Trifluoroethanol as a metal-free, homogeneous, and recyclable medium for the efficient one-pot synthesis of dihydropyrimidones

Article abstract of DOI:10.1080/00397911.2010.525335

Trifluoroethanol is an efficient and recyclable medium in promoting one-pot, three-component condensation reactions of b-ketoesters, aldehydes, and urea (or thiourea) to afford the corresponding dihydropyrimidones in good yields. This protocol does not re

Full text of DOI:10.1080/00397911.2010.525335

This article was downloaded by: [McGill University Library]
On: 24 September 2012, At: 15:05
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
Trifluoroethanol as a Metal-Free,
Homogeneous, and Recyclable Medium
for the Efficient One-Pot Synthesis of
Dihydropyrimidones
S. V. Rashmi a , N. C. Sandhya a , B. Raghava a , M. N. Kumara a , K.
Mantelingu a & K. S. Rangappa a
a Department of Studies in Chemistry, University of Mysore, Mysore,
India
Accepted author version posted online: 29 Jul 2011.Version of
record first published: 06 Oct 2011.
To cite this article: S. V. Rashmi, N. C. Sandhya, B. Raghava, M. N. Kumara, K. Mantelingu & K. S.
Rangappa (2012): Trifluoroethanol as a Metal-Free, Homogeneous, and Recyclable Medium for the
Efficient One-Pot Synthesis of Dihydropyrimidones, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:3, 424-433
To link to this article: http://dx.doi.org/10.1080/00397911.2010.525335
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, 42: 424–433, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.525335
TRIFLUOROETHANOL AS A METAL-FREE,
HOMOGENEOUS, AND RECYCLABLE MEDIUM
FOR THE EFFICIENT ONE-POT SYNTHESIS
OF DIHYDROPYRIMIDONES
S. V. Rashmi, N. C. Sandhya, B. Raghava, M. N. Kumara,
K. Mantelingu, and K. S. Rangappa
Department of Studies in Chemistry, University of Mysore, Mysore, India
GRAPHICAL ABSTRACT
Abstract Trifluoroethanol is an efficient and recyclable medium in promoting one-pot,
three-component condensation reactions of b-ketoesters, aldehydes, and urea (or thiourea)
to afford the corresponding dihydropyrimidones in good yields. This protocol does not
require the use of an acid or base catalyst.
Keywords Biginelli reaction; cyclization; homogeneous catalysis; multicomponent;
trifluoro ethanol
INTRODUCTION
Multicomponent reactions (MCRs) are of increasing importance in organic and
medicinal chemistry.[1,2] MCR strategies offer significant advantages over conven-
tional linear-type syntheses. In such reactions, three or more reactants come together
in a single reaction vessel to form new products that contain portions of all the
components.[3,4] Aryl substituted 3,4-dihydropyrimidine-2-ones (DHPMs) and their
derivates have been receiving much attention in the recent years owing to their
applications in the field of drugs and pharmaceuticals.[5–7] They occupy an important
place in the realm of natural and synthetic organic chemistry because of their broad
range of biological activities, including antiviral, antitumor, antibacterial, and
anti-inflammatory activities, and use as anti-HIV agents.[8–12] They also attract
Received August 3, 2010.
Address correspondence to K. Mantelingu or K. S. Rangappa, Department of Studies in Chemistry,
University of Mysore, Manasagangothri, Mysore 570006, India. E-mail: rangappaks@gmail.com;
rangappaks@chemistry.uni-mysore.ac.in
424

ONE-POT SYNTHESIS OF DIHYDROPYRIMIDONES
425
considerable interest because of their promising activities as calcium channel blockers
and orally active antihypertensive agents. A very recent important highlight in this
aspect is the identification of the structurally simple DHPM monstrol as a mitotic
kinesis EG5 motor protein inhibitor and as a potential new lead for the development
of anticancer drugs.[12,13] In 1893, Italian chemist Pietro Biginelli first reported the syn-
thesis of DHPMs by multi component cyclocondensation,[14a] which involves a reaction
of a b-keto ester, an aldehyde, and urea or thiourea under strongly acidic conditions.
