Microwave assisted solvent-free one pot biginelli synthesis of dihydropyrimidinone compounds on melamine-formaldehyde as a solid support

Article abstract of DOI:10.14233/ajchem.2013.14209

An effective one-pot synthesis of dihydropyrimidinonoes using Melamine-formaldehyde resin supported H+ (MFRH) as an inexpensive and readily available reagent through Biginelli condensation reaction of aldehyde, 1,3-dicarbonyl compounds and (thio)urea in c

Full text of DOI:10.14233/ajchem.2013.14209

Asian Journal of Chemistry; Vol. 25, No. 8 (2013), 4588-4590
http://dx.doi.org/10.14233/ajchem.2013.14209
Microwave Assisted Solvent-Free One Pot Biginelli Synthesis of Dihydropyrimidinone
Compounds on Melamine-Formaldehyde as a Solid Support
1
,*
2
1
RAMIN REZAEI , MOHAMMAD KAZEM MOHAMMADI and ADIBA KHALEDI
1
2
Department of Chemistry, Firoozabad Branch, Islamic Azad University, P.O. Box 74715-117, Firoozabad, Iran
Faculty of Science, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
*
Corresponding author: E-mail: rezaieramin@yahoo.com
Received: 18 June 2012;
(
Accepted: 18 February 2013)
AJC-13018
+
An effective one-pot synthesis of dihydropyrimidinonoes using Melamine-formaldehyde resin supported H (MFRH) as an inexpensive
and readily available reagent through Biginelli condensation reaction of aldehyde, 1,3-dicarbonyl compounds and (thio)urea in conventional
and under microwave irradiation conditions is described. Excellent yields, short reaction times for formation of the products and simple
work-up are attractive features of this green protocol.
Key Words: Biginelli reaction, Dihydropyrimidinones, Melamine-formaldehyde resin, One-pot, Solvent-free.
The synthesis of this important heterocyclic nucleus
reported by Biginelli in 1893, involved a one pot condensation
of ethyl acetoacetate, benzaldehyde and urea under strong
acidic conditions. However, one serious drawback of the
Biginelli reaction is low yields in the case of substituted
INTRODUCTION
The main benefits of performing reactions under micro-
wave irradiation conditions are the significant rate enhance-
ments and the higher product yields that can frequently be
observed. These features have recently attracted interest from
the drug discovery and medicinal chemistry communities, for
7
aromatic and aliphatic aldehydes . This has led to the develop-
ment of multistep strategies resulting in marginally improved
8
yields . However, the multistep methods lack the simplicity
1,2
which reaction speed is of great importance . The combination
of microwave and combinatorial chemistry applications there-
fore seems a logical consequence of the increased speed and
effectiveness offered by using microwave irradiation instead
of conventional methods.
of the one-pot, one-step procedure. Consequently, the Biginelli
reaction for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones
has attracted renewed attention and many improved procedures
have been reported. In recent years several methods for the
synthesis of 3,4-dihydropyrimidin-2-(1H)-ones have been
developed to improve and modify this reaction by means of
In recent years, 3,4-dihydropyrimidin-2-(1H)-ones
DHPMs) and their derivatives have attracted considerable
(
interest because of their therapeutic and pharmacological
3
properties . They have emerged as integral backbones of
9
10
11
microwave irradiation , ultrasound irradiation , ionic liquids ,
12
Lewis and protic acid promoters such as lanthanide triflate,
several channel blockers, antihypertensive agents, α-1a
4
antagonists and neuropeptide Y (NPY) antagonists . More-
13
14
15
16
17
H
3
BO
3
, VCl , V(HSO
3
4
3 2 3
) , Sr(OTf) , PPh , indium(III)
18
halides , KAl(SO
20
acid, Mn(OAc)
19
O supported on silica, silicasulfuric
21
O, Y(NO
4 2
) ·12H
2
over several alkaloids containing the 3,4-dihydropyrimidin-
2-(1H)-one unit have been isolated from marine sources, which
22
23
24
3
·2H
2
3
)
3
·6H
26
2
3 5
O, In(OTf) , TaBr ,
25
27
3 3 2
Ce(NO ) ·6H O, silica chloride, HCOOH, 1,3-dichloro-
28
,5-dimethylhydantion , etc. However, many of these methods
5
also exhibit interesting biological properties . The scope of
this pharmacophore has been further increased by the identi-
fication of the 4-(3-hydroxyphenyl)-2-thione derivative called
5
involve expensive reagents, long reaction times, strongly acidic
conditions and stoichiometric amount of catalysts and difficult
to handle especially on a large scale. Therefore, to avoid these
limitations, the introduction of a milder and more efficiently
methods accompanied with higher yields are needed.
6
monastrol , as a novel cell-permeable lead compound for the
development of new anticancer drugs bearing the dihydro-
pyrimidinone core. Thus the development of facile and
environmentally friendly synthetic methods towards dihydro-
pyrimidinones constitutes an active area of investigation in
organic synthesis.
In connection with our previous work on melamine-form-
29a,b
+
aldehyde resin supported H (MFRH) as a catalyst, we wish
to report the results obtained from a study of the preparation

