3H), 2.53 (s, 3H),
3.82 (s, 3H), 3.97–4.06 (q, 2H, J ¼ 6 Hz), 5.83 (s, 1H), 6.75–6.85 (m, 3H),
7.15 (t, 1H, J ¼ 2 Hz), 7.86 (s, 1H), 8.80 (s, 1H). 13C NMR (200 MHz,
DMSO-d6): 12.79, 17.03, 18.28, 48.22, 54.29, 57.74, 95.92, 108.47,
121.68, 126.62, 129.19, 136.27, 146.37, 150.06, 157.75, 164.93. Mass
(C16H20N2O4, 304.21): 304, 289, 275, 257, 243, 231, 215, 201, 183, 155.
Ethyl-6-methyl-2-oxo-4-(4-methyl-3-carbomethoxy-2,6-dihydroxy-
phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Entry 11, Table 1)
IR (CHCl3, cmꢂ1): nmax 3483, 3400, 3262, 3018, 1713, 1644, 1582, 1437,
1364. 1H NMR (200 MHz, CDCl3): d 1.33 (t, 3H, J ¼ 6 Hz), 1.90 (s, 3H),
2.48 (s, 3H), 3.04 (s, 1H), 3.95 (s, 3H), 4.27 (q, 2H, J ¼ 6 Hz), 4.99 (s, 1H),
5.52 (s, 1H), 5.60 (s, 1H), 6.24 (s, 1H), 2.22 (s, 1H). 13C NMR (200 MHz,
CDCl3): d 20.5, 29.6, 57.1, 57.9, 60.1, 99.7, 103.4, 113.2, 113.7, 116.1,
116.5, 117.0, 118.5, 145.0, 149.0, 151.4, 152.7, 167.8, 169.9, 170.3. Mass:
365 (Mþ þ 1), 346, 335, 332, 318, 304, 291, 285, 274, 259, 235, 203, 183,
175, 150, 137, 105, 77. Anal. calcd. for C17H20N2O7 (364.35): found:
C, 55.89; H, 5.34; N, 7.85. Required: 56.04; H, 5.53; N, 7.69.

3,4-Dihydropyrimidin-2-(1H)-ones
1305
Ethyl-4-(2-chloroquinolin-3-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (Entry 16, Table 1)
IR (CHCl3, cmꢂ1): nmax 3555, 3385, 3206, 3080, 1699, 1643, 1462, 1377.
1H NMR (200 MHz, CDCl3): d 1.07 (t, 3H, J ¼ 4 Hz), 1.85 (b, 1H), 2.55
(s, 3H), 4.07 (q, 2H, J ¼ 8 Hz), 5.99 (s, 1H), 7.46 (t, 1H), 7.75 (t, 1H,
J ¼ 4 Hz), 7.79 (d, 1H, J ¼ 4 Hz), 7.95 (s, 1H), 8.01 (d, 1H, J ¼ 4 Hz),
8.46 (s, 1H). Mass: 345 (Mþ), 330, 316, 310, 300, 280, 272. Anal. calcd
for C17H16ClN3O3 (345.78): found: C, 58.79; H, 4.56; N, 12.31. Required:
C, 59.05; H, 4.68; N, 12.15.
Methyl-6-methyl-2-oxo-4-furfuryl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (Entry 21, Table 1)
IR (CHCl3, cmꢂ1): nmax 3415, 3413, 2513, 1697, 1644, 1426, 1218.
1H NMR (200 MHz, CDCl3): d 2.09 (s, 3H), 3.62 (s, 3H), 5.27 (s, 1H),
6.05 (s, 1H), 6.25 (s, 1H), 7.34 (s, 1H), 7.55 (s, 1H), 9.15 (s, 1H).
13C NMR (200 MHz, CDCl3): d 16.5, 29.1, 49.2, 95.9, 103.7, 108.7,
140.1, 147.9, 151.4, 154.5, 164.2. Mass: 236 (Mþ), 219, 208, 193, 182,
177. Anal. calcd. for C11H12N2O4 (236.226): found: C, 55.79; H, 5.09;
N, 8.52. Required: C, 55.88; H, 5.12; N, 8.47.