Under strongly acidic conditions, the yields are very poor (around 20%).[14b–d]
To enhance the efficiency of the Biginelli condensation, various catalysts and
reaction conditions have been studied including classical conditions, microwave-
assisted irradiation, solid support, ionic liquids,[15] and Lewis acid as well as protic acid
promoters such as BF3 ꢀ OEt,[16] InCl3,[17] LaCl3 ꢀ 7H2O,[18,19] FeCl3 ꢀ 6H2O, Mn(OAc)2,
Cu(OTf)2, LiClO4, Cu(NO3)2 ꢀ 3H2O, and H2SO4.[20–24] Homogeneous catalyst sup-
ported on the solid matric has also been used for the synthesis of DHPMs.[25] However,
some of these one-pot procedures generally require strong protic or Lewis acids, pro-
longed reaction time, high temperature, drastic reaction conditions, tedious work up
procedure, and the use of toxic and inflammable solvents while giving poor yields or
several side reactions. These factors caused us to search for better catalysts. The dis-
covery of a milder and more efficient procedure for the synthesis of DHPMs is of prime
importance. There is need to develop new methods using less hazardous solvents.
Herein, we report a novel trifluoroethanol (TFE)- and hexafluoroisopropanol
(HFIP)-catalyzed Biginelli reaction applied to the one-pot, three-component conden-
sation of aldehyde, b-keto ester, and urea or thiourea to synthesize DHPMs, which is
simple and high yielding. To best of our knowledge, there have been no reports for
the synthesis of DHPMs catalyzed by TFE. Treatment of aldehyde (2 mmol), ethyl
aectoacetate (2 mmol), and urea (3 mmol) in TFE at reflux temperature for 4–5 h
afforded the corresponding 3,4-DHPMs. After the reaction was complete, the sol-
vent was evaporated, and the products were isolated with acceptable purity [by liquid
chromatography–mass spectrometry (LCMS) and NMR]. The 98% recovery of the
TFE by fractional distillation below 80 ꢁC was sufficient for its reuse. For example,
the reaction of benzaldehyde, b-ketoester, and urea or thiourea gave corresponding
DHPMs in 95%, 95% and 93%, yields over three cycles. Thus we explored the effec-
tiveness of TFE as reusable solvent and catalyst for generation of DHPMs. The
highlight of this procedure is the tolerance of acid-sensitive aldehydes such as cinna-
maldehyde and furfuralhyde without formation of side products. The crude products
are obtained are highly pure (>95% by LCMS). Another, important feature of this
protocol is survival of a variety of functional groups such as OCH3, OH, NO2, F, Cl,
=
and conjugated C C double bond under the reaction conditions. In general, the pro-
ducts were obtained in good yields with an environmentally friendly process. New
compounds were adequately characterized by physical and spectral data, and data
of known compounds are in good agreement with those reported in the literature.
Spectral data of new compounds are shown.
RESULTS AND DISCUSSION
Fluorinated alcohols possess interesting physiochemical properties, which
include lower boiling points and higher melting points than their nonfluorinated

426
S. V. RASHMI ET AL.
Table 1. TFE-catalyzed synthesis of dihydropyrimidones 4a–y in reflux conditions
Entry
Product
R
X
Yielda (%)
Ref.
1
2
4a
4b
4c
4d
4e
4f
Ph
O
O
O
O
O
O
O
S
95
94
92
94
86
90
87
90
84
94
85
90
92
94
95
25
25
4-(OMe)-C6H4
4-(OH)-C6H4
2-(Cl)-C6H4
4-(Cl)-C6H4
4-(NO2)-C6H4
2-Furfuryl
3
25
25
4
5
25
25
6
7
4g
4h
4i
26
26
8
Ph
9
4-(NO2)-C6H5)
2-(Br)-C6H5
4-(isobutyl)-C6H5
4-(OPr)-C6H4
3-C6H4N
S
26
26
10
11
12
13
14
15
4j
O
O
O
O
O
O
4k
4l
New
New
New
New
25
4m
4n
4o
4-Thiazole
4-(NMe2) C6H4
16
17
4p
4q
O
O
82
90
New
New
1-Bipheynyl
Cinnamyl
18
19
4r
4s
O
O
90
80
New
26
20
4t
90
New
21
22
23.
4u
4v
4x
2-Thienyl
5-Thiazole
n-Propyl
O
O
O
82
86
84
26
New
New
24.
4y
90
New
aYields refer to those of pure isolated products characterized by IR, 1H NMR, LCMS, and elementary
analysis.
counterparts and high polarity, strong hydrogen bond donation properties, and the
ability to solvate water. The electron-withdrawing character of CF3 confers high
acidity to the hydrogen of the hydroxyl group. Besides these properties, fluorinated
alcohols are not nucleophiles or hydrogen bond acceptors. The main advantage of
TFE is operational simplicity; the reaction was carried out in the absence of promot-
ing agents. (These reactions usually require the aid of Lewis acids or catalysts.) This
constitutes an improvement from an environmental point of view, with suffression of
effluents, in particular, heavy metals. In addition to this, TFE was separated easily

ONE-POT SYNTHESIS OF DIHYDROPYRIMIDONES
427
Scheme 1.
from the reaction mixture for subsequent reuse. It is also important to note that the
workup of the reaction mixture is very simple. The Biginelli reactions were strongly
facilitated by the acidic character and strong hydrogen bond donor ability of TFE.
