A one pot green synthesis of 3,4 dihydropyrimidin-2-(1H)-ones/thiones catalyzed by MgO-ZrO2 under solvent-free conditions

Article abstract of DOI:10.2174/157017812799303980

An efficient green synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones (DHPMs) using MgO/ZrO₂ as heterogeneous basic catalyst from an aldehyde, β-keto ester and urea/thiourea under solvent-free conditions is described. A variety of aldehydes

Full text of DOI:10.2174/157017812799303980

1
2
Letters in Organic Chemistry, 2012, 9, 12-18
A One Pot Green Synthesis of 3,4 Dihydropyrimidin-2-(1H)-ones/Thiones
Catalyzed By MgO-ZrO Under Solvent-Free Conditions
2
,a
b
c
Manoj B. Gawande* , Deepak M. Nagrik and Damodar M. Ambhore
a
Departamento de Química, Faculdade de Ciências and Tecnologia, New University of Lisbon, Quinta da Torre,
2
829-516 Caparica, Lisbon, Portugal
b
Department of Applied Chemistry, Pankaj Laddhad Institute of Technology and Management Studies, Buldana, M.S.
India-443001
c
Department of Chemistry, Jijamata Mahavidyalaya, Buldhana, Amravati University Amravati, M.S. India-443001
Received March 21, 2011: Revised August 01, 2011: Accepted September 30, 2011
2
Abstract: An efficient green synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones (DHPMs) using MgO/ZrO as
heterogeneous basic catalyst from an aldehyde, ꢀ-keto ester and urea/thiourea under solvent-free conditions is described.
A variety of aldehydes were studied with ꢀ-keto ester and urea/thiourea giving good to excellent yield of corresponding
3
,4-dihydropyrimidin-2-(1H)-ones/thiones. This protocol has advantage of excellent yield, reusability, inexpensive and
short reaction time at room temperature. The synthesized catalyst can be reused up to 5 consecutive cycles without any
decrease in the yield.
Keywords: DHPMs, green synthesis, multicomponent reactions (MCR
s
2
), MgO-ZrO .
INTRODUCTION
Ar
Ar
E
E
A multicomponent reaction (MCR) is defined as an event
in which three or more different starting materials that react
to form a product, where most, if not all of the atoms are
incorporated in the final product. This reaction tool allows
compounds to be synthesized in a few steps and usually in
E
NH
R'
N
H
R'
R'
N
H
X
one-pot operation. The multicomponent reactions (MCR
define the new horizons towards the development of organic
synthesis. Obviously, due to this reason MCR are
s
)
1.DHPM
2.DHP
E = Ester,Amide,Acyl
R',R"= Alkyl
s
underlined as important routes and protocols in organic
synthesis and medicinal chemistry [1]. The diversity,
efficiency and rapid access to small and highly
functionalized organic molecules are few features of
multicomponent reactions. These features attract the
researchers to construct the combinatorial libraries and
thoroughly study the drug discovery process [2]. Now-a-
days, these aspects become approach of central current
interest for the development of organic synthesis and drug
discovery through multicomponent reactions. The attempt
was made by an Italian chemist Pietro Biginelli in 1893 to
synthesize Dihydropyrimidinones (DHPMs) through
multicomponent reactions [3].
X = O,S
Ar =Substituted Aryl
Fig. (1). Structural comparison of Biginelli dihydropyrimidinones
(1. DHPMs) and Hantzsh dihydropyrimidines (2. DHPs).
The dihydropyrimidine core unit containing alkaloids
exhibiting interesting biological properties have been
isolated from marine source [6-8]. From these isolated
moieties, few were found to be potent HIV gp-120-CD4
inhibitors such as the crambine [6] and batzelladine alkaloids
[7]. The 4-(3-hydroxy-phenyl)-2-thione derivative i.e.
monastol [9] has increased the scope of this pharmacophore.
The main function of pharmacophore is for permeable lead
molecule to the development of anticancer drugs.
The biological activities of DHPMs and DHPs are always
compared due to the structural analogy exist between them.
Recent interest in dihydropyrimidinones has increased
rapidly mainly due to apparent structural similarity to the
well known dihydropyrimidine calcium channel modulators
of the Hantzsh type [4, 5] (DHP) Fig. (1):
Also, the dihydropyrimidinones exhibit wide range of
biological activities such as antibacterial, antiviral,
antitumor, and anti-inflammatory actions [10]. Due to its
interesting and important biological activities, scientist
attracts towards synthetic evaluation of Biginelli compounds.
Infacted, the classical protocols often suffers from low yields
practically, especially in case of aliphatic and some aromatic
aldehydes [11-13]. Even though, high yields could be
achieved by following complex multistep procedures [14-
16]. But these methods are having several drawbacks.
*
Address correspondence to this author at the Departamento de Química,
Faculdade de Ciências and Tecnologia, New University of Lisbon, Quinta
da Torre, 2829-516 Caparica, Portugal; Tel: 00351-964223243;
0
0351(212948550);
E-mail: mbgawande@yahoo.co.in, manoj.gawande@dq.fct.unl.pt
1
875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