Methyl-6-benzyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (Entry 23, Table 1)
IR (CHCl3, cmꢂ1): nmax 3523, 3424, 3238, 3088, 3018, 1700, 1643, 1432,
1
1229, 1217. H NMR (200 MHz, CDCl3): d 3.61 (s, 3H), 4.00 (q, 2H,
J ¼ 12 Hz), 5.37 (s, 1H), 6.30 (s, 1H), 7.24 (s, 10 Hz), 7.89 (s, 1H).
13C NMR (200 MHz, CDCl3): d 30.7, 36.5, 51.1, 55.4, 101.8, 126.4,
126.9, 127.8, 128.7, 136.2, 143.6, 148.1, 153.5, 165.8. Mass: 304
(Mþ H2O), 276 (304 CO), 231 (322 PhCH2), 216 (231 CH3), 200, 199,
187, 173. Anal. calcd. for C19H18N2O3 (322.36): found: C, 69.51;
H, 5.99; N, 9.21. Required: C, 69.66; H, 5.84; N, 9.06.
Ethyl-2-thiooxo-6-phenyl-4(3,4-dimethoxyphenyl)-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (Entry 27, Table 1)
IR (CHCl3, cmꢂ1): nmax 3346, 3176, 3053, 2935, 2915, 1901, 1682, 1457.
1H NMR (200 MHz, CDCl3): d 0.83 (t, 3H, J ¼ 6 Hz), 3.81–3.98 (m, 8H),
5.50 (d, 1H, J ¼ 4 Hz), 6.84–7.00 (m, 3H), 7.35–7.44 (m, 5H), 7.71 (s, 1H),
7.88 (s, 1H). Mass: 398 (Mþ), 369, 352, 325, 309, 293, 283, 261, 250, 220,

1306
S. Ramalingam and P. Kumar
208, 165, 151, 129, 105, 91, 77, 65. Anal. calcd. for C21H22N2O4S
(398.48): found: C, 63.43; H, 5.402; N, 6.915. Required: C, 63.30;
H, 5.56; N, 6.91.
5-Acetyl-6-methyl-2-oxo-4-(4-hydroxy-3-methoxyphenyl)-1,2,3,4-
tetrahydropyrimidine (Entry 32, Table 1)
1
IR (CHCl3, cmꢂ1): nmax 3415, 3325, 3295, 1698, 1665, 1455. H NMR
(200 MHz, CDCl3): d 2.02 (s, 3H), 2.25 (s, 3H), 3.73 (s, 3H), 5.15
(s, 1H), 6.58 (d, 1H, J ¼ 8 Hz), 6.67 (d, 1H, J ¼ 8 Hz), 6.83 (s, 1H),
7.666 (s, 1H), 8.85 (b, 1H), 9.07 (b, 1H). 13C NMR (200 MHz, CDCl3):
d 16.8, 28.0, 52.2, 53.9, 107.6, 109.6, 113.6, 116.9, 133.4, 144.3, 145.7,
145.8, 150.3, 192.7. Mass: 276 (Mþ þ 1) 275, 260, 243, 232, 271. Anal.
calcd. for C14H16N2O4 (276.29): found: C, 60.95; H, 5.38; N, 10.01.
Required: C, 60.86; H, 5.47; N, 10.14.
5-Acetyl-6-methyl-2-oxo-4-(4-methyl-2-carbomethoxy-2,6-dihydroxy-
phenyl)-1,2,3,4-tetrahydro-pyrimidine (Entry 34, Table 1)
IR (CHCl3, cmꢂ1): nmax 3248, 1721, 1696, 1625, 1461. 1H NMR
(200 MHz, CDCl3): 1.76 (s, 3H), 2.38 (s, 3H), 2.50 (s, 3H), 3.95 (s, 3H),
4.93 (s, 1H), 5.96 (s, 1H), 6.31 (s, 1H), 7.06 (s, 1H), 8.97 (s, 1H), 12.12
(s, 1H). Mass (C16H18N2O6, 334.34): 334, 316, 301, 291, 285, 274, 259,
243, 216, 204, 182, 175.
5-Acetyl-6-methyl-2-oxo-4-cinnamyl-1,2,3,4-tetrahydropyrimidine
(Entry 35, Table 1)
IR (CHCl3, cmꢂ1): nmax 3276, 3201, 1692, 1642, 1609, 1462, 1378, 1364,
1232. 1H NMR (200 MHz, CDCl3): 2.32 (s, 3H), 2.45 (s, 3H), 5.03 (d, 1H),
7.09–7.52 (m, 5H), 7.81 (s, 1H). Mass (C15H16N2O2, 256.15): 256, 241,
224, 213, 179, 165, 153, 141, 128.