The solvent was recovered once the reaction was completed and reused. The results
are summarized in Table 1.
Table 1 shows the generality of the present protocol, which is equally effec-
tive for urea and thiourea. In most cases, the reactions proceeded smoothly to pro-
duce the corresponding DHPMs in good yields. Aromatic aldehydes containing
either electron-donating or electron-withdrawing substitutes, heterocyclic, and ali-
phatic aldehydes all produced improved yields compared to the classical Biginelli
protocol; surprisingly, even sterically hindered aldehyde gave the corresponding
DHPM 4t.
CONCLUSION
We have developed a simple, convenient, and practical method for the syn-
thesis of DPHMs and their derivatives using substituted aldehydes, b-ketoester,
and urea or thiourea at reflux temperature using TFE a reusable, ecofriendly,
homogeneous solvent and catalyst. This method is applicable to a wide range of
substrates including aromatic, aliphatic, heterocyclic, and a,b-unsaturated alde-
hydes. This method is not only simple but clean with good yield (80–95%) and
greatly decreases environmental pollution because TFE as a reusable solvent and
catalyst (Scheme 1).
EXPERIMENTAL
Prepration of Dihydropyrimidinones: General Procedure for the
Synthesis of 3,4-Dihydropiridinones and -Thiones
A mixture of b-keto ester (2 mmol), corresponding aldehyde (2 mmol), and
urea or thiourea (3 mmol in TFE was stirred rapidly and heated to 80 ꢁC in pre-
heated oil bath for 4–6 h (completion of the reaction was monitored by thin-layer
chromatography, TLC). The TFE was separated by distillation. The solid product
was filtered and passed through a column of silica gel of 60–120 mesh to get the pure
product. All the products were identified by comparing their spectral and physical
data with those of authentic samples.

428
S. V. RASHMI ET AL.
Selected Data
5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one
1
(4a). Mp 202–204 ꢁC, lit.[25] 202–204 ꢁC; H NMR (400 MHz, DMSO-d6): d ¼ 9.20
(s, 1H, NH), 7.74 (s, 1H, NH), 7.25 (s, 5H, C6H5), 5.14 (s, 1H, CH), 3.97 (q,
J ¼ 6.5 Hz, 2H, OCH2CH3), 2.24 (s, 3H, CH3), 1.08 (t, J ¼ 6.5 Hz, 3H, OCH2CH3).
5-Ethoxycarbonyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-
1
2(1H)-one (4b). Mp 202–204 ꢁC, lit.[25] 201–203 ꢁC; H NMR (400 MHz, DMSO-
d6): d ¼ 9.14 (s, 1H, NH), 7.66 (s, 1H, NH), 7.15–6.84 (m, 4H, C6H4), 5.07 (s, 1H,
CH), 3.96 (q, J ¼ 6.8 Hz, 2H, OCH2CH3), 3.70 (s, 3H, OCH3), 2.23 (s, 3H, CH3),
1.09 (t, J ¼ 6.8 Hz, 3H, OCH2CH3).
5-Ethoxycarbonyl-4-(4-hydroxyphenyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one (4c). Mp 230–232 ꢁC, lit.[25] 230–232 ꢁC; 1H NMR (400 MHz,
DMSO-d6): d ¼ 9.34 (s, 1H, OH), 9.10 (s, 1H, NH), 7.64 (s, 1H, NH), 7.03–6.65
(m, 4H, C6H4), 5.02 (s, 1H, CH), 3.96 (q, J ¼ 7.0 Hz, 2H, OCH2CH3), 2.21 (s, 3H,
CH3), 1.08 (t, J ¼ 7.0 Hz, 3H, OCH2CH3).
