3,4-Hydropyrimidin-2-(1H)one derivatives: Solid silica-based sulfonic acid catalyzed microwave-assisted synthesis and their biological evaluation as antihypertensive and calcium channel blocking agents

Article abstract of DOI:10.1007/s00044-014-0988-y

Microwave assisted simple, efficient procedure for one-pot Biginelli condensation reaction of aldehydes, β-ketoesters, and urea or thiourea in solvent-free condition employing solid silica-based sulfonic acid as a novel, heterogeneous reusable catalyst is

Full text of DOI:10.1007/s00044-014-0988-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0988-y
ORIGINAL RESEARCH
3
,4-Hydropyrimidin-2-(1H)one derivatives: solid silica-based
sulfonic acid catalyzed microwave-assisted synthesis and their
biological evaluation as antihypertensive and calcium channel
blocking agents
Srinivasa Rao Jetti
Shubha Jain
•
Amitbodh Upadhyaya
•
Received: 4 December 2013 / Accepted: 6 March 2014
Ó Springer Science+Business Media New York 2014
Abstract Microwave assisted simple, efficient procedure
for one-pot Biginelli condensation reaction of aldehydes,
b-ketoesters, and urea or thiourea in solvent-free condition
employing solid silica-based sulfonic acid as a novel,
heterogeneous reusable catalyst is described. Compared to
the classical Biginelli reaction conditions, the present
method has the advantages of good yields, short reaction
times, and experimental simplicity. The newly synthesized
compounds have been screened to in vitro antihypertensive
and calcium channel blocking activity done by IC50 mea-
surement method with nifedipine as standard.
2002). In this context, heterogeneous catalysis (Deepak et
al., 2006; Vassylyev et al., 2005) is emerging as an alter-
native to homogeneous processes, since catalysts can be
recovered after the reaction and reused several times to
achieve very high turn-over numbers. One strategy to
transform a homogeneous into heterogeneous process is to
anchor the active site onto a large surface solid carrier
provided that the anchoring methodology maintains the
intrinsic activity and selectivity of the catalytic center
(Mark et al., 2005). Among various solid supports, silica is
usually preferred, since it displays many advantageous
properties—excellent stability (chemical and thermal),
high surface area, good accessibility, and organic groups
can be robustly anchored to the surface, to provide catalytic
centers (Mark et al., 2005; Overman et al., 1995).
Keywords Solid silica-based sulfonic acid ꢀ
3
,4-Dihydropyrimidin-2-(1H)ones ꢀ Microwave irradiation ꢀ
Antihypertensive and calcium channel
blocking activity ꢀ IC50 ꢀ Nifedipine
In recent years, attention has turned toward solid acid
catalysts for catalyzing organic reactions (James, 2002).
Recently, silica functionalized sulfonic acid as heteroge-
neous solid acid catalyst has been used to carry out variety
of reactions (Van Rhijn et al., 1998).
Introduction
In recent years, there has been an increasing interest in
developing greener processes (Anastas and Kirchhoff,
Nowadays, there has been renewed interest in the three
component cyclocondensation of ethyl acetoacetate with
aromatic aldehydes and urea (or thiourea) discovered by
Biginelli in 1893 (Kappe, 2000a). 3,4-Dihydropyrimidi-
nones and their sulfur analogs have been reported to pos-
sess diverse pharmacological properties such as antiviral,
antibacterial, and antihypertensive, as well as efficiency as
calcium channel modulators, and a-1a-antagonists (Kappe,
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-0988-y) contains supplementary
material, which is available to authorized users.
S. R. Jetti (&) ꢀ S. Jain
Laboratory of Heterocycles, School of Studies in Chemistry &
Biochemistry, Vikram University, Ujjain 456010,
Madhya Pradesh, India
2000b). The batzelladine alkaloids containing the dihy-
dropyrimidine unit are particularly notable, as they recently
were found to be potent HIV gp-120-CD4 inhibitors
e-mail: srinujetti479@gmail.com
(
Overman et al., 1995). Therefore, the preparation of this
A. Upadhyaya
heterocyclic core unit is under active investigation (Zhang
et al., 2006). However, many of these reported methods
suffer from drawbacks such as low yield of products, harsh
Department of Engineering Chemistry, Lakshmi Narain College
of Technology & Science, Bhopal 462021, Madhya Pradesh,
India
123

Med Chem Res
OH
OH
OH
O
O
O
Table 1 Yields of the reaction in different conditions
S
(MeO) Si
NH
2
S
3
i
i
O
O
NH2
Si
2
2
Toluene, reflux,18 h
Amount of
catalyst (% mol)
Reaction time
(min)/temperature (°C)
Yields (%)
1
0
1
2
3
4
5
7/90
7/90
7/90
7/90
7/90
7/90
67
74
82
95
95
94
O
O
O
S
1
2
) ClSO H/CHCl /4h
3 3
i
O
NH
SO3
H
Si
2
) Washing with EtOH
2
Scheme 1 Preparation of solid silica-based sulfonic acid
reaction conditions, cumbersome experimental procedures,
use of moisture sensitive, toxic, and costly catalysts.
Therefore, there is a need to develop new catalysts which
are easily available or prepared, cost effective, recoverable,
reusable, and environment friendly. Moreover, the work-up
procedure should be simpler.
stopped. Then, the mixture was filtered and washed with
ethanol (30 mL) and dried at room temperature to obtain
silica solid-based sulfonic acid (2) as a cream powder
(5.13 g). Sulfur content of the samples determined by
conventional elemental analysis was 9.29 %.
Keeping in view the importance of Biginelli compounds
and heterogeneous catalysis, we wish to report a mild and
efficient method for one-pot synthesis of 3,4-dihydropyr-
imidinones/thiones in the presence of catalytic amount of
solid silica-based sulfonic acid onto silica gel under het-
erogeneous conditions. The preparation procedure for cat-
alyst 2 is outlined in Scheme 1 with slight modification
than the already reported method (Biswanath et al., 2006).
General procedure for the synthesis of 3,4-
dihydropyrimidin-2(1H)-ones and thiones 1(a–n) using
solid silica-based sulfonic acid as catalyst
The mixture of ethyl acetoacetate (2.5 mmol), aldehyde
(2.5 mmol), urea or thiourea (2.5 mmol), and solid silica-
based sulfonic acid (3 mol% of SO H) was subjected to
3
microwave irradiation in solvent-free condition for appro-
priate time (Table 1) in 900 W microwave oven for
6–7 min (successive irradiation of 30–40 s with cooling
Experimental
intervals of time as the temperature being 90 °C). After
completion of the reaction as indicated by TLC, the reac-
tion mixture was diluted with EtOAc (10 mL) and then
solid silica-based sulfonic acid was separated by simple
filtration due to its heterogeneous nature. The product was
obtained after removal of the EtOAc under reduced pres-
sure followed by treatment with water and crystallization
from EtOH.
General
Silica gel (K100, 0.063–0.200 mm) was purchased from
Merck (Germany) and 3-aminopropyltrimethoxy silane
from Aldrich Chemical Company. All melting points were
determined on a perfit melting point apparatus and are
1
13
uncorrected. H- and C-NMR spectra were recorded on
Brucker DRX-400 (400 MHz) spectrometer in DMSO-d6
using tetramethylsilane as an internal standard, and IR
spectra were recorded on Perkin-Elmer FTIR spectropho-
tometer using KBr disks. Mass spectral data were recorded
on Jeol JMS D-300 mass spectrometer at 70 eV. All yields
refer to the isolated yields.