A One Pot Green Synthesis of 3,4 Dihydropyrimidin-2-(1H)-ones/Thiones
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
13
O
Ar
O
O
O
X
o
MgO/ZrO , 25 C
+
2
R
NH
+
Ar
H
R
Me
H N
2
NH2
Solvent free
Me
N
H
X
(1)
(2)
(3)
(4)
R=OEt
X=O,S
Scheme 1. Biginelli synthesis by using several aromatic aldehydes with ꢀ-keto ester and urea/thiourea over MgO/ZrO
2
under catalyst-free
conditions.
Table 1. Biginelli Reaction of Aromatic Aldehydes, ꢀ-keto Ester and Urea/Thiourea Catalyzed by MgO/ZrO
2
Solid Base*
o
Melting point( C)
No.
Product
Time (Min.)
Isolated Yield (%)
Observed
Reported
O
0
1
30
93
205
206[34]
EtO
NH
Me
N
O
H
OMe
NH
O
0
2
30
30
30
30
68
73
91
92
257
255-257[28]
259-260[34]
209-212[34]
213-214[27]
EtO
Me
N
O
H
OMe
O
0
0
0
3
4
5
203
220
214
EtO
NH
Me
N
H
O
Cl
NH
O
EtO
Me
N
H
O
Cl
O
EtO
NH
Me
N
H
O

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4
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
Gawande et al.
(
Table 1). Contd…..
No.
o
Melting point( C)
Product
Time (Min.)
Isolated Yield (%)
Observed
Reported
NO2
O
0
6
20
93
224
222-225[27]
EtO
NH
Me
N
H
O
NO2
O
0
7
20
92
207
206-207[27]
EtO
NH
Me
N
H
O
OH
O
0
0
1
8
9
0
20
30
30
94
87
83
230
208
214
230-231[27]
208-209[28]
216-217[28]
EtO
NH
Me
N
H
O
CH3
O
EtO
NH
Me
N
O
H
CH3
O
EtO
NH
Me
N
H
O
Cl
O
1
1
30
78
207
199-200[29]
EtO
NH
Me
N
H
S

A One Pot Green Synthesis of 3,4 Dihydropyrimidin-2-(1H)-ones/Thiones
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
15
(
Table 1). Contd…..
o
Melting point( C)
No.
Product
Time (Min.)
Isolated Yield (%)
Observed
Reported
NO2
O
1
2
30
87
206
203-205[34]
EtO
NH
Me
N
H
S
O
1
3
50
93
212
209-211[34]
EtO
NH
Me
N
S
H
CH3
O
1
4
90
87
189
192-194[28]
EtO
NH
Me
N
S
H
o
*
Reaction conditions: aldehyde = 10 mmol, urea/thiourea=15 mmol, ꢀ-keto-ester =10 mmol, catalyst = 20 wt. % with respect to aldehyde, solvent free, temp. = 25 C. All compounds
are well characterized by spectroscopic techniques.
Therefore, it is essential to synthesize DHPMs via simple
and milder methodology.
wastes and future resources, particularly from the view point
of green chemistry.
In continuation of our research in heterogeneous catalyst
In similar line, herewith, we have reported novel and
mild multicomponent reaction of various aromatic
aldehydes, urea/thiourea and ꢀ-keto-ester for the synthesis of
[
2
17-21], green organic chemistry and its applications [22,
3]. Previously, we have reported MgO-ZrO
2
,
a
heterogeneous basic catalyst for knoevenagel condensation
and some important organic reactions [24, 25] and synthesis
of ꢀ-amino carbonyl compounds [26].
2
dihydropyrimidinones using reusable MgO/ZrO catalyst
under solvent-free conditions (Scheme 1).
2
To check the activity of MgO-ZrO for the synthesis of
In recent years, several synthetic procedures for
preparation of DHPMs have been reported including
classical conditions by using promoters such as
chlorosulfonic acids [27], triphenyl phosphine [28], alumina-
supported trifluromethane sulfonic acid [29], chloro-
trimethyl silane [30], mesoporous silica catalyst [31], ꢀ-
dihydropyrimidinones, we have studied the model reaction
with 4-hydroxy benzaldehyde, urea and ethylacetoacetate
under solvent-free conditions and 20 wt % of MgO-ZrO
2
catalyst. This model reaction was completed within 20 min.
under solvent-free conditions to yield a corresponding
product in 94 % of yield. After getting a good result, we
have explored the catalyst activity for other important
substrates, depicted in Table 1.
aminobutyric acid [32], SiO
2 2 4
-H SO [33] and other reagents
have been found to be effective.
Many of these methods involve expensive reagents,
stoichiometric amount of catalyst, strongly acidic conditions,
long reaction time, unsatisfactory yields and incompatibility
with other functional groups and difficult product isolation
procedures. Therefore, there is still a need for the
development of neutral alternative for simple and general
procedure to synthesize dihydropyrimidinones and thiones
under mild conditions.
The aromatic aldehydes with electron-withdrawing or
electrondonating groups in the ortho,meta and para positions
give high yields for the corresponding products. One of the
important features of this procedure is compatibility of
various functional groups such as methyl, methoxy,
hydroxyl, chloride, nitro, etc. under the given reaction
conditions. Thiourea was used successfully to yield
respective 3, 4-dihydropyrimidin-2(1H)-thiones which also
acts as biologically active compound.
Solvent-free organic synthesis has received considerable
attention due to growing worldwide concerns over chemical
The role of component and mixed oxides for the
synthesis of biginelli products were carried out. The result of