4-(2-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-
1
2(1H)-one (4d). Mp 222–224 ꢁC; H NMR (400 MHz, DMSO-d6): d ¼ 9.25 (s, 1H,
NH), 7.70 (s, 1H, NH), 7.37–7.29 (m, 4H, C6H4), 5.61 (s, 1H, CH), 3.87 (q,
J ¼ 6.9 Hz, 2H, OCH2CH3), 2.28 (s, 3H, CH3), 0.97 (t, J ¼ 6.9 Hz, 3H, OCH2CH3);
IR (KBr): 3150, 1688, 1626 cmꢂ1, Calcd. for C14H15O3N2Cl: C, 57.03; H, 5.13; N,
9.51. Found: C, 56.89; H, 5.44; N, 9.30.
4-(4-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-
1
2(1H)-one (4e). Mp 212–214 ꢁC, lit,[25] 213–215 ꢁC; H NMR (400 MHz, DMSO-
d6): d ¼ 9.24 (s, 1H, NH), 7.78 (s, 1H, NH), 7.40–7.21 (m, 4H, C6H4), 5.12 (s, 1H,
CH), 3.97 (q, J ¼ 6.9 Hz, 2H, OCH2CH3), 2.24 (s, 3H, CH3), 1.08 (t, J ¼ 6.9 Hz,
3H, OCH2CH3).
5-Ethoxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-one (4f). Mp 207–209 ꢁC, lit.[25] 208–211 ꢁC; 1H NMR (400 MHz,
DMSO-d6): d ¼ 9.35 (s, 1H, NH), 7.89 (s, 1H, NH), 8.23–7.47 (m, 4H, C6H4), 5.26
(s, 1H, CH), 3.97 (q, J ¼ 7.0 Hz, 2H, OCH2CH3), 2.25 (s, 3H, CH3), 1.08
(t, J ¼ 7.0 Hz, 3H, OCH2CH3).
5-Ethoxycarbonyl-4-(2-furfuryl)-6-methyl-3,4-dihydropyrimidin-2(1H)-
one (4g). Mp 208–211 ꢁC; lit.[25] 209–211 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d ¼ 9.24 (s, 1H, NH), 7.75 (s, 1H, NH), 7.54 (s, 1H, CH-Ar.), 6.34 (s, 1H, CH-
Ar), 6.08 (s, 1H, CH-Ar.), 5.19 (s, 1H, CH), 4.01 (q, J ¼ 6.9 Hz, 2H, OCH2CH3),
2.22 (s, 3H, CH3), 1.12 (t, J ¼ 6.9 Hz, 3H, OCH2CH3); IR (KBr): 3320, 3225,
3100, 1695, 1640 cmꢂ1
.
5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-thione
(4h). Mp 151–153 ꢁC; lit.[26] 150–152 ꢁC; 1H NMR (400 MHz, DMSO-d6): d ¼ 10.33
(s, 1H, NH), 9.64 (s, 1H, NH), 7.35–7.19 (m, 5H, C6H5), 5.16 (d, J ¼ 3.5 Hz, 1H,
CH), 4.00 (q, J ¼ 7.0 Hz, 2H, OCH2CH3), 2.28 (s, 3H, CH3), 1.09 (t, J ¼ 7.0 Hz,
3H, OCH2CH3).

ONE-POT SYNTHESIS OF DIHYDROPYRIMIDONES
429
5-Ethoxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-thione (4i). Mp 209–211 ꢁC; lit.[26] 209–211 ꢁC; 1H NMR (400 MHz,
DMSO-d6): d ¼ 10.40 (s, 1H, NH), 9.62 (s, 1H, NH), 8.25–7.45 (m, 4H, C6H4),
5.26 (s, 1H, CH), 4.00 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 2.30 (s, 3H, CH3), 1.12 (t,
J ¼ 7.1 Hz, 3H, OCH2CH3).
Ethyl 4-(2-(bromophenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-
1
5-carboxylate (4j). Mp 210–212 ꢁC; H NMR (400 MHz, DMSO-d6): d ¼ 9.26(s,
1H, NH), 7.68 (d, 1H, NH), 7.55 (d, J ¼ 5.9, 1H, Ar-H), 7.35 (m, 2H, C6H4), 7.17
(m, J ¼ 12.5 Hz, 1H, C6H4), 5.58 (s, 1H, CH), 3.87 (q, J ¼ 6.8 Hz, 2H, OCH2-
CH3), 2.29 (s, 3H, CH3), 0.95 (t, 3H, J ¼ 7.1 Hz, OCH2-CH3); IR (KBr): 3340,
3208, 3106, 2972, 1685, 1633, 1367, 1249 cmꢂ1; MS (ESI þion): m=z ¼ 340, 341.0.
Anal. (%) calcd. for C14H15O3N2Br: C, 49.58; H, 4.46; N, 8.26. Found: C, 49.62;
H, 4.53; N, 8.33.