General procedure for the synthesis of 4,6-diaryl-3,4-
dihydropyrimidin-2(1H)-ones 2(a–f)
The mixture of cyclic ketone (1.0 mmol), aldehyde
(1.0 mmol), urea (1.5 mmol), and solid silica-based sul-
fonic acid (3 mol% of SO
irradiation in solvent-free condition for appropriate time
Table 1) in 900 W microwave oven for 7 min (successive
H) was subjected to microwave
3
(
Catalyst preparation
irradiation of 30–40 s with cooling intervals of time as the
temperature being 80 °C). After completion of the reaction
as indicated by TLC, the reaction mixture was diluted with
EtOAc (10 mL) and then solid silica-based sulfonic acid
was separated by simple filtration due to its heterogeneous
nature. The product was obtained after removal of the
EtOAc under reduced pressure followed by treatment with
water and crystallization from EtOH.
Solid silica-based sulfonic acid (2)
To a mixture of 3-aminopropylsilica 1 (5 g) in chloroform
(
20 mL), chlorosulfonic acid (1 g, 0.6 mL) was added
dropwise at 0 °C over 2 h. After addition was complete,
the mixture was stirred for 2 h until HCl gas evolution
1
23

Med Chem Res
Ethyl-6-methyl-4-(3-methylfuran-2-yl)-2-oxo-1,2,3,4-
(aromatic C–H stretch), 3012 (aliphatic C–H stretch), 1659
(C=O stretch), 1583 (C=C stretch), 1497 (C=C bend), 1423
tetrahydropyrimidine-5-carboxylate (1a)
(
O–CH –CH bend), 1136 (C–NH bend), 1023 (CH –C–H
2 3 3
1
Mp 217–219 °C; H-NMR (400 MHz, DMSO-d ) d :
bend), 934 (thiophenic C–C bend), 679 (thiophinic C–H
6
H
1
.12–1.13 (t, 3H, J = 7.13 Hz, CH ), 1.82 (s, 3H, CH ),
bend); ESI–MS 265 (M?H); C H N O S (280.09): Calcd.
13 16 2 3
3
3
2
.17 (s, 3H, furanic CH ), 8.87–3.92 (q, 2H, J = 7.17 Hz,
3
C, 55.70; H, 5.75; N, 9.99; O, 17.12; S, 11.44; Found. C,
55.69; H, 5.74; N, 9.97; O, 17.16; S, 11.47.
CH ), 4.7 (d, 1H, J = 2.14 Hz, CH), 6.1 (d, 1H,
2
J = 2.21 Hz, furanic H), 6.2 (d, 1H, J = 2.19 Hz, furanic
1
3
H), 8.1 (s, 1H, NH), 8.9 (s, 1H, NH); C-NMR (100 MHz,
Ethyl-6-methyl-4-(5-thiophene-2-yl)-2-oxo-1,2,3,4-
DMSO-d ) d : 13.8 (CH –CH ), 16.3 (CH ), 18.9 (CH -
tetrahydropyrimidine-5-carboxylate (1d)
6
c
3
2
3
3
HetAr), 54.4 (C–NH), 65.3 (OCH ), 106.7, 119.7, 109.8,
2
1
1
1
23.1 (C–HetAr), 145.2 (C=C–CO), 153.4 (C=C–NH),
-
Mp 223–225 °C; H-NMR (400 MHz, DMSO-d d ) d
:
H
6
6
1
65.1, 168.9 (C=O); IR (mmax; KBr, cm ): 3231 (NH
0.81 (t, 3H, J = 7.37 Hz, CH ), 2.1 (s, 3H, thiophenic
3
stretch), 3125 (aromatic CH stretch), 2934 (aliphatic C–H
CH ), 2.87 (s, 3H, CH ), 3.7–3.8 (q, 2H, J = 7.33 Hz,
3
3
stretch), 1726 (C=O stretch), 1623 (C=C stretch), 1472
CH ), 5.1 (d, 1H, J = 2.25 Hz, 2H), 7.2–7.3 (m, 2H,
2
1
thiophenic H), 8.7 (s, 1H, NH), 8.9 (s, 1H, NH); C-NMR
3
(
C=C bend), 1443 (O–CH –CH3 bend), 1165 (C–NH
2
bend), 1010 (CH –C–H bend), 903 (furan C–C bend), 692
3
(100 MHz, DMSO-d ) d : 13.5 (CH –CH ), 15.9 (CH ),
6
c
3
2
3
(
(
furan C–H bend); ESI–MS 265 (M?H); C H N O
1
22.5 (CH -HetAr), 53.5 (C–NH), 67.7 (OCH ), 107.7,
3 2
3
16
2
4
264.11): Calcd. C, 59.08; H, 6.10; N, 10.60; O, 24.22;
115.6, 122.5, 127.7 (C-HetAr), 143.3 (C=C–CO), 152.7
-
1
Found. C, 59.10; H, 6.12; N, 10.56; O, 24.18.
(C=C–NH), 163.2, 173.6 (C=O); IR (mmax; KBr, cm ):
323, 3244 (NH stretch), 3124 (aromatic C–H stretch),
3
Ethyl-6-methyl-4-(5-methylfuran-2-yl)-2-oxo-1,2,3,4-
3028 (aliphatic C–H stretch), 1671 (C=O stretch), 1601
(C=C stretch), 1509 (C=C bend), 1450 (O–CH –CH
tetrahydropyrimidine-5-carboxylate (1b)
2
3
bend), 1170 (C–NH bend), 1011 (CH –C–H bend), 954
3
1
Mp 229–301 °C; H-NMR (400 MHz, DMSO-d ) dH
:
(thiophenic C–C bend), 698 (thiophinic C–H bend); ESI–
6
1
.05–1.06 (t, 3H, J = 7.09 Hz, CH ), 1.94 (s, 3H, CH ),
MS 265 (M?H); C H N O S (280.09): Calcd. C, 55.70;
13 16 2 3
3
3
2
.20 (s, 3H, furanic CH ), 3.94–4.01 (q, J = 7.11 Hz, 2H,
3
H, 5.75; N, 9.99; O, 17.12; S, 11.44; Found. C, 55.67; H,
5.72; N, 9.94; O, 17.15; S, 11.41.