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6
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
Gawande et al.
component oxides and mixed oxides is depicted in Table 2.
For this study the reactions 4-hydroxybenzaldehyde, urea
and ethyl acetate were chosen as model reaction.
Therefore, we carried out further study with 20 wt % of
catalyst.
The catalytic efficiency of MgO-ZrO
with other methodology reported for biginelli reactions. The
MgO-ZrO mixed metal oxides have advantage over some
2
catalyst compared
2
MgO-ZrO mixed oxides have good activity (Table 2,
entry 3) compared to component oxides. (Table 2, entry 1
2
and 2).
reported methods depicted in Table 4.
Table 2. Influence of Component and Mixed Oxides
The Representative Data of Few Compounds
Entry
catalyst
Isolated Yield (%)
5
-Ethoxycarbonyl-4-phenyl-6-methyl-3,4-dihydropyri-
1
2
3
MgO
55
20
94
midin-2-(1H)-one (Table 1, Entry 1)
o
ZrO
2
White solid, obtained in 93 % yield, Mp: 205 C, IR
(
1
KBr) ꢀmax : 3242, 3117, 2980, 1721, 1637, 1522, 1462,
288, 1092, 770 cm . H NMR (DMSO-d ): ꢀ=9.18 (s, 1H,
6
MgO-ZrO
2
-
1 1
Reaction conditions: 4-hydroxybenzaldehyde =10 mmol, urea =15 mmol,
ethylacetoacetate =10 mmol, catalyst = 20 wt. % with respect to aldehyde, solvent free,
Temp. = 25 C, Time = 20 min.
NH), 7.74 (s, 1H, NH), 7.22 (m, 5H arom), 5.14(d, 1H, J=3.6
Hz, H-4), 3.40 (q, 2H, J=6.9 Hz, OCH ), 2.24 (s, 3H, CH ),
o
2
3
1
.09 (t, 3H, J=6.9 Hz, CH
3
). Mass (ES/MS): m/z 259 (M-H).
Reusability of MgO-ZrO
2
5
- Ethoxycarbonyl -4-(2-methoxyphenly)-6-methly-3, 4-
dihydropyrimidin -2 (IH)-one (Table 1 Entry 2)
Reusability of catalyst was tested with the reactions 4-
hydroxybenzaldehyde, urea and ethyl acetate as starting
o
White solid, obtained in 68 % yield, Mp: 257 C. IR
materials under solvent-free conditions over MgO-ZrO
2
.
-1
(
KBr) ꢀmax: 3240, 3174, 2960, 1693, 1643, 1514, 1462 cm .
After each cycle, the catalyst was filtered off, washed with
1
H
NMR (DMSO-d
.31(s,1H,NH),7.24 ( m,1H,CH ), 7.05(d,1H, J= 6.2 Hz,CH),
.99 (d,1H,J=8.2 Hz,CH), 6.88(m,1H, CH), 5.49 (d,1H, 3=
.9 Hz CH), 3.92 (q, 2H, J=7.1 HzOCH ), 3.94
), 2.28(s,3H,CH ), 1.03 (t, 3H, J = 7.1Hz, CH ).
Mass (ES/MS): M/Z 290 (M-H).
6
):
ꢀ
=
9.14 (s,1H, NH ),
o
acetone and ether successively, dried at 60 C, under vacuum
7
6
2
for 3 h and then used for successive cycles. The catalyst
activity of MgO-ZrO
87 %) Fig. (2).
2
slightly decreased after fifth cycle (94
,
2
–
(
s,3H,OCH
3
3
3
Catalyst Loading Study of Catalyst MgO-ZrO
2
In conclusion, the present work offers an efficient and
improved modification of classical Biginelli reaction. Mild
reaction conditions, easy work up, high yields, stability and
recyclability of catalyst are characteristics of this protocol.
Also, this protocol sustain with respect to different
substituents of aldehydes. The results are reproducible and
reaction can be performed at micro level.
For the catalyst loading study, we chose model reactions
of 4-hydroxy-benzaldehyde, urea and ethylacetoacetate
under solvent-free conditions. We have studied various
catalysts loadings for the model reaction. The wt % of MgO-
ZrO
2
is depicted in Table 3. The 20 wt % of catalyst gave
excellent yield as compared to 5, 10 and 15 wt % of catalyst.
1
00
9
8
7
6
0
0
0
0
Yield (%)
50
4
3
2
1
0
0
0
0
0
1
2
3
4
5
No of cycle
2
Fig. (2). Reusability of MgO-ZrO with respect to reaction of 4-hydroxybenzaldehyde with ethylacetoacetate and urea.
Reaction conditions: 4-hydroxybenzaldehyde = 10 mole, urea =15 mmol, ethylacetoacetate =10 mmol, Catalyst = 20 wt. % with respect to
o
aldehydes, solvent-free, Time = 20 min, Temp. = 25 C.

A One Pot Green Synthesis of 3,4 Dihydropyrimidin-2-(1H)-ones/Thiones
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
17
as
Table 3. Reaction of 4-hydroxy-benzaldehyde, Urea and Ethylacetoacetate in the Presence of Various wt % of MgO-ZrO
Catalyst with Respect to 4-hydroxy-benzaldehyde
2
No.
Wt. % of MgO-ZrO
2
Isolated Yield %
0
0
0
0
1
2
3
4
5
40
57
60
94
10
15
20
o
Reaction conditions: 4-hydroxy-benzaldehyde=10 mmol, urea = 15 mmol, ethylacetoacetate =10 mmol, solvent free, Temp. = 25 C, Time = 20 min.
Table 4. Comparison of MgO-ZrO
Ethylacetoacetate
2
Catalyst with other Reported Catalysts for the Reaction of 4-hydroxybenzaldehyde, Urea and
No.
Catalyst
Time (Min./h)
Yield %
0
0
0
0
0
0
0
0
1
2
3
4
5
6
7
8
MgO/ZrO
2
20 min
5 h
93
Cu(NH
Ph
2
SO
3
)
2
79 [37]
70[28]
84[35]
68[36]
92[38]
82[39]
91[40]
3
P
10 h
12 h
1 h
[Hmim]OTs
Alumina sulphuric acid(ASA)
Yttrium acetate hydrate
3.5 h
40 min
17 h
TaBr
5
Phenyl boronic acid
EXPERIMENTAL
ammonia solution was added dropwise with vigorous stirring
until the precipitation was complete (pH = 10.0). The
obtained solution was filtered and washed with distilled
water till free from ammonium nitrate and chloride ions. The
residue was dried for 24 h at 85 C in an oven and further
calcined at 873 K for 6 h, in a closed muffle furnace in air
atmosphere.
All commercially available chemicals and reagents were
purchased from Aldrich and used without further
purification. IR spectra were recorded on a Perkin-Elmer
o
1
13
1
640 FT-IR instrument. The H- and C-NMR spectra were
recorded on a Bruker DPX-300 NMR machine. Unless
otherwise specified, CDCl was used as solvent. Mass
spectra were recorded with a Bruker Daltonic Data Analysis
.0 spectrometer.
3
2
ACKNOWLEDGEMENT
DMN is thankful to Head, Department of Chemistry,
JMVB, Buldhana, India for providing necessary laboratory
facilities and also grateful to his mother for constant
inspiration and moral support.
Typical Experimental Procedure
In a typical synthesis of dihydropyrimidinones, a mixture
of ꢀ-keto ester (10 mmol), aldehydes (10 mmol),
urea/thiourea (15 mmol) and 20 wt. % of MgO-ZrO
2
catalyst
(
with respect to aldehyde) were added to 25 mL flat bottom
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sintered crucible and washed with acetone and ether
successively, and reused for the next cycle. The crude
products were obtained by recrystallization by using ethanol.
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