Ethyl 1,2,3,4-tetrahydro-4-(isobutylphenyl)-6-methyl-2-oxopyrimdidine-
5-carboxylate (4k). Mp 172.8–174.3 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d ¼ 9.12 (s, 1H, NH), 7.64 (d, 1H, NH), 7.11 (d, J ¼ 6.5 Hz, 2H, C6H4), 6.83 (d,
J ¼ 6.2 Hz, 2H, C6H4), 5.06 (s, 1H, CH), 3.93–3.99(q, J ¼ 6.8 Hz, 2H, OCH2-CH3),
3.85–3.88 (t, J ¼ 6.9 Hz, 2H, OCH2-CH3), 1.66–1.71 (q, 2H, CH3), 1.10 (t, 3H,
CH3-CH2), 0.95 (t, 3H, CH3-CH2); IR (KBr): 3237, 3113, 2952, 1698, 1643,
1217 cmꢂ1; MS (ESI þion): m=z 317.2. Anal. (%) calcd. for C18H24O3N2: C, 68.33;
H, 7.65; N, 8.85. Found: C, 68.35; H, 7.68; N, 8.92.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-(propoxyphenyl)pyrimidine-
3-yl)pyrimidine-5-carboxylate (4l). Mp 166–168 ꢁC; 1H NMR (400 MHz,
DMSO-d6): d ¼ 9.12(s, 1H, NH), 7.64 (s, 1H, NH), 7.11 (d, 2H, C6H4), 6.83 (d,
2H, C6H4), 5.06 (s, 1H, CH), 3.93–3.99 (q, J ¼ 6.6 Hz, 2H, OCH2-CH3), 3.85–3.88
(t, J ¼ 6.9 Hz, 2H, OCH2-CH3), 2.23 (s, 3H, CH3), 1.66–1.71 (q, 2H, -CH2-CH2-),
1.10 (t, 3H, OCH3-CH3), 0.95 (t, 3H, CH2-CH3); IR (KBr): 3215, 3113, 2966,
1703, 1644, 1511, 1219, 1089 cmꢂ1; MS (ESI þion): m=z ¼ 319.2. Anal. (%) calcd.
for C17H22N2O4: C, 64.13; H, 6.97; N, 8.80. Found: C, 64.16; H, 6.93; N, 8.89.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-(pyridine-3-yl)pyrimidine-5-
1
carboxylate (4m). Mp 217–218 ꢁC; H NMR (400 MHz, DMSO-d6): d ¼ 9.31(s,
1H, NH), 8.39–8.45 (m, 2H, C6H4), 7.79 (d, 1H, NH, C6H4), 7.60 (d, J ¼ 2.7 Hz,
1H, C6H4), 7.34–7.37 (q, 1H, C6H4), 5.17 (s, 1H, CH), 3.91–4.02(q, J ¼ 6.9 Hz,
2H, OCH2CH3), 2.25 (s, 3H, CH3), 1.06 (t, J ¼ 7.1 Hz, 3H, OCH2-CH3); IR
(KBr): 3339, 3215, 3100, 2972, 1679, 1636, 1222, 1114 cmꢂ1; MS (ESI þion):
m=z ¼ 262.2. Anal. (%) calcd. for C13H15O3N3: C, 59.76; H, 5.79; N, 16.08. Found:
C, 59.81; H, 5.82; N, 16.12.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-(thiazol-4-yl)pyridine-3-yl)
1
pyrimidine-5-carboxylate (4n). Mp 226–228 ꢁC; H NMR (400 MHz, DMSO-
d6): d ¼ 9.15(s, 1H, NH), 8.98 (d, 1H, ArH), 7.65 (s, 1H, NH), 7.32 (d, 1H, ArH),
5.31 (s, 1H, CH), 3.96–4.03 (q, 2H, J ¼ 6.7 Hz, OCH2-CH3), 2.21 (s, 3H, CH3),
1.11 (t, J ¼ 6.9 Hz, 3H, OCH2-CH3). IR (KBr): 3196, 3093, 1699, 1660, 1370,
1246, 1091 cmꢂ1; MS (ESI þion): m=z ¼ 268. Anal. (%) calcd. for C11H13O3N3S:
C, 49.43; H, 4.90; N, 15.72. Found: C, 49.52; H, 4.88; N, 15.68.