CH ), 4.9 (d, 1H, J = 2.14 Hz, CH), 6.3 (d, 1H,
2
J = 2.24 Hz, furanic H), 6.4 (d, 1H, J = 2.04 Hz, furanic
1
H), 8.3 (s, 1H, NH), 9.1 (s, 1H, NH); C-NMR (100 MHz,
3
Ethyl-6-methyl-4-(1-methyl-1H-pyrrol-2-yl)-2-oxo-1,2,3,4-
DMSO-d ) d : 13.4 (CH –CH ), 15.9 (CH ), 18.3 (CH -
tetrahydropyrimidine-5-carboxylate (1e)
6
c
3
2
3
3
HetAr), 53.5 (C–NH), 64.7 (OCH ), 107.7, 110.6, 118.7,
2
1
1
1
22.5 (C-HetAr), 143.3 (C=C–CO), 152.7 (C=C–NH),
-
Mp 194–196 °C; H-NMR (400 MHz, DMSO-d ) dH
:
6
1
63.2, 167.2 (C=O); IR (mmax; KBr, cm ): 3220 (NH
1.06–1.11 (t, 3H, J = 7.21 Hz, CH ), 2.24 (s, 3H, CH ),
3 3
stretch), 3150 (aromatic C–H stretch), 2958 (aliphatic C–H
stretch), 1748 (C=O stretch), 1611 (C=C stretch), 1452 (O–
CH –CH ), 1170 (C–NH), 1005 (CH –C–H), 907 (furan
3.9–4.0 (q, 2H, J = 7.29 Hz, CH ), 5.1 (d, 1H, J = 2.12 Hz,
2
CH), 7.2–7.3 (m, 3H, pyrrolic H), 8.7 (s, 1H, NH), 9.1 (s, 1H,
1
3
2
3
3
NH); C-NMR (100 MHz, DMSO-d ) d : 14.4 (CH –CH ),
6
c
3
2
C–C), 699 (furan C–H); ESI–MS 265 (M?H); C H N O
1
25.5 (CH ), 36.1 (CH -HetAr), 53.7 (C–NH), 67.2 (OCH ),
3 3 2
3
16
2
4
(
264.23): Calcd. C, 59.08; H, 6.10; N, 10.60; O, 24.22;
102.8 (C=C–CO), 107.2, 109.4, 126.2. 127.1 (C-HetAr),
-1
Found. C, 59.12; H, 6.07; N, 10.52; O, 24.24.
157.9 (C=C–NH), 163.3, 168.8 (C=O); IR (mmax; KBr, cm ):
564, 3488 (NH stretch), 3082 (aromatic C–H stretch), 3025
3
Ethyl-6-methyl-4-(3-thiophene-2-yl)-2-oxo-1,2,3,4-
(aliphatic C–H stretch), 1745 (C=O stretch), 1610 (C=C
stretch), 1513 (C=C bend), 1450 (O–CH –CH bend), 1166
tetrahydropyrimidine-5-carboxylate (1c)
2
3
(
C–NH bend), 1110 (CH –C–H bend), 906 (pyrrolic C–C
3
1
Mp 217–219 °C; H-NMR (400 MHz, DMSO-d ) d : 0.93
bend), 696 (pyrrolic C–H bend); ESI–MS 264 (M?H);
6
H
(
t, 3H, J = 7.29 Hz, CH ), 2.3 (s, 3H, thiophenic CH ), 2.82
C H N O (263.32): Calcd. C, 59.30; H, 6.51; N, 15.96; O,
13 17 3 3
3
3
(
s, 3H, CH ), 3.6–3.7 (q, 2H, J = 7.26 Hz, CH ), 5.3 (d, 1H,
3
18.23; Found. C, 59.28; H, 6.47; N, 15.93; O, 18.26.
2
J = 2.21 Hz, 2H), 7.1–7.3 (m, 2H, thiophenic H), 8.6 (s,
1
3
H, NH), 9.0 (s, 1H, NH); C-NMR (100 MHz, DMSO-d6)
1
Ethyl-4-(furan-2-yl)-6-metyl-2-oxo-1,2,3,4-
d : 14.1 (CH –CH ), 15.2 (CH ), 21.4 (CH -HetAr), 55.6
tetrahydropyrimidine-5-carboxylate (1f)
c
3
2
3
3
(
C–NH), 68.8 (OCH ), 108.8, 116.7, 123.6, 128.8 (C-
2
1
HetAr), 144.4 (C=C–CO), 153.8 (C=C–NH), 164.3, 174.7
Mp 211–213 °C; H-NMR (400 MHz, DMSO-d ) dH
:
6
-1
(
C=O); IR (mmax; KBr, cm ): 3318 (NH stretch), 3116
1.15–1.19 (t, 3H, J = 7.32 Hz, CH ), 1.98 (s, 3H, CH ),
3
3
123

Med Chem Res
3
.88 (q, 2H, J = 7.19 Hz, CH ), 5.12–5.13 (d, 1H,
2
697 (pyrrolic C–H bend); ESI–MS 250 (M?H);
J = 2.07 Hz, CH), 6.40–6.50 (m, 2H, furanic H), 7.42 (d,
J = 2.23 Hz, furanic H), 9.30 (s, 1H, NH), 10.02 (s, 1H,
C H N O (249.62): Calcd. C, 57.82; H, 6.07; N, 16.86;
12 15 3 3
O, 19.26; Found. C, 57.80; H, 6.05; N, 16.83; O, 19.25.
1
3
NH); C-NMR (100 MHz, DMSO-d ) d : 13.9 (CH –
6
c
3
CH ), 16.9 (CH ), 47.6 (C–NH), 59.4 (OCH ), 98.17
2
5-(Ethoxycarbonyl)-4-(4-nitrophenyl)-6-methyl-3,4-
3
2
(
(
C=C–CO), 106.0, 110.3, 122.1, 142.4 (C-HetAr), 154.5
1
dihydropyrimidin-2(1H)-one (1i)
-
C=C–NH), 162.8, 164.6 (C=O); IR (mmax; KBr, cm ):
1
3
247, 3365 (NH stretch), 3181 (aromatic C–H stretch),
Mp 212–214 °C; H-NMR (400 MHz, DMSO-d ) d : 1.11
6
H
3
042 (aliphatic C–H stretch), 1740 (C=O stretch), 1601
(t, 3H, J = 7.04 Hz, OCH CH ), 2.32 (s, 3H, CH ), 4.03
2
3
3
(
C=C stretch), 1509 (C=C bend), 1451 (O–CH –CH3
2
(q, 2H, J = 7.12 Hz, OCH CH ), 5.78 (d, 1H,
2 3
bend), 1172 (C–NH bend), 1002 (CH –C–H bend), 905
3
J = 2.28 Hz, –CH), 7.51 (d, 2H, J = 9.18 Hz, Ar–H), 7.69
(s, 1H, NH), 8.16 (d, 2H, J = 9.16 Hz, Ar–H), 9.05 (s, 1H,
(
(
furanic C–C bend), 697 (furanic C–H bend); ESI–MS 251
1
3
M?H); C H N O (250.57): Calcd. C, 57.59; H, 5.64;
4
NH); C-NMR (100 MHz, DMSO-d ) d : 14.22 (CH –
1
2
14
2
6
C
3
N, 11.19; O, 25.57; Found. C, 57.56; H, 5.62; N, 11.23; O,
5.60.
CH ), 18.71 (CH ), 55.81 (C–NH), 60.15 (OCH ), 101.60
2 3 2
2
(C=C–CO), 118.15, 125.3, 130.37, 138.34, 146.5, 152.26
Ar–C), 153.41 (C=C–NH), 159.15, 165.85 (C=O); IR
(
-
1
Ethyl-4-(thiophen-2-yl)-6-methyl-2-oxo-1,2,3,4-
(mmax; KBr, cm ): 3235, 1740, 1631; ESI–MS 306
(M?H); C H N O (305.10): Calcd. C, 55.08; H, 4.95;
tetrahydropyrimidine-5-carboxylate (1g)
1
4 15 3 5
N, 13.76; O, 26.20; Found. C, 55.10; H, 4.93; N, 13.78; O,
26.22.