Vol. 25, No. 8 (2013)
Synthesis of Dihydropyrimidinone Compounds on Melamine-Formaldehyde 4589
TABLE-1
MFRH-CATALYZED ONE-POT SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2(1H)-ONES/THIONES
a
b
Method A
Method B
m.p. (ºC)
Reported [7-26]
Entry
R1
R2
R3
X
c
c
Time (min)
15
Yield (%)
90
Time (s)
90
Yield (%)
Found
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
H
O
O
O
O
O
O
O
O
O
O
S
92
200-202
199-201
212-214
208-210
205-207
230-232
235-237
221-223
213-215
204-206
204-206
138-140
183-185
228-230
175-177
198-200
228-230
154-156
202-204
233-235
201-203
202-204
216-217
212-214
207-210
231-233
234-236
226-228
216-218
208-210
205-207
140-142
184-186
233-236
178-180
203-204
229-231
157-159
208-210
235-237
p-OCH3
p-CH3
20
85
120
90
88
15
90
85
p-Cl
15
80
120
180
120
120
120
120
120
120
120
120
180
180
180
180
180
120
90
90
p-NO2
20
78
86
p-OH
15
90
90
C H CH=CH
2
20
78
70
6
5
m-NO2
o-Cl
o-CH3
H
20
82
85
15
77
80
10
11
12
13
14
15
16
17
18
19
20
15
85
88
15
88
90
p-OCH3
m-OH
H
S
15
90
90
S
20
80
85
O
O
O
S
25
75
80
Me
p-OCH3
H
20
80
82
Ph
25
78
80
Ph
H
25
70
70
OEt
OMe
OMe
H
O
O
O
25
70
77
Me
Me
H
15
85
90
p-NO2
20
75
80
a
b
c
Reactants were heated using microwave irradiation; Reactants were heated using conventional heating; Isolated yields
of 3,4-dihydropyrimidin-2-(1H)-ones with melamine-formal-
+
dehyde resin supported H (MFRH) as a thermal and chemical
and the solid product was recrystallized from ethanol to give
the pure product (Scheme-I).
stable resin, very inexpensive and easily available catalyst,
under solvent-free conditions in conventional and microwave
irradiation conditions.
R
3
CHO
X
MFRH
O
O
O
+
EXPERIMENTAL
+
2
80 ºC / mw
2
H N
NH
2
R
1
R
R
2
NH
All chemicals and analytical grade solvents were purchased
from Merck or Fluka chemical company. Melting points were
R
3
X = O, S
R
1
N
H
X
1
13
determined using a Mettler FP51 instrument. H NMR and C
NMR spectra were recorded on a Bruker AVANCE DRX 300
spectrometer. Experiments were carried out in closed vessels of
a multimode Microsynth Milstone laboratory 450W west pointe
microwave operating at 3.67 GHz. All experiments had good
reproducibility by repeating the experiments in the same condi-
tions. The reaction was monitored by TLC using pre-coated
Scheme-I: Solvent-free one pot synthesis of dihydropyrimidone compounds
on the melamine-formaldehyde as a solid support
Microwave method (method B): A mixture of aromatic
aldehyde (1 mmol), the β-dicarbonyl compound (1 mmol),
urea or thiourea (1.5 mmol) and MFRH (0.05 g, equal to 0.6
+
+
mmol H ) in a beaker was exposed to microwave irradiation
plates (Merck).melamine-formaldehyde resin supported H
(MFRH) was prepared according to the below procedure.
for the appropriate time according to Table-1. The progress of
the reaction was monitored by TLC. Upon completion of the
reaction, reaction mixture was washed with cold water to
remove excess urea or thiourea and then filtered. The remaining
solid material was washed with hot ethyl acetate. The filtrate
was concentrated and the solid product was recrystallized from
ethanol to give the pure product (Scheme-I).
Preparation of melamine-formaldehyde resin supported
H (MFRH): HCl (3.0 g, as a 36.5 % aq solution) was added
+
to a suspension of melamine-formaldehyde resin (5 g