430
S. V. RASHMI ET AL.
Ethyl 4-(4-(dimethylamin)phenyl)-1,2,3,4-tetrahydro-6-methyl-2-
oxopyrimidine-5-carboxylate (4o). Mp 255–256 ꢁC; 1H NMR (400 MHz,
DMSO-d6): d ¼ 9.05(s, 1H, NH), 7.58 (s, 1H, NH), 7.0 (d, J ¼ 6.5 Hz, 2H, C6H4),
6.64 (d, 2H, C6H4), 5.01 (s, 1H, CH) 3.93–3.99 (q, J ¼ 7.0 Hz, 2H, OCH2CH3),
2.83 [s, 6H, N(CH3)2], 2.21 (s, 3H, CH3), 1.11 (t, J ¼ 6.5 Hz, 3H, OCH2CH3); IR
(KBr): 3236, 3110, 2928, 2806, 2214, 1698, 1562, 1216, 1085 cmꢂ1; MS (ESI þ ion):
m=z ¼ 304.2. Anal. (%) calcd. for C16H21O3N3: C, 63.35, H, 6.98; N, 13.85. Found:
C, 63.36; H, 6.96; N, 13.79.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-(4-oxo-4H-chromen-3-yl)
pyrimidine-5-carboxylate (4p). Mp 266–268 ꢁC; 1H NMR(400 MHz, DMSO-
d6): d ¼ 9.24(s, 1H, NH), 8.28 (d, 1H, C6H4), 8.17 (s, 1H, NH), 8.08 (d, 1H,
C6H4), 7.79–7.83 (t, J ¼ 6.5 Hz, 1H, C6H4), 7.65 (d, J ¼ 6.2 Hz, 1H, C6H4), 7.50 (t,
1H, C6H4), 7.26 (s, 1H, C6H4), 6. 95 (t, 1H, C6H4), 5.23 (s, 1H, CH), 3.93–4.00
(q, 2H, OCH2-CH3), 2.22 (s, 2H, CH3), 1.08 (t, 3H, OCH2-CH3), IR (KBr): 3274,
3212, 3093, 2966, 1706, 1663, 1634, 1461, 1350, 1234, 1088, 759 cmꢂ1; MS (ESI
þion): m=z ¼ 329. Anal. (%) calcd. for C17H16O3N2O5: C, 62.19, H, 4.91; N, 8.53.
Found: C, 62.23; H, 4.96; N, 8.62.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-bipheylpyrimidine-5-carbox-
ylate (4q). Mp 216–217 ꢁC; 1H NMR (400 MHz, DMSO-d6): d ¼ 10.04 (s, 1H,
NH), 9.22 (d, 1H, C6H4), 7.99 (s, 1H, NH), 7.90 (d, 1H, C6H4), 7.77 (t, J ¼ 6.84 Hz,
Hz, 4H, C6H4), 7.62 (t, 2H, C6H4), 7.50 (t, 1H, C6H4), 7.45 (t, 2H, C6H4), 7.30–7.35
(t, 3H, C6H4), 5.18 (s, 1H, CH), 4.00 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 2.25 (s, 3H,
CH3), 1.11 (t, J ¼ 6.8 Hz 3H, OCH2-CH3); IR (KBr): 3233, 3095, 2974, 1697,
1675, 1259 cmꢂ1; (ESI þion): m=z ¼ 337. Anal. (%) calcd. for C20H20O3N2: C,
71.41, H, 5.99; N, 8.33. Found: C, 71.44; H, 5.96; N, 8.28.
Ethyl 4-(benzo[d][1,3]dixol-5-yl)-1,2,3,4-tetrahydro-6-methyl-2-oxopyri-
midine-5-carbxoylate (4r). Mp 189–191 ꢁC; 1H NMR (400 MHz, DMSO-d6):
d ¼ 9.16(s, 1H, NH), 7.66 (s, 1H, NH), 6.83 (d, J ¼ 5.97 Hz, 1H, C6H4), 6.72 (s,
1H, C6H4), 6.67 (d, J ¼ 7.2 Hz, 1H, C6H4), 5.97 (s, 1H, -OCH2O-), 5.05 (s, 1H,
CH), 3.97 (q, J ¼ 6.5 Hz, 2H, OCH2-CH3), 2.23 (s, 3H, CH3), 1.09 (t, J ¼ 6.8 Hz,3H,
Hz,3H, OCH2-CH3); IR (KBr): 3354, 3217, 3094, 2975, 1692, 1638, 1218, 1089 cmꢂ1
;
MS (ESI þion): m=z ¼ 305.2. Anal. calcd. for C15H16 N2O5: C, 59.21; H, 5.30; N,
9.21. Found: C, 59.14; H, 5.36; N, 9.28.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-styrylpyrimidine-5-carboxy-
late (4s). Mp 189–191 ꢁC; lit.[27] 189–192 ꢁC; 1H NMR(400 MHz, DMSO-d6):
d ¼ 9.16 (s, 1H, NH), 7.66 (d, 1H, C6H4), 6.83 (d, J ¼ 5.97 Hz, 1H, C6H4), 6.72 (s,
1H, C6H4), 6.67 (d, J ¼ 7.2 Hz, 1H, C6H4), 5.97 (d, 1H, C6H4), 5.05 (s, 1H, CH),
3.97 (q, J ¼ 6.5 Hz, 2H, OCH2-CH3), 2.23 (s, 3H, CH3), 1.09 (t, 3H, OCH2-CH3).