REFERENCES
1. Mizuno, N.; Misono, M. Heterogeneous catalysis. Chem. Rev. 1998, 98,
199–218.
2. (a) Kappe, C. O. One hundred years of the Biginelli dihydropyrimidine
synthesis. Tetrahedron 1993, 49, 6937–6963. (b) Kappe, C. O.; Kumar, D.;
Varma, R. S. Microwave-assisted high speed parallel synthesis of 4-aryl-
3,4-dihydropyrimidin-2-(1H)-ones using a solvent-less Biginelli condensation
protocol. Synthesis 1999, 1799–1803, and the references therein.

3,4-Dihydropyrimidin-2-(1H)-ones
1307
3. (a) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. Substituted
1,4-dihydropyrimidines: Synthesis of selectively functionalized 2-hetero-1,4-
dihydropyrimidines. J. Org. Chem. 1989, 54, 5898–5907; (b) Atwal, K. S.;
Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.; Swanson,
B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. Dihydro-
pyrimidine calcium channel blockers II: 3-Substituted-4-aryl-1,4-dihydro-6-
methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyri-
midines. J. Med. Chem. 1990, 33, 2629–2635; (c) Atwal, K. S.; Swanson, B.
N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C.
Dihydropyrimidine calcium channel blockers 3: 3-Carbamoyl-4-aryl-1,2,3,4-
tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective
antihypertensive agents. J. Med. Chem. 1991, 34, 806–811; (d) Rovnyak, G.
C.; Atwal, K. S.; Hedgberg, A.; Kimball, S. D.; Moreland S.; Gougoutas,
J. Z.; O’ Reilly, B. C.; Schwartz, J.; Malley, M. F. Dihydropyrimidine calcium
channel blockers 4: Basic 3-substituted-4-aryl-1,4-dihydropyrimidine-5-
carboxylic acid esters: Potent antihypertensive agents. J. Med. Chem. 1992,
35, 3254–3263, and the references therein; (e) Rovnyak, G. C.; Kimball,
S. D.; Beyer, B.; Cucinotta, G.; DiMarco, J. D.; Gougoutas, J.; Hedberg,
A.; Malley, M.; McCarthy, J. P.; Moreland, S. Calcium entry blockers and
activators: Conformational and structural determinants of dihydropyrimi-
dine calcium channel modulators. J. Med. Chem. 1995, 38, 119–129; (f)
Kappe, C. O.; Fabian, W. M. F. Conformational analysis of 4-aryl-dihydro-
pyrimidine calcium channel modulators: A comparison of ab initio, semiem-
pirical, and x-ray crystallographic studies. Tetrahedron 1997, 53, 2803–2816.
4. (a) Patil, A. D.; Kumar, N. N.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.;
DeBrosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J. Novel alkaloids from
the sponge Batzella sp.: Inhibitors of HIV gp120-Human CD4 binding. J.
Org. Chem. 1995, 60, 1182–1188; (b) Snider, B. B.; Chen, J.; Patil, A. D.;
Freyer, A. Synthesis of the tricyclic portions of batzelladines A, B, and D:
Revision of the stereochemistry of batzelladines A and D. Tetrahedron Lett.
1996, 37, 6977–6980.
5. Biginelli, P. Acid-catalyzed cyclocondensation reaction of ethyl acetoacetate,
benzaldehyde, urea. Gazz. Chim. Ital. 1893, 23, 360–416.
ꢀ
ꢀ
6. (a) Barluenga, J.; Tomas, M.; Ballesteros, M.; Lopez, L. A. 1,4-Cycloaddition
of 1,3-diazabutadiene with enamines: An efficient route to the pyrimidine ring.
Tetrahedron Lett. 1989, 30, 4573–4576; (b) O’Reilly, B. C.; Atwal, K. S.
