Biginelli reaction in aqueous medium: a greener and sustainable approach to substituted 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2007.08.031

An environmentally benign aqueous Biginelli protocol for the synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones using polystyrenesulfonic acid (PSSA) as a catalyst has been achieved. These microwave-assisted reactions proceed efficiently in water in

Full text of DOI:10.1016/j.tetlet.2007.08.031

Tetrahedron Letters 48 (2007) 7343–7346
Biginelli reaction in aqueous medium: a greener
and sustainable approach to substituted
3
,4-dihydropyrimidin-2(1H)-ones
Vivek Polshettiwar and Rajender S. Varma*
Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency,
2
6 W. Martin Luther King Dr., MS 443, Cincinnati, OH 45268, USA
Received 6 June 2007; revised 7 August 2007; accepted 7 August 2007
Available online 11 August 2007
Abstract—An environmentally benign aqueous Biginelli protocol for the synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones
using polystyrenesulfonic acid (PSSA) as a catalyst has been achieved. These microwave-assisted reactions proceed efficiently in
water in the absence of organic solvent, with simple filtration as the product isolation step.
Ó 2007 Elsevier Ltd. All rights reserved.
Green chemistry is a rapidly developing new field that
provides us a proactive avenue for the sustainable develop-
ment of future science and technologies. Green
reported the polystyrenesulfonic acid (PSSA) catalyzed
greener synthesis of 1,3-dioxanes and hydrazones
8
a
8b
1
in aqueous medium using microwave (MW) irradiation.
8
chemistry uses highly efficient and environmental benign
synthetic protocols to deliver life saving medicines,
accelerating lead optimization processes in drug discov-
ery, with reduced unnecessary environmental impact.
Green chemistry also offers enhanced chemical process
economics concomitant with a reduced environmental
burden. From this view point, it is desirable to use water
instead of organic solvents as a reaction medium, since
water is a safe, abundant and environmentally benign
In continuation of our green chemistry programme, we
decided to explore the use of polymer supported poly-
styrenesulfonic acid as a catalyst for the synthesis of
various substituted 3,4-dihydropyrimidin-2(1H)-ones
(Scheme 1) using Biginelli protocol in water.
During initial exploratory reactions, we studied the con-
densation of ethyl acetoacetate, 4-chloro benzaldehyde
and urea in water under MW irradiation, to establish
the feasibility of our strategy to 3,4-dihydropyrimidin-
2
solvent.
2(1H)-ones systems and to optimize the reaction condi-
Dihydropyrimidinones are an important class of organic
compounds, which show prominent biological activity
and are normally prepared using Biginelli reaction. A
tions (Table 1).
3
First the reaction was tested without any catalyst under
MW irradiation conditions in aqueous medium and no
reaction (NR) was observed at 80 and 100 °C. The use
large number of reports are available in the literature
4
for this protocol, including a few examples of Biginelli
5
,6
9
10
reaction in water. Very recently, Zumpe et al. used
of Lewis acid and Nafion-H afforded poor yields of
the products whereas acetic acid (AcOH) gave moderate
7
propane phosphonic acid anhydride as a catalyst.
9
,11
Although yield is good, the main concern for this proto-
col is the separation of catalyst from product that
requires column chromatography. Recently, we
yield.
However, PSSA efficiently catalyzed this
reaction and afforded high yields of the desired product
(Table 1, entry 5).
Using these optimized reaction conditions, the scope
and efficiency of this aqueous approach was explored
for the synthesis of a wide variety of substituted 3,4-
dihydropyrimidin-2(1H)-ones and results are summa-
rized in Table 2.
Keywords: Biginelli reaction; 3,4-Dihydropyrimidin-2(1H)-ones; Poly-
styrenesulfonic acid (PSSA); Aqueous medium; Microwave irradia-
tion; Greener; Sustainable.
*
Corresponding author. Tel.: +1 513 487 2701; fax: +1 513 569
677; e-mail: varma.rajender@epa.gov
7
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.031

7344
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 7343–7346
R2
O
O
O
O
X
PSSA/H O
80 C, MW
2
R1
ο
1
O
H
R O
NH
H N
2
NH2
R2
N
H
X
Scheme 1. Biginelli reaction in aqueous medium.
Table 1. Optimization of reaction conditions using MW irradiation
All the aforementioned reactions (Table 2) proceeded
expeditiously, delivered excellent product yields and
accommodated a wide range of aromatic aldehydes
bearing both, electron-donating and electron-withdraw-
ing substituents; substrates with electron-withdrawing
groups gave relatively higher yields. These three-compo-
nent condensation reactions also proceeded smoothly
with thiourea (Table 2, entries 11–15) and were complete
within 20 min. In contrast, the reaction requires 5–6 h
ref
Entry Catalyst
Solvent Temperature Reaction
Yield
(°C)
time (min) (%)
1
2
2
3
4
5
—
—
Water
Water
Water
Water
Water
Water
80
30
30
30
30
30
20
NR
NR
100
80
80
80
80
9
Ni (NTf
Nafion-H
AcOH
2
)
2
55
1
9
0
50
58
91
,11
PSSA
Table 2. PSSA catalyzed synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones in water under MW irradiation
1
2
a
Entry
R
R
X
Product
Yield (%)
References
4e,7,11,12
EtO
O
O
1
Et
Et
H
O
89
88
HN
NH
EtO
O
2
4-OCH
3
O
7,11,12
HN
O
OMe
NH
EtO
O
3
4
5
6
7
Et
4-Cl
4-F
O
O
O
O
O
91
90
88
88
89
7,11,12
HN
O
Cl
NH
EtO
O
Et
4e
HN
O
F
NH
O
OEt
O
Et
4-NO
2
4e,7
HN
O
NO2
NH
MeO
Me
Me
H
11
HN
O
NH
MeO
O
4-OCH
3
4e,12
HN
O
OMe
NH