1,2,3,4-tetrahydro-4-(2-metoxy-6-pentacecylphenyl)-6-methyl-2-
oxopyrimidin-5-yl propionate (4t). Mp 250–253 ꢁC; 1H NMR (400 MHz,
D2O): 7.086 (t, 1H, C6H3), 6.76 (d, 1H, C6H4), 6.66 (d, 1H, C6H3), 5.61 (s, 1H,
CH), 3.80 (q, J ¼ 6.5 Hz, 2H, OCH2-CH3), 3.77 (s, 3H, OCH3), 2.11 (s, 3H, CH3),
1.45 (q, 2H, (CH2-CH3), 1.04–1.26 [m, 26H, ꢂ(CH2)15], 0.929 (t, 3H, CH3-CH2-),
0.80 (t, 3H, -CH3-CH2-); IR (KBr): 3354, 3217, 3094, 2975, 1692, 1638, 1218,

ONE-POT SYNTHESIS OF DIHYDROPYRIMIDONES
431
1089 cmꢂ1; MS (ESI þion): m=z ¼ 501.34. Anal. calcd. for C30H48 N2O4; C, 72.12; H,
9.67; N, 5.60. Found: C, 72.15, H, 9. 69; N, 5.68.
Ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-(thiophen-2-yl)pyrimidine-5-
carboxylate (4u). Mp 209–211 ꢁC; lit.[26] 209–211 ꢁC; 1H NMR (400 MHz,
DMSO-d6): d ¼ 9.13 (s, 1H, NH), 7.70 (s, 1H, NH), 7.12 (s, 1H, Ar-H), 6.96 (9d,
1H, Ar-H), 5.12 (s, 1H, CH), 4.02 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 2.19 (s, 3H,
CH3), 1.13 (t, 3H, OCH2-CH3).
Materials and Methods
All analytical TLC was performed with E. Merck silica-gel 60 F254 aluminum
sheets and was visualized with ultraviolet (UV) light. The following mobile phases
were employed for TLC: chloroform=methanol and hexane=ethyl acetate in different
ratios.
The instrumental techniques employed for the characterization of the newly
1
synthesized compounds include H NMR and mass spectroscopy. The details of
instrumentation is briefly given below. 1H (400-MHz) spectra were recorded on
CDCl3 solution in a 5-mm tube on a Bruker AMX 400 and 300 Fourier transform
(FT) spectrophotometer (at SIF, Indian Institute of Science, Bangalore, India) with
tetramethylsilane (TMS) as internal standard. The spectrophotometer was internally
locked to the deuterium frequency of the solvent. Chemical shifts were recorded in
parts per million (ppm) relative to tetramethylsilane (TMS). Mass and purity were
recorded on a LC–MSD-Trap-XCT.
ACKNOWLEDGMENTS
K. S. R. Acknowledges the University Grants Commission (phase 2) vide
No. F. 540=10=2004-05 (SAP II) and the Department of Science and Technology–
Funding for Infrastructure in Science and Technology program.
REFERENCES
1. Armstrong, R. W.; Combs, A. P., Tempest, P. A.; Brown, S. D.; Keating, T. A. Multiple-
component condensation strategies for combinatorial library synthesis. Acc. Chem. Res.
1996, 29, 123–131.
2. Tietze, L. F.; Lieb, M. E. Domino reactions for library synthesis of small molecules in
combinatorial chemistry. Curr. Opin Chem. Biol. 1998, 2, 363–371.
3. Dax, S. L.; Mcnally, J. J.; Youngman, M. A. Multi-component methodologies in
solid-phase organic synthesis. Curr. Med. Chem. 1999, 6, 255–270.
4. Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery.
Science 2000, 287, 1964–1969.
5. Kappe, C. O. One hundred years of the Biginelli dihydropyrimidine synthesis. Tetrahedron
1993, 49, 6937–6963.
6. Kappe, C. O. Recent advances in the Biginelli dihydropyrimdine in the Biginelli dihydro-
pyrimidine synthesis: New tricks from an old dog. Acc. Chem. Res. 2000, 33(12), 879–888.
7. Kappe, C. O. Biologically active dihydropyrimidones of the Biginelli type: A literature
survey. Eur. J. Med. Chem. 2000, 35, 1043–1052.