Synthesis of substituted 1,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidine
carboxylic acid esters: The Biginelli condensation revisited. Heterocycles
1987, 26, 1185–1188; (c) O’ Reilly, B. C.; Atwal, K. S.; Gougoutas, J. Z.;
Malley, M. F. Synthesis of substituted 1,2,3,4-tetrahydro-6-methyl-2-thioxo-5-
pyrimidine carboxylic acid esters. Heterocycles 1987, 26, 1189–1192.
7. (a) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. Unprecedented catalytic three-
component one-pot condensation reaction: An efficient synthesis of 5-alkoxy-
carbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones. J. Org. Chem. 1998, 63,
3454–3457; (b) Lu, J.; Ma, H. Iron(III)-catalyzed synthesis of dihydropyrimi-
dinones: Improved conditions for the Biginelli reaction. Synlett 2000, 63–64;

1308
S. Ramalingam and P. Kumar
(c) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. One-pot synthesis of
3,4-dihydropyrimidin-2(1H)-ones using lanthanum chloride as a catalyst.
Tetrahedron Lett. 2000, 41, 9075–9078; (d) Ma, Y.; Qian, C.; Wang, L.; Yang,
M. Lanthanide triflate catalyzed Biginelli reaction one-pot synthesis of
dihydropyrimidinones under solvent-less conditions. J. Org. Chem. 2000,
65, 3864–3868; (e) Kappe, C. O.; Falsone, S. F. Polyphosphate ester-mediated
synthesis of dihydropyrimidines: Improved condition for the Biginelli reac-
tion. Synlett 1998, 718–720; (f) Ranu, B. C.; Hajra, A.; Jana, U. Indium(III)
chloride-catalyzed one-pot synthesis of dihydropyrimidinones by a three-
component coupling of 1,3-dicarbonyl compounds, aldehydes, and urea:
An improved procedure for the Biginelli reaction. J. Org. Chem. 2000, 65,
6270–6272; (g) Fu, N.-Y.; Yuan, Y.-F.; Cao, Z.; Wang, S.-W.; Wang, J.-T.;
Peppe, C. Indium(III) bromide-catalyzed preparation of dihydropyrimidine:
Improved protocol conditions for the Biginelli reaction. Tetrahedron 2002,
58, 4801–4807; (h) Yadav, J. S.; Subba Reddy, B. V.; Srinivas, R.; Venugopal,
C.; Ramalingam, T. LiClO4-catalyzed one-pot synthesis of dihydropyrimidi-
nones: An improved protocol for Biginelli reaction. Synthesis 2001, 1341–
1345; (i) Lu, J.; Bai, Y. Catalysis of the Biginelli reaction by ferric and nickel
chloride hexahydrate: One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones.
Synthesis 2002, 466; (j) Reddy, C. V.; Mahesh, M.; Raju, P. V. K.; Babu, R.;
Reddy, V. V. N. Zirconium(IV) chloride catalyzed one-pot synthesis of
3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. 2002, 43, 2657–2659; (k)
Kumar, K. A.; Kasthuraiah, M.; Reddy, C. S.; Reddy, C. D. Mn(OAc)3.
2H2O-mediated, three-component, one-pot condensation reaction: An efficient
synthesis of 4-aryl substituted 3,4-dihydropyrimidin-2-ones. Tetrahedron Lett.
2001, 42, 7873–7875.
8. (a) Rani, V. R.; Srinivas, N.; Kishan, M. R.; Kulkarni, S. J.; Ragavan, K. V.
Zeolite- catalyzed cyclocondensation reaction for the selective synthesis of 3,4-
dihydropyrimidin-2-ones. Green Chem. 2001, 42, 305–306; (b) Peng, J.; Deng,
Y. Ionic liquids catalyzed Biginelli reaction under solvent-free conditions. Tetra-
hedron Lett. 2001, 42, 5917–5919; (c) Yadav, J. S.; Subba Reddy, B. V.; Jagan
Reddy, E.; Ramalingam, T. Microwave-assisted efficient synthesis of dihydro-
pyrimidine: Improved high yielding protocol for the Biginelli reaction. J. Chem.
Res., Synop. 2000, 354–355; (d) Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P.
L. Improved syntheses of some ethyl 4-aryl-6-methyl-1,2,3,4-tetrahydropyrimi-
din-2-one=thione-5-carboxylate by microwave irradiation. Indian J. Chem.
1995, 34B, 151–152; (e) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Raj, K.
