Synthesis of dihydropyrimidinones via Biginelli multi-component reaction

Article abstract of DOI:10.1016/j.tetlet.2011.12.134

Five percentage perchloric acid doped silica is successfully used as an efficient mild catalyst for the synthesis of 4-aryl dihydropyrimidine-2(1H)- ones. This method offers significant advantages such as efficiency and mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2011.12.134

Tetrahedron Letters 53 (2012) 1543–1545
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Synthesis of dihydropyrimidinones via Biginelli multi-component reaction
Srinivasa Reddy Narahari a,b, , Buchi Reddy Reguri a, Omprakash Gudaparthi a, K. Mukkanti b
⇑
a Inogent Laboratories Private Ltd, Ranga Reddy District, Hyderabad 500 062, India
b J.N.T. University, Kukatpally, Hyderabad 500 072, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2011
Revised 19 December 2011
Accepted 22 December 2011
Available online 12 January 2012
Five percentage perchloric acid doped silica is successfully used as an efficient mild catalyst for the syn-
thesis of 4-aryl dihydropyrimidine-2(1H)-ones. This method offers significant advantages such as effi-
ciency and mild reaction conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
HClO4 doped silica
MCR
Dihydropyrimidinones
Biginelli multi-component reaction is a convenient method for
the synthesis of 4-aryl-1,4-dihydropyridinones, whichare an impor-
tant class of bio-active compounds due to their therapeutic and
pharmaceutical properties. They possess a broad spectrum of
pharmacological activities such as antiviral,1 antiinflammatory,2
O2N
x
RO2C
Me
E
Z
i-PrO2C
CONH2
O
N
N
N
H
1
Me
N
H
2
antibacterial,3
anticarcinogenic,4
antihypertensive,5
a1-1a-
antagonists, neuropeptide Y (NPY) antagonist,6 and calcium channel
blockers (Fig 1).7 Moreover this motif also is a key component in
natural marine alkaloid batzelladine A and B, ptilocaulin, and
saxitoxin which are inhibitors for the binding of HIV gp-120 to
CD4 cells for the treatment of AIDS.8 DHPMs-1 is a precursor in the
synthesis of pyrimidine bases,9 the basic skeleton of nucleic acid.
Few of the marketed antihypertensive drugs such as SQ 32.926, SQ
32.547 (Fig 1) were already synthesized via the Biginelli multi-
component reaction.5
R= alkyl, Z=O, S
X= 2/3-NO2, 2-CF3
E= ester, acyl, amide
SQ 32.926
Figure 1. 4-Aryl-1,4-dihydropyridinones.
Lewis acid catalysts such as BF3ÁOEt,11 CoCl2Á6H2O,12 FeCl3Á6H2O
NiCl2Á6H2O,13 In (III) halides,14 SnCl2Á2H2O,15 LaCl3Á7H2O,16
CeCl3Á7H2O,17 ZrCl4,18 metal triflates such as Zn(OTf)2,19 Cu(OTf)2,20
Our objective is to achieve valuable dihydropyrimidinones
(DHPMs) moieties through the Biginelli MCR using a novel acid
catalyst, which should be eco friendly and can be applicable to
the large scale preparation. Reactions on solid surface are gaining
much interest of organic chemists due to the fact that it is easy
to carry out the reaction, simple work-up, environmentally
friendly, and the solid support can be recycled.
We have successfully synthesized 4-aryal dihydropyrimidine-
2(1H)-ones (DHPMs-1) through the Biginelli multi-component syn-
thesis protocol10 by using an aromatic aldehyde, urea/thiourea and
b-ketoester in the presence of 5% perchloric acid doped silica as a
mild acid catalyst. Various synthetic methods have been used to
catalyze the Biginelli reaction, some of them the include use of
Bi(OTf)2,21 Yb(OTf)2 and La(OTf)2,23 ionic liquids,24 TMSI,25 solid
22
phase,26 polymer support,27 Li salts,28 heterogeneous catalysis by
SiO2,29 ultrasound,30 and microwave.31 Most of these available pro-
tocols suffer from harsh reaction conditions and longer reaction
times. Hence, there is scope for exploration of synthetic methodol-
ogy to achieve experimental simplicity and effectiveness.
Recently, HClO4 doped silica was employed as a mild and effi-
cient catalyst in Ferrier reaction33 and in the protection of phenol,
thiols, alcohols effectively.34 To the best of our knowledge this cat-
alyst has not been reported to promote the Biginelli reaction.
Herein, we report for the first time a simple, economical and
efficient synthesis of DHPMs through the Biginelli three-
component condensation mediated by perchloric acid doped silica
as a mild acid catalyst (Scheme 1).
Substituted tetrahydro-1H-benzo[h]quinazolin-2-thione/qui-
nazolin-2-one is prepared by the reaction of urea, aldehyde, and
⇑
Corresponding author.
E-mail address: naraharisree@gmail.com (S.R. Narahari).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.134

1544
S. R. Narahari et al. / Tetrahedron Letters 53 (2012) 1543–1545
Table 2
R
The products obtained through the Biginelli type reaction of 6-methoxy-1-tetralone
O
Entry
R
X
Time (h)
Yield %
Product
R2O2C
R1
X
R2O
HClO4-SiO2
NH
1
2
3
–CH3
–OCH3
–CH3
O
O
S
3
3
3
40
38
36
6a
6b
6c
+
R-Ar
+
H2N
CHO
NH2
R1
O
N
H
X
3
4(a-l)
2
1
X= O or S
Scheme 1. Preparation of dihydropyrimidinones through the Biginelli
condensation.
evaporation. The crude products were further purified by
re-crystallization from ethanol. These reaction conditions are mild
enough to tolerate sensitive functionalities such as Cl, NO2, OH,
OMe, and heterocyclic moieties. Cyclic ketones like tetralones also
worked well under these conditions to give the Biginelli type prod-
uct (6a–c) (Table 2). The recovered absorbed silica gel can be recy-
cled at least two times without fall in the yield. On carrying out the
reaction in the presence of perchloric acid (0.2–0.3 mL) in refluxing
alcohol for the same period of time (3 h), only trace of the product
could be isolated, thereby clearly showing the facilitation of the
reaction on the solid surface.
X
O
X
HN
NH
R
H2N
NH2
MeO
HClO4-SiO2
+
MeO
2
5
CHO
6a-c
X= O or S
In conclusion we have developed a new one-pot procedure for
synthesis of DHPMs by using solvent-free, environmentally
friendly HClO4 absorbed SiO2 as solid support. The low cost, ease
of handling makes the catalyst useful in industrial applications.
Furthermore this present protocol is readily applicable to parallel
synthesis and the generation of combinatorial DHPM’s libraries.
R
3
Scheme 2. MCR synthesis of tetrahydro-1H-benzo[h]quinazolin-2-thione/
quinazolin 2-one.
Table 1
Acknowledgments
Products obtained through the Biginelli reaction with variation of aldehydes and
b-keto ester
S.R.N., B.R.R. and G.O. thank Inogent Laboratories Private Ltd
Hyderabad, S.R.N. and M.K. thank J.N.T. University, Hyderabad.
Entry R-Ar
1
R1
R2
X
O
O
S
Time (h) Yield % Product
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
1.5
1.25
1.5
3
89
91
87
80
84
4a
References and notes
2
3
4
5
4b32a
4c
Cl
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12
CH3 C2H5
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O
1.5
1.5
83
89
4k
4l
S
O
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(Scheme 2).
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simply by extraction with appropriate solvent and filtration and

S. R. Narahari et al. / Tetrahedron Letters 53 (2012) 1543–1545
1545
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solid. (0.255 g, 91%). mp 204–206 °C. IR (Potassium bromide): 1659, 1702,
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.
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1H, NH). 13C NMR (DMSO-d6): d = 165.7, 152.0, 149.0, 143.6, 131.8, 128.4,
128.1, 98.6, 53.4, 50.8, 17.8. MS-FAB m/z: 281[M+H]+. Anal. Calcd for
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155 °C. IR (Potassium bromide): 1583, 1613, 1651, 1710, 2928, 3280,
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.
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5.05 (s, 1H), 6.62(d, J = 9.1 Hz, 2H), 7.0 (d, J = 9.1 Hz, 2H), 9.52 (s, 1H, NH), 10.21
(s, 1H, NH). 13C NMR (DMSO-d6): d = 173.8, 165.7, 149.9, 144.6, 131.0, 127.1,
112.2, 100.9, 53.4, 51.0, 40.1, 17.1. MS-FAB m/z: 290 [M+H]+. Anal. Calcd for
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8-Methoxy-4-p-tolyl-3,4,5,6-tetrahydro-1H-benzo[h]quinazolin-2-thione (6c).
This compound was obtained as a brown solid. (0.120 g, 36%). mp 206–208 °C.
IR (Potassium bromide): 1217, 1644, 1708, 1740, 2358, 3204, 3022, cmÀ1 1H
.
NMR (DMSO-d6): d = 2.0 (m, 2H), 2.28 (s, 3H), 2.60 (m, 2H), 3.75 (s, 3H), 4.95
(s,1H), 6.78 (m, 2H), 7.20 (m, 4H), 7.64 (d, 1H), 9.0 (s, 1H, NH), 9.62 (s, 1H, NH).
13C NMR (DMSO-d6): d = 174.0, 158.8, 140.1, 137.4, 137.0, 129.1, 126.9, 126.4,
123.0, 120.6, 113.9, 110.7, 108.5, 58.2, 55.1, 27.7, 23.5, 20.7. MS-FAB m/z: 337
[M+H]+. Anal. Calcd for C20H20N2OS: C, 71.40; H, 5.99; N, 8.33; O, 4.76; S, 9.53;
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4-(4-Chloro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-
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