432
S. V. RASHMI ET AL.
8. Atwal, K. S.; Rovnyak, G. C.; Reilly, B. C. O.; Schwatrz, J. Substituted 1,4-dihydropyr-
imidines: Synthesis of selectively functionalized 2-hetero-1,4-dihydropyrimidines. J. Org.
Chem. 1989, 54, 5589–5907.
9. Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Conformational analysis of 4-aryl-
dihydropyrimidine calcium channel modulators. A comparison of ab initio, semiempirical,
and x-ray crystallographic studies. Tetrahedron 1997, 53, 2803–2816.
10. Barrow, J. C.; Nantermet, P. G.; Selnick, H. G. In vitro and in vivo evaluation of
dihydropyrimidinone C-5 amides as potent and selective a1A receptor antagonists for
the treatment of benign prostatic hyperplasia. J. Med. Chem. 2000, 43, 2703–2718.
11. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.; Mitchison, T.
J. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based
screen. Science 1999, 286, 971–974.
12. Haggarty, S. J.; Mayer, T. U.; Miyamoto, D. T.; Fathi, R.; King, R. W. T. J.; Mitchison,
T. J.; Schreiber, S. L. Dissecting cellular processes using small molecules: Identification of
colchicine-like, taxol-like and other small molecules that perturb mitosis. Chem. Biol.
2000, 7, 275–286.
13. Paraskar, A. S.; Dewkar, G. K.; Sudlai, A. Cu(OTf)2: A reusable catalyst for high-
yield synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. 2003, 44,
3305–3308.
14. (a) Biginelli, P. G. Aldehyde–urea derivatives of aceto- and oxaloacetic acids. Chim. Ital.
1893, 23, 360–416; (b) Syamala, M. Recent progress in three-component reactions: An
update. Org. Prep. Proced. Internat. 2009, 41, 1–68; (c) Saini, A.; Kumar, S.; Sandhu,
J. S. Biginelli reaction (review). J. Indian Chem. Soc. 2007, 84, 959–970; (d) Kumaravel,
K.; Vasuki, G. Multicomponent reactions in water. Curr. Org. Chem. 2009, 13,
1820–1841.
15. Peng, J.; Deng, Y. Ionic–liquids catalyzed Biginelli reaction under solvent-free conditions.
Tetrahedron Lett. 2001, 42, 5917–5919.
16. Hu, E. H.; Sidler, D. R.; Dolling, U. H. Unprecedented catalytic three-component
one-pot condensation reaction: An efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-
dihydropyrimidin-2(1H)-ones. J. Org. Chem. 1998, 63, 3454–3457.
17. 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.
18. 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.
19. Carloni, B. F.; Frullanti, B.; Maggi, R.; Sartori, G. Revision of the Biginelli reaction
under solid acid catalysis. Solvent-free synthesis of dihydropyrimidines over montmoril-
lonite KSF. Tetrahedron Lett. 1999, 40, 3465–3468.
20. Wang, D.-C.; Guo, H.-M.; Qu, G.-R. Efficient, green, solvent-free synthesis of
3,4-dihydropyrimidin-2(1H)-ones via Biginelli reaction catalyzed by Cu(NO3)2 ꢀ 3H2O:
Efficient, green, solvent-free. Synth. Commun. 2010, 40(8), 1115–1122.
21. Kumar, K. A.; Kashthuraiahm, M C.; Reddy, 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.
22. Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.; Ramalingam, T. LiClO4-
Catalyzed one-pot synthesis of dihydropyrimidinones: An improved protocol for Biginelli
reaction. Synthesis 2001, 1341–1345.
23. Bussolari, J. C.; McDonnell, P. A. A new substrate for the Biginelli cyclocondensation:
Direct preparation of 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones from a b-keto
carboxylic acid. J. Org. Chem. 2000, 65, 6777–6779.

ONE-POT SYNTHESIS OF DIHYDROPYRIMIDONES
433
24. Zhang, M.; Li, Y. Q. Facile one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-one
catalyzed by Zn(NH2SO3)2. Synth. Commun. 2006, 36, 835–841.
25. Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.; Peppe, C. Tetrahedron 2002,
58, 4801–4807.
26. Lu, J.; Bai, Y. Catalysis of the Biginelli reaction by ferric and nickel chloride
hexahydrates. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Synthesis 2002,
466–470.
27. Hu, E. H.; Sidler, D. R.; Dolling, U.-H. Unprecedented catalytic three-component,
one-pot condensation reaction: An efficient synthesis of 5-alkoxycarbonyl-4-aryl-
3,4-dihydropyrimidin-2(1H)-ones. J. Org. Chem. 1998, 63, 3454–3457.