S.; Prasad, A. R. Ultrasound-accelerated synthesis of 3,4-dihydropyrimidin-
2(1H)-ones with ceric ammonium nitrate. J. Chem. Soc. Perkin, Trans. 2001,
1, 1939–1941; (f) Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. P.
A revision of the Biginelli reaction under solid acid catalysis: Solvent-free synth-
esis of dihydropyrimidines over montmorillonite KSF. Tetrahedron Lett. 1999,
40, 3465–3468.
9. (a) Shaabani, A.; Bazgir, A.; Teimouri, F. Ammonium chloride-catalyzed
one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free
conditions. Tetrahedran Lett. 2003, 44, 857–859; (b) Rosi Reddy, K.;

3,4-Dihydropyrimidin-2-(1H)-ones
1309
Venkateshwar Reddy, C.; Mahesh, M.; Raju, P. V. K.; Narayana Reddy, V.
V. New environmentally friendly solvent-free synthesis of dihydropyrimidi-
nones catalyzed by N-butyl-N,N-dimethyl-a-phenylethylammonium bromide.
Tetrahedron Lett. 2003, 44, 8173–8175; (c) Tu, S.; Fang, F.; Miao, C.; Jiang,
H.; Feng, Y.; Shi, D.; Wanf, X. One-pot synthesis of 3,4-dihydropyrimidin-
2(1H)-ones using boric acid as catalyst. Tetrahedron Lett. 2003, 44,
6153–6155; (d) (i) Varala, M. R.; Alam, M.; Adapa, S. R. Bismuthtriflates–
catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones: An
improved protocol for the Biginelli reaction. Synlett 2003, 67–70; (ii)
Paraskar, A. S.; Dewkar, G. K.; Sudalai, A. Cu(OTf)2: A reusable catalyst
for high-yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron
Lett. 2003, 44, 3305–3308; (e) (i) Narasaiah, V. A.; Basak, A. K.; Nagaiah,
K. Cadmium chloride: An efficient catalyst for one-pot synthesis of 3,4-dihy-
dropyrimidin-2(1H)-ones. Synthesis 2004, 8, 1253–1256; (ii) Sun, Q.; Wang,
Y.-Q.; Ge, Z-M.; Cheng, T.-M.; Li, R.-T. A highly efficient solvent-free
synthesis of dihydropyrimidinones catalyzed by zinc chloride. Synthesis
2004, 7, 1047–1050; (f) Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav,
J. S. One-pot synthesis of dihydropyrimidinones using iodotrimethylsilane:
Facile and new improved protocol for the Biginelli reaction at room tempera-
ture. Synlett 2003, 858–860; (g) Yadav, J. S.; Reddy, B. V. S.; Sridhar, P.;
Reddy, J. S. S.; Nagaiah, K.; Ligaiah, N.; Saiprasad, P. S. Green protocol
for the Biginelli three-component reaction: Ag3PW12O20 as a novel-tolerant
heteropolyacid for the synthesis of 3,4-dihydropyrimidinones. Eur. J. Org.
Chem. 2004, 552–557. (h) Gangadasu, B.; Palaniappan, S.; Rao, J. V.
One-pot synthesis of dihydropyrimidinones using polyaniline-bismoclite com-
plexes: A facile and reusuable catalyst for the Biginelli reaction. Synlett 2004,
1285–1287.
10. (a) Keshava Raja, A.; Hegde, V. R.; Pandey, B.; Ramaswamy, A. V.; Kumar,
P.; Ravindranathan, T. A yttrium-based strong Lewis acid for the hetero-
geneous catalysis of the Diels–Alder reaction. Angew. Chem., Int. Ed. Engl.
1995, 34, 2143–2145; (b) Kumar, P.; Pandey, R. K.; Bodas, M. S.; Dagade,
S. P.; Dongare, M. K.; Ramaswamy, A. V. Acylation of alcohols, thiols,
and amines with carboxylic acid catalyzed by yttria-zirconia-based Lewis
acid. J. Mol. Catal. A 2002, 181, 207–213.
11. Furniss, B. S.; Hannaford, A. J.; Rogeres, V.; Smith, P. W. G.; Tatchell, A.
R. (Eds.). Vogel’s Textbook of Practical Organic Chemistry. 4th ed.; ELBS=
Longman: London, 1978.