1
Mp 200–202 °C; H-NMR (400 MHz, DMSO-d ) d : 0.9
6
H
(
t, 3H, J = 7.18 Hz, CH ), 2.22 (s, 3H, CH ), 3.9–4.0 (q,
3 3
2
6
H, J = 7.23 Hz, CH ), 5.1 (d, 1H, J = 2.07 Hz, CH),
2
5-(Ethoxycarbonyl)-4-(4-chlorophenyl)-6-methyl-3,4-
.9–7.3 (m, 3H, thiophenic H), 9.4 (s, 1H, NH), 9.6 (s, 1H,
1
dihydropyrimidin-2(1H)-one (1j)
3
NH); C-NMR (100 MHz, DMSO-d ) d : 15.7 (CH –
CH ), 23.9 (CH ), 55.6 (C–NH), 67.4 (OCH ), 107.0
2
6
c
3
1
Mp 215–217 °C; H-NMR (400 MHz, DMSO-d ) d : 1.12
3
2
6
H
(
(
C=C–CO), 122.3, 126.5. 131.8, 142.4 (C-HetAr), 154.5
1
C=C–NH), 164.6, 174.8 (C=O); IR (mmax; KBr, cm ):
(t, 3H, J = 7.14 Hz, OCH CH ), 2.30 (s, 3H, CH ), 3.91
2 3 3
-
(q, 2H, J = 7.16 Hz, OCH CH ), 5.70 (d, 1H, J =
2 3
3
278, 3385 (NH stretch), 3210 (aromatic C–H stretch),
2.28 Hz, –CH), 7.21 (d, 2H, J = 9.18 Hz, Ar–H), 7.69 (s,
1H, NH), 7.94 (d, 2H, J = 9.18 Hz, Ar–H), 9.16 (s, 1H,
3
029 (aliphatic C–H stretch), 1739 (C=O stretch), 1609
1
3
(
C=C stretch), 1510 (C=C bend), 1450 (O–CH –CH3
2
NH); C-NMR (100 MHz, DMSO-d ) d : 14.18 (CH –
6
C
3
bend), 1171(C–NH bend), 1010 (CH –C–H bend), 905
3
CH ), 18.62 (CH ), 55.72 (C–NH), 60.21 (OCH ), 101.55
2 3 2
(
thiophenic C–C bend), 697 (thiophenic C–H bend); ESI–
(C=C–CO), 118.17, 122.9, 126.6, 130.32, 142.29, 152.31
(Ar–C), 153.39 (C=C–NH), 159.17, 165.83 (C=O); IR
MS 267 (M?H); C H N O S (266.24): Calcd. C, 54.12;
2 14 2 3
1
-
1
H, 5.30; N, 10.52; O, 18.02; S, 12.04; Found. C, 54.16; H,
.27; N, 10.55; O, 18.05; S, 12.01.
(mmax; KBr, cm ): 3225, 1720, 1615; ESI–MS 295
(M?H); C H ClN O (294.07): Calcd. C, 57.05; H, 5.13;
5
1
4
15
2 3
Cl, 12.03; N, 9.50; O, 16.29; Found. C, 57.08; H, 5.15; N,
9.47; O, 16.31.
Etyhyl-4-(1H-pyrrol-2-yl)-6-metyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1h)
5
-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-
1
Mp 182–184 °C; H-NMR (400 MHz, DMSO-d ) dH
:
dihydropyrimidin-2(1H)-one (1k)
6
0
.9–1.0 (t, 3H, J = 7.10 Hz, CH ), 2.81 (s, 3H, CH ), 3.6
3 3
1
(
q, 2H, J = 7.16 Hz, CH ), 4.8 (d, 1H, J = 2.14 Hz, pyr-
2
Mp 206–208 °C; H-NMR (400 MHz, DMSO-d ) d : 1.09
(t, 3H, J = 7.1 Hz, OCH CH ), 2.25 (s, 3H, CH ), 3.97 (q,
2 3 3
6
H
rolic H), 5.2 (d, 1H, J = 2.07 Hz, CH ), 7.2–7.3 (m, 3H,
2
1
pyrrolic H), 8.8 (s, 1H, NH), 9.1 (s, 1H, NH); C-NMR
3
2H, J = 7.1 Hz, OCH ), 5.05 (d, 1H, J = 2.15 Hz, –CH),
2
(
100 MHz, DMSO-d ) d : 15.9 (CH –CH ), 24.2 (CH ),
7.6 (C–NH), 68.1 (OCH ), 107.7 (C=C–CO), 110.6,
2
7.28 (m, 5H, Ar–H), 7.75 (s, 1H, NH), 9.20 (s, 1H, NH);
1
6
c
3
2
3
3
5
1
1
C-NMR (100 MHz, DMSO-d ) d : 14.11 (CH –CH ),
6
C
3
2
13.7, 122.5. 134.7 (C-HetAr), 158.2 (C=C–NH), 165.2,
-
17.94 (CH ), 54.91 (C–NH), 60.05 (OCH ), 100.95 (C=C–
3 2
1
70.7 (C=O); IR (mmax; KBr, cm ): 3298, 3231 (NH
CO), 113.05, 125.15, 127.81, 129.05, 131.20, 147.9 (Ar–
stretch), 3068 (aromatic C–H stretch), 2988 (aliphatic C–H
C), 150.16 (C=C–NH), 155.47, 163.81 (C=O); IR (mmax;
KBr, cm ): 3240, 1722, 1638; ESI–MS 261 (M?H);
-
1
stretch), 1716 (C=O stretch), 1610 (C=C stretch), 1511
(
C=C bend), 1452 (O–CH –CH3 bend), 1171 (C–NH
2
C H N O (260.11): Calcd. C, 64.60; H, 6.20; N, 10.76;
14 16 2 3
bend), 1011 (CH –C–H bend), 884 (pyrrolic C–C bend),
3
O, 18.44; Found. C, 64.63; H, 6.18; N, 10.78; O, 18.45.
1
23

Med Chem Res
5
-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-
alkylic H, aliphatic H), 6.19–6.31 (m, 2H, furanic H), 6.7
1
(a, 1H, NH), 6.9 (s, 1H, NH), 7.2 (m, 3H, furanic H); C-
3
dihydropyrimidin-2(1H)-thione (1l)
NMR (100 MHz, DMSO-d ) d : 15.9 (CH -HetAr), 53.5
6
C
3
1
Mp 208–210 °C; H-NMR (400 MHz, DMSO-d ) d : 1.11 (t,
(C–NH), 101.2 (C=C-olefin carbon), 105.7, 110.6, 150.6,
152.7 (C-furan ring), 122.5, 126.6, 132.3, 137.7 (C-thio-
phene ring), 142.2 (C=C–NH), 163.6 (C=O); IR (mmax;
6
H
3
H, J = 7.21 Hz, OCH CH ), 2.29 (s, 3H, CH ), 4.12 (q, 2H,
2 3 3
J = 7.24 Hz, OCH ), 5.16 (d, 1H, J = 2.05 Hz, –CH), 7.51
2
13
-1
(
m, 5H, Ar–H), 7.81 (s, 1H, NH), 9.41 (s, 1H, NH); C-NMR
KBr, cm ): 3477, 3411 (NH stretch), 3159 (aromatic C–H
(
100 MHz, DMSO-d ) d : 14.23 (CH –CH ), 17.91 (CH ),
4.85 (C–NH), 60.15 (OCH ), 100.90 (C=C–CO), 112.84,
2
stretch), 2970 (aliphatic C–H stretch), 1753 (C=O stretch),
1650 (C=C stretch), 1403 (C–N bend), 1137 (C–O–C
bend); ESI–MS 261 (M?H); C H N O S (260.43):
6
C
3
2
3
5
1
15.12, 125.15, 127.2, 129.64, 131.45 (Ar–C), 150.27 (C=C–
1
3 12 2 5
-1
NH), 162.63 (C=O), 180.25 (C=S); IR (mmax; KBr, cm ):
240, 1720, 1640, 1595, 1530; ESI–MS 277 (M?H); C H
4 16
Cacld. C, 59.98; H, 4.65; N, 10.76; O, 12.29; S, 12.32;
Found. C, 59.96; H, 4.67; N, 10.75; O, 12.31; S, 12.35.
3
1
N O S (276.09): Calcd. C, 60.85; H, 5.84; N, 10.14; O, 11.58;
2
2
S, 11.60; Found. C, 60.83; H, 5.86; N, 10.16; O, 11.55; S, 11.62.
4-(5-Methylthiophen-2-yl)-6-(thiophen-2-yl)-3,4-
dihydropyrimidin-2-(1H)-one (2b)
5
-(Ethoxycarbonyl)-4-(3-nitrophenyl)-6-methyl-3,4-
1
dihydropyrimidin-2(1H)-thione (1m)
Mp 241–243 °C; H-NMR (400 MHz, DMSO-d ) d : 2.42
6
H
(
s, 3H, thiphenic CH ), 5.2 (d, 1H, J = 4.12 Hz, pyrimi-
3
1
Mp 205–207 °C; H-NMR (400 MHz, DMSO-d ) d : 1.15 (t,
3
dine CH), 5.3 (d, 1H, J = 4.21 Hz, olefinic H), 6.5 (s, 1H,
6
H
H, J = 7.14 Hz, OCH CH ), 2.27 (s, 3H, CH ), 4.02 (q, 2H,
NH), 6.7 (s, 1H, NH), 7.21–7.48 (m, 5H, thiophenic H);
1
C-NMR (100 MHz, DMSO-d ) d : 14.6 (CH -HetAr),
2
3
3
3
J = 7.11 Hz, OCH CH ), 5.81 (d, 1H, J = 2.06 Hz, –CH),
2
3
6
C
3
7
.23–7.37 (m, 4H, Ar–H), 7.78 (s, 1H, NH), 9.34 (s, 1H, NH);
51.7 (C–NH), 105.3 (C=C-olefin carbon), 118.2, 127.1,
1
3
C-NMR (100 MHz, DMSO-d ) d : 14.14 (CH –CH ),
136.1, 143.9, 121.3, 132.7, 139.1(C-thiophene rings), 174.8
6
c
3
2
-
1
1
8.60 (CH ), 55.64 (C–NH), 60.21 (OCH ), 101.34 (C=C–
3
(C=O); IR (mmax; KBr, cm ): 3550, 3477 (NH stretch),
3140 (aromatic C–H stretch), 2924 (aliphatic C–H stretch),
1759 (C=O stretch), 1674 (C=C stretch), 1348 (C–C bend),
1186 (C–O–C bend); 1129 (C–S–C bend), ESI–MS 277
(M?H); C H N OS (276.73): Cacld. C, 56.49; H, 4.38;
2
CO), 126.25, 128.02, 129.32, 130.75, 135.65, 144.34 (Ar–C),
160.40 (C=C–NH), 165.64 (C=O), 182.65 (C=S); IR (mmax;
KBr, cm ): 3245, 1725, 1632, 1575, 1545; ESI–MS 322
-1
(
M?H); C H N O S (321.07): Calcd. C, 52.33; H, 4.70; N,
14 15 3 4
13 12 2
1
3.08; O, 19.92; S, 9.98; Found. C, 52.30; H, 4.72; N, 13.10;
N, 10.14; O, 5.79; S, 23.20; Found. C, 56.50; H, 4.35; N,
10.15; O, 5.80; S, 23.23.
O, 19.89; S, 9.95.
5
-(Ethoxycarbonyl)-4-(4-methoxyphenyl)-6-methyl-3,4-
4-(5-Methyl-1H-pyrrol-2-yl)-6-(thiophen-2-yl)-3,4-
dihydropyrimidin-2(1H)-thione (1n)
dihydropyrimidin-2-(1H)-one (2c)
1
1
Mp 153–155 °C; H-NMR (400 MHz, DMSO-d ) d : 1.17
Mp 227–229 °C; H-NMR (400 MHz, DMSO-d ) d : 2.31
6
H
6
H
(
t, 3H, J = 7.11 Hz, OCH CH ), 2.37 (s, 3H, CH ), 4.12
(s, 3H, pyrrolic CH ), 5.4 (d, 1H, J = 4.7 Hz, pyrimidine
2
3
3
3
(
s, 3H, –OCH ), 4.15 (q, 2H, J = 7.10 Hz, OCH CH ),
3
CH), 5.1 (d, 1H, J = 4.5 Hz, olefinic H), 6.8 (s, 1H, NH),
2
3
1
7.1 (s, 1H, NH), 7.34–7.45 (m, 5H, pyrrolic H); C-NMR
3
5
.44 (d, 1H, J = 2.15 Hz, –CH), 7.11 (d, 2H, J = 8.15 Hz,
Ar–H), 7.37 (d, 2H, J = 8.11 Hz, Ar–H), 7.84 (s, 1H, NH),
1
(100 MHz, DMSO-d6) d : 15.7 (CH -HetAr), 52.8
(C–NH), 103.8 (C=C-olefin carbon), 119.3, 122.4, 128.2
C
3
3
9
.43 (s, 1H, NH); C-NMR (100 MHz, DMSO-d d ) d :
6
6
C
1
4.32 (CH –CH ), 18.05 (CH ), 55.49 (C–NH), 60.45
3
(C-pyrrole ring), 133.8, 137.2, 140.2, 144.0 (C-thiophene
3
2
-
1
(
OCH ), 101.84 (C=C–CO), 114.32, 124.6, 127.74, 137.25,
2
ring), 175.9 (C=O); IR (mmax; KBr, cm ): 3577 (NH
stretch), 3167 (aromatic C–H stretch), 3024 (aliphatic C–H
stretch), 1763 (C=O stretch), 1658 (C=C stretch), 1361
(C–C bend), 1194 (C–O–C bend); 1143 (C–NH–C bend),
ESI–MS 260 (M?H); C H N OS (259.53): Cacld. C,
1
1
1
41.1, 147.15 (Ar–C), 159.45 (C=C–NH), 165.62 (C=O),
-
1
82.48 (C=S); IR (mmax; KBr, cm ): 3240, 1725, 1635,
574, 1540; ESI–MS 307 (M?H); C H N O S (306.10):
1
5 18 2 3
Calcd. C, 58.80; H, 5.92; N, 9.14; O, 15.67; S, 10.47;
Found. C, 58.82; H, 5.90; N, 9.15; O, 15.65; S, 10.45.
1
3 12 3
60.21; H, 5.05; N, 16.20; O, 6.17; S, 12.36; Found. C,
0.19; H, 5.02; N, 16.15; O, 6.15; S, 12.34.
6
4
-(5-Methylfuran-2-yl)-6-(thiophen-2-yl)-3,4-
dihydropyrimidin-2-(1H)-one (2a)
4,6-Diphenyl-3,4-dihydropyrimidin-2(1H)-one (2d)
1
1
Mp 223–225 °C; H-NMR (400 MHz, DMSO-d ) d : 2.31
Mp 234–236 °C; H-NMR (400 MHz, DMSO-d ) d : 9.51
6
H
6
H
(
s, 3H, furanic CH ), 5.33–5.44 (dd, 2H, J = 6.08 Hz,
(s, 1H, NH), 9.21 (s, 1H, NH), 7.21–7.62 (m, 10H, Ar–H),
3
123

Med Chem Res
5
.20 (d, 1H, J = 4.1 Hz, C=CH), 5.12 (d, 1H, J = 4.1 Hz,
1
activity was performed by in-vitro method in which effect of
test compounds on blood pressure is measured (Guan et al.,
2007).
3
CH); C-NMR (100 MHz, DMSO-d ) d : 51.9 (C–NH),
9
6
C
6.8 (C=C-olefin carbon), 126.9, 126.4, 128.6, 128.7,
1
34.2, 136.6, 143.2, (AR–C), 150.2 (C=O); IR (mmax; KBr,
cm ): 3312, 1685, 1598, 1449; ESI–MS 251 (M?H);
-
1
Procedure
C H N O; (250.30); Calcd. C, 76.78; H, 5.64; N, 11.19;
16 14 2
O, 6.39. Found. C, 76.53; H, 5.34; N, 11.02; O, 6.13.
Animals were procured from School of Life Sciences,
University of Hyderabad, Hyderabad. All animals were
kept in polyacrylic cages and maintained under standard
housing conditions (room temperature 24–27 °C and
humidity 60–65 % with 12:12 light: dark cycles). Food was
provided in the form of dry pellets and water ad libitum.
All experiments involving animals complies with the eth-
ical standards of animal handling and approved by Insti-
tutional Animal Ethics Committee (Approval number
LSCP/IAEC/06/01). Spontaneous hypertensive rats (SHRs)
of 200 ± 20 g body weight were used. Rats were divided
into 2 groups, each group had 9 animals.
4
-(4-Chlorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-
one (2e)
1
Mp264–266 °C; H-NMR(400 MHz, DMSO-d ) d : 9.42(s,
6
H
1
H, NH), 9.12 (s, 1H, NH), 7.19–7.78 (m, 9H, Ar–H), 5.60 (d,
1
H, J = 4.3 Hz, C=CH), 5.01 (d, 1H, J = 4.3 Hz, CH); C-
3
1
NMR (100 MHz, DMSO-d ) d : 52.7 (C–NH), 97.5 (C=C-
6
C
olefincarbon), 126.4, 128.3, 141.3, 132.3, 128.6, 128.7, 134.2,
-
1
1
36.6 Ar–C), 150.2(C=O);IR(mmax; KBr, cm ):3319, 1683,
569, 1463; ESI–MS 285 (M?H); C H ClN O ; (284.74);
1
1
6
13
2 3
Calcd. C, 67.49;H, 4.60; Cl, 12.45, N, 9.84, O, 5.62. Found. C,
Heparin at the dose of 2,000 IU/kg by I.V. route has
been administered to rats of either sex. Rats of either sex
have been anesthetized with pentothal sodium 80 mg/kg
given by intraperitoneally. Blood pressure transducer was
calibrated initially by using of mercury manometer. For
each rat, the carotid artery was cannulated and attached to
blood pressure transducer to record the initial arterial blood
pressure which will be calibrated initially by using of
mercury manometer. In the similar way on the opposite
side, the jugular vein was cannulated to administer 0.3 ml
heparinised saline for checking normal flow of fluid in the
vein then the different doses of test samples were used to
measure the effect on blood pressure by inhibition of
adrenaline response (Hiroyuki et al., 2000).
6
7.18; H, 4.24; Cl, 12.21; N, 9.32, O, 5.41.
4
2
-(4-Methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-
(1H)-one (2f)
1
Mp257–259 °C; H-NMR(400 MHz, DMSO-d ) d : 9.23(s,
6
H
1
H, NH), 8.87 (s, 1H, NH), 7.18–7.56 (m, 9H, Ar–H), 5.85 (d,
1
H, J = 5.6 Hz, C=CH), 5.26 (d, 1H, J = 5.6 Hz, CH), 3.69
1
3
(
s, 3H, OCH ); C-NMR (100 MHz, DMSO-d ) d : 51.9(C–
3
6
C
NH), 97.5 (C=C-olefin carbon), 114.1, 126.4, 127.9, 128.0,
28.7, 134.2, 135.5, 136.6, 150.2 (Ar–C), 158.6 (C=O); IR
1
-1
(mmax; KBr, cm ): 3345, 1645, 1536, 1422; ESI–MS 281
(
M?H); C H N O ; (280.32); Calcd. C, 72.84; H, 5.75, N,
17 16 2 2
9
.99; O, 11.42. Found. C, 72.53; H, 5.42; N, 9.73; O, 11.19.
Pharmacological evaluation
Calcium antagonism in the isolated rat ileum
Pharmacological evaluation is a crucial thing to ensure the
activity of the compounds. In this era, the prevalence of
heart diseases has increased to a great extent. Antihyper-
tensive agents are among the most commonly used to treat
the variety of heart diseases. Literature review revealed
that substituted dihydropyrimidine containing compounds
show different biological activities. So, the newly synthe-
sized compounds are also evaluated for their antihyper-
tensive activity and calcium channel blocking activity.
Purpose and rationale
Contraction of ileum was induced by adding potassium
chloride & calcium chloride to the organ bath containing
slightly modified Tyrode solution (NaCl = 8.0 g/l, KCl =
0.2 g/l, CaCl = 0.18 g/l, NaH PO = 0.1 g/l, MgCl =
2
2
4
2
0.1 g/l, Glucose = 1.0 g/l, NaHCO = 1.0 g/l). Test drugs
3
with calcium channel blocking activity have a relaxing
effect (Gilani et al. 2012).
Procedure
Antihypertensive activity
The adult (# or $) Wistar rats (200–310 g) were maintained
in plastic cages (47 9 34 9 18 cm ) with sawdust lining
3
Purpose and rationale
(
renewed on alternate days), kept at 23–25 °C, 60 ± 4 %
There are various in-vivo and in-vitro methods are available
for evaluation of antihypertensive activity. Antihypertensive
humidity, and 12/12 h light/dark cycles. The animals were
provided with standard diet and tap water ad libitum. The
1
23

Med Chem Res
diet constituted of mixture of the following ingredients (g):
flour (380), fiber (380), molasses (11.5), NaCl (5.8), vita-
mins mixture (2.5), potassium metabisulphate (1.2), vege-
table oil (38), fish meal (170), and powdered milk (150). All
experiments involving animals complies with the ethical
standards of animal handling and approved by Institutional
Animal Ethics Committee. Rats were divided into two
groups each group had 9 animals.
sulfonic acid, which indicated that the catalyst should be
necessary. Then, the model reaction to synthesize 1k by the
reaction of ethyl acetoacetate, benzaldehyde, and urea was
investigated with different amounts of solid silica-based
sulfonic acid (0–5 mol%). Yields of the reaction in dif-
ferent conditions are shown in Table 1.
We found that most of the Lewis acids could promote
the reaction, but the yields were not so high. In comparison
with other catalysts, the use of 3 mol% of solid silica-based
sulfonic acid could make the yield 95 % under the
microwave power of 900 W and the irradiation time of
7 min. It could be seen that 3 mol% of solid silica-based
sulfonic acid gave the best result of this reaction, although
other factors could not yet be optimized.
The assembly was being set up and arrangement was
made for experiment. The animal kept for overnight fasting
was stunned by a sharp blow on the head and sacrificed by
cutting neck blood vessels. The abdominal cavity was
quickly opened and a piece of ileum was isolated. It was
placed in a petridish containing tyroide solution maintained
at 37 °C. The mesentery of ileum was removed and the
interior contend was washed by blowing tyrode solution
Based on the above optimized results, i.e., 3 mol%
amount of solid silica-based sulfonic acid as a catalyst, we
further examined the effects of the microwave power and
the irradiation time on the same model reaction to afford
1k, as shown in Scheme 2. The results are listed in Table 2.
It could be found that with the increase of the microwave
power from 250 to 900 W, the yield of 1k showed a linear
increase from 48 % to 85 % when the irradiation time was
4 min. However, with the microwave power of 900 W,
when we increased the microwave irradiation time, the
yield of 1k increased first, but a slight decrease was
observed for more than 7 min. So, the optimized micro-
wave power and the irradiation time were 900 W and
7 min, respectively.
(
NaCl = 8.0 g/l, KCl = 0.2 g/l, CaCl = 0.18 g/l, NaH2-
2
PO = 0.1 g/l, MgCl = 0.1 g/l, Glucose = 1.0 g/l, NaH-
4
2
CO = 1.0 g/l) with help of pipette. The tissue was mounted
3
in mammalian organ bath and connected to isotonic frontal
writing lever. The tissue was allowed to stabilize for 30 min.
The responses of acetylcholine were taken till the maximum
effect was obtained. The normaltyrode solution was changed
with tyrode containing test solution. The responses of ace-
tylcholine were taken with same dose and continued till
maximum effect obtained. The percentage of relaxation from
the test-drug, precontracted level was calculated for each
concentration of test compound. An IC50 was calculated by
linear regression analysis:
The method can be used for wide range of reactants with
different functional groups. We have synthesized some
novel compounds containing methyl-substituted heteroaryl
aldehydes (Table 3) and heteroaryl ester units (Table 4).
All reactions proceeded expeditiously and delivered good
yields with broad range of structurally diverse aryl and
heteroaryl aldehydes used in this condensation. a, b-
unsaturated aldehydes react selectively with aldehyde
functional group, whereas acid sensitive heterocyclic
aldehydes exclusively gave dihydropyrimidones in high
yield. We found that electron donating or withdrawing
group on aromatic aldehydes gave almost good to excellent
yield. In all the cases, the pure product was isolated by
simple filtration without use of any chromatography or
cumbersome reaction workup.
y ¼ 96:18x þ 1:372
If y = 50 %, then x = 0.5 ml dose
IC50 of nifedipine ¼ dose for 50 % inhibition ꢁ conc:
ꢂ bath capacity ¼ ð0:5 mlÞ
ꢁ
¼
ð1; 000 lg=mlÞ ꢂ 25 ml
20 lg=ml
Results and discussion
It was showed that no desirable product could be detected
when a mixture react in the absence of solid silica-based
Scheme 2 Synthesis of 3,4-
dihydropyrimidin-2-(1H)-ones/
thiones 1 (a–n)
Ar
O
Ar
O
O
O
S
i
O
H
O
NH
SO3
H
O
Si
2
EtO
NH
NH2
EtO
MWI, Solvent-free
-7 min
6
Me
N
H
X
H N
X
Me
O
2
1(a-n)
123

Med Chem Res
Table 2 Effect of the microwave power and the irradiation time on
the formation of 1k
Table 3 Solid-silica-based sulfonic acid catalyzed synthesis of
3,4-dihydropyrimidin-2-(1H)-ones/thiones 1 (a–n)
a
a
Entry
Time (min)
Power (W)
Yields (%)
Entry Ar
X
Product Yield M.p (°C)
b
(
%)
c
Found
Reported
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
4
4
4
2
3
5
7
8
9
250
300
400
500
600
700
750
800
900
900
900
900
900
900
900
48
53
58
63
67
72
77
81
85
36
62
88
95
94
93
1
2
3
4
5
6
7
8
9
1
1
1
1
1
a
3-CH
3
3
3
3
3
–C
–C
–C
–C
–C
4
4
4
4
4
H
H
H
H
H
2
2
2
2
3
O
O
S
O
O
O
O
O
O
O
O
O
O
O
S
1a
1b
1c
1d
1e
1f
93
92
91
90
87
94
93
85
92
89
95
89
87
91
217–219
229–301
217–219
223–225
194–196
–
–
–
–
–
5-CH
3-CH
5-CH
1-CH
S
N
C
C
C
4
H
4
H
4
H
3
3
4
O
S
211–213 210–212
200–202 202–203
182–184 181–183
212–214 211–213
215–217 213–215
206–208 205–207
208–210 209–211
205–207 204–205
153–155 151–153
1g
1h
1i
N
1
1
1
1
1
1
a
0
1
2
3
4
5
4-NO
2
–C
6
H
4
0
1
2
3
4
4-Cl–C
6
H
4
1j
C
C
6
H
5
5
1k
1l
6
H
3-NO
2
–C
6
H
4
S
1m
1n
4-OCH
3
–C
6
H
4
S
Reaction conditions: benzaldehyde (2.5 mmol), ethyl acetoacetate
2.5 mmol), urea (2.5 mmol), solid silica-based sulfonic acid
3 mmol) in microwave irradiation of 900 W at 90 °C under solvent-
Reaction conditions: aldehyde (2.5 mmol), ethyl acetoacetate
2.5 mmol), urea/thiourea (2.5 mmol), solid silica-based sulfonic acid
3 mmol) in microwave irradiation 990 W at 90 °C under solvent-free
(
(
(
(
free condition
condition
b
Isolated yields
c
Products were characterized by comparison of their physical and
spectroscopic data with those reported in the literature (Atul et al.
This investigation has been extended to cyclic ketones
like acetophenone and 2-acetyl thiophene (Scheme 3). The
products formed 2(a–f) are listed in Table 4.
2
009; Hitendra et al., 2007)
With catalyst 2, the proposed mechanism for the Bigi-
nelli reaction involves the acid-catalyzed formation of an
N-acyliminium ion intermediate of the type A from alde-
hyde and urea component. Interception of the iminium ion
A by ethyl acetoacetate produces an open chain ureide B,
which subsequently cyclizes to dihydropyrimidinone
C (Scheme 4).
conditions. After completion of the reaction, the catalyst was
filtered, washed with worm ethanol, dried at 100 °C under
vacuum for 2 h, and reused for the same reaction process. As
shown in Fig. 1, the catalyst could be reused for eight times
with out reduction in the catalytic activity of the catalyst.
All the eight newly synthesized compounds 1(a–e) and
2(a–c) were screened for antihypertensive and calcium
channel blocking activity. The results are summarized in
Tables 5 and 7. Nifedipine was used as standard reference
drug (Table 6) for screening of antihypertensive and
The reusability of the catalyst was also investigated. For
this purpose, the same model reaction to synthesize the
compound 1k was again studied under the optimized
Table 4 Solid-silica-based sulfonic acid catalyzed synthesis of 4,6-diaryl-3,4-dihydropyrimidin-2(1H)-ones 2(a–f)
a
b
Yield (%)
Entry
R
Ar
Products
M.P (°C)
c
Found
Reported
1
2
3
4
5
7
a
5-CH
5-CH
1-CH
3
3
3
–C
–C
–C
4
4
4
H
H
H
2
2
3
O
C
C
C
C
C
C
4
4
4
6
6
6
H
H
H
H
H
H
3
3
3
5
5
5
S
S
S
2a
2b
2c
2d
2e
2f
90
92
86
91
87
89
223–225
241–243
227–229
234–236
264–266
257–259
–
S
–
N
–
C
H
6 5
233–235
267–269
259–261
4-(Cl)–C
6 4
H
4-(CH O)–C H
3
6 4
Reaction conditions: aldehyde (1 mmol), cyclic keto ester (1 mmol), urea/thiourea (1.5 mmol), solid silica-based sulfonic acid (3 mmol) in
microwave irradiation of 900 W at 90 °C under solvent-free condition
b
Isolated yields
c
Products were characterized by comparison of their physical and spectroscopic data with those reported in the literature (Anil et al., 2007)
1
23

Med Chem Res
Scheme 3 Synthesis of 4,6-
diaryl-3,4-dihydropyrimidin-
R
R
2
(1H)-ones 2(a–f)
O
O
O
S
i
O
H
O
NH
SO3
H
Si
2
NH
Ar
NH2
MWI, Solvent-free
Ar
N
H
X
7
min
O
CH3
H N
2
X
2(a-f)
2
Scheme 4 Proposed
mechanism for the formation of
pyrimidine derivative
O i S
O O O
Si
Ar
OH
Ar
H
H
X
H
O S NH
3
X
N
NH
2
N
NH2
SO3
-
H O
2
O
H
2
HN
Si
O
O
i O
A
S
H N
NH2
X
2
O
O
O
O
O
H
N
2
Ar-CHO
i O
HO S
Si
3
S
Me
OEt
O
Ar
O
O
Ar
O
NH
O
NH
-
H O
2
Me
X
H N
Me
N
H
X
2
C
B
(
(
C=O) of nifedipine (dihydropyridine ring). The ester
–COO–) linkage of nifedipine is similar to the test
compounds.
R
X
NO2
O
H COOC
COOCH3
3
C H O
NH
2
5
H C
N
CH3
H
3
C
N
O
3
H
H
Fig. 1 Reusability of solid silica-based sulfonic acid
X = NH, O, S
Synthesized molecule
Nifedipine
calcium channel blocking because nifedipine and test
compounds both have similar bioisosteric nucleus. In the
test samples (dihydropyrimidine ring) there are two nitro-
gen (N) atoms which are bioisosteric with (CH) and one
Compound 1c was found to have better antihypertensive
activity and compound 2a found to have better calcium
channel blocking activity.
methyl group (CH ) which is bioisosteric with ketone
3
123

Med Chem Res
Table 5 Screening of antihypertensive activity
Compound Dose Control Test
Table 7 Screening of calcium channel blocking activity
% inhibition in
blood pressure
Compound
Dose
(ml)
Control
(cm) (H)
Test
(cm) (h)
%
Inhibition
IC50
(ml) (mmHg) (H) (mmHg)
(
(lg/ml)
h)
1
1
1
1
1
2
2
2
a
b
c
0.1
3.3
3.3
3.4
3.4
3.4
3.3
3.3
3.3
3.3
3.3
3.4
3.3
3.4
3.4
3.3
3.4
3.4
3.4
3.4
3.3
3.3
3.4
3.4
3.4
3.0
2.3
1.9
3.1
2.5
2.4
3.1
2.4
1.9
3.0
2.1
2.0
3.0
2.8
1.7
2.8
2.2
1.7
2.5
2.3
1.9
3.0
2.4
2.0
9.09
Nifedipine 0.3
.3
0.3
.3
0.3
.3
0.3
.3
0.3
.3
0.3
.3
0.3
.3
0.3
.3
0.3
.3
29.17
28.34
29.17
30.00
27.50
29.17
29.17
30.00
29.17
29.17
29.17
29.17
28.34
27.50
28.34
28.34
28.34
27.50
20.00
20.84
24.17
23.34
21.67
22.50
20.00
21.67
25.00
25.84
24.17
23.84
22.50
24.17
22.50
24.17
25.00
22.50
31.44
26.46
17.14
22.20
21.20
22.87
31.44
27.77
14.30
11.16
17.14
18.27
20.61
12.10
20.61
14.71
11.79
17.14
0
.3
.5
30.30
44.12
8.82
22
0
0
1
1
1
1
1
2
2
2
a
b
c
0.1
0
0
.3
.5
26.47
27.72
6.06
36.54
21.06
22
0
0
0.1
0
.3
.5
27.27
42.43
9.09
0
0
d
e
d
e
0.1
0
0
.3
.5
38.23
41.18
11.76
17.65
48.48
17.64
35.29
50.00
26.47
30.30
42.42
11.76
29.41
41.18
0
0
0.1
a
b
c
0
.3
.5
21.10
19.76
28.99
24.26
0
0
a
b
c
0.1
0
0
.3
.5
0
0
0.1
0
.3
.5
0
0.1
0
.3
.5
Table 6 Screening of Calcium channel blocking activity of
Nifedipine
0
Compound Dose Control (cm) Test (cm)
(h)
%
IC50
Conclusion
(
ml) (H)
inhibition (lg/ml)
Nifedipine 0.1
3.4
3.4
3.4
3.3
3.3
3.3
3.0
2.7
2.3
2.1
1.7
1.2
11.76
20.58
32.35
35.29
48.48
61.76
20
In summary we have developed a simple, efficient, and
green protocol for the synthesis of dihydropyrimidinones
using solid silica-based sulfonic acid catalyst under micro-
wave irradiation in solvent-free conditions. The short reac-
tion times, simple work-up in isolation of the products in
high yields with high purity, mild reaction conditions, and
recyclability of supported catalyst are features of this new
procedure. The newly synthesized compounds 1(a–e) and
0
0
0
0
0
.2
.3
.4
.5
.6
2
(a–c) have been screened to antihypertensive and calcium
channel blocking activity. Among them, compound 1c was
found to have better antihypertensive activity and compound
2a found to have better calcium channel blocking activity.
The remaining compounds revealed moderate to good
antihypertensive and calcium channel blocking activity.
O
S
CH3
CH3
O
NH
C H O
NH
2
5
Acknowledgments The corresponding author is highly grateful to
Madhya Pradesh Council of Science & Technology for financial
support. Authors are also thankful to Deputy Director and Head,
SAIF, Central Drug Research Institute (CDRI), Lucknow for pro-
viding elemental analysis and spectral data and R. V. Sree Harsha,
N
O
H C
N
O
3
H
H
S
2a
1c
1
23

Med Chem Res
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