V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 7343–7346
7345
Table 2 (continued)
1
2
a
Entry
R
R
X
O
Product
Yield (%)
References
MeO
O
O
8
Me
4-Cl
92
11
HN
Cl
F
NH
MeO
O
9
Me
Me
Et
4-F
4-NO
H
O
O
S
90
89
87
87
88
88
86
4e
HN
O
NH
O
OMe
1
1
1
1
1
1
0
1
2
3
4
5
2
4e,7
HN
O
NO2
NH
EtO
O
4e,7,12
4e,12
11,12
4e
HN
S
NH
EtO
O
Et
4-OCH
3
S
HN
S
OMe
Cl
NH
EtO
O
Et
4-Cl
S
HN
S
NH
EtO
O
Et
4-F
S
HN
S
F
NH
O
OEt
Et
4-NO
2
S
4e,12
HN
S
NO2
NH
a
1
Isolated yields. All the compounds are known in the literature and were characterized by H NMR and MS.
for completion under conventional heating condition
the observed acceleration similar to that observed in
ultrasound irradiation.
1
3b
(
oil bath). In all cases, the pure product was isolated
by simple filtration, without any chromatography or
cumbersome workup procedure.
Thus, we have demonstrated an elegant protocol for the
synthesis of substituted 3,4-dihydropyrimidin-2(1H)-
ones using PSSA, which proceeds efficiently in water
without use of organic solvent, under microwave irradi-
ation. Also the use of polymer supported, low toxic
and inexpensive PSSA as a catalyst renders this method
eco-friendly, with a very simple isolation procedure that
entails the filtration of the precipitated products.
It is noteworthy to mention that these reactions are
working well in an aqueous medium without using any
phase-transfer catalyst (PTC). This may be due to selec-
tive absorption of microwaves by polar molecules and
intermediates in a multiphase system, which could sub-
1
4
1
3a
stitute as a phase transfer catalyst, thereby providing

7346
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 7343–7346
7. Zumpe, F. L.; Fluß, M.; Schmitz, K.; Lender, A.
Acknowledgement
Tetrahedron Lett. 2007, 48, 1421.
8
. (a) Polshettiwar, V.; Varma, R. S. J. Org. Chem. 2007, 72,
doi:10.1021/jo701337j; (b) Polshettiwar, V.; Varma, R. S.
Tetrahedron Lett. 2007, 48, 5649; (c) Ju, Y.; Kumar, D.;
Varma, R. S. J. Org. Chem. 2006, 71, 6697; (d) Ju, Y.;
Varma, R. S. J. Org. Chem. 2006, 71, 135; (e) Ju, Y.;
Varma, R. S. Org. Lett. 2005, 7, 2409; (f) Wei, W.; Keh, C.
C. K.; Li, C.-J.; Varma, R. S. Clean Technol. Environ.
Policy 2005, 7, 62; (g) Kumar, D.; Chandra Sekhar, K. V.
G.; Dhillon, H.; Rao, V. S.; Varma, R. S. Green Chem.
V.P. is a postgraduate research participant at the Sus-
tainable Technology Division, National Risk Manage-
ment Research Laboratory administered by the Oak
Ridge Institute for Science and Education.
References and notes
2
004, 6, 156; (h) Yang, X.-F.; Wang, M.; Varma, R. S.; Li,
1
. (a) Varma, R. S. In Green Chemistry: Challenging
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Warner, J. C. Green Chemistry: Theory and Practice;
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14. Typical experimental procedure: The alkylacetoacetate
(1 mmol), aldehyde (1 mmol) and urea/thiourea
(1.2 mmol) were taken in a 10 mL crimp-sealed thick-
walled glass tube equipped with a pressure sensor and a
magnetic stirrer, and were dissolved in 20% PSSA solution
in water (three times the weight of aldehyde). The reaction
tube was then placed inside the cavity of a CEM Discover
focused microwave synthesis system, operated at
80 ± 5 °C (temperature monitored by a built-in infrared
sensor), power 40–100 W and pressure 20–30 psi for
20 min. After completion of reaction, products were
isolated with simple filtration (few ml of water was added
to facilitate easy filtration) and recrystallized to afford
pure 3,4-dihydropyrimidin-2(1H)-ones.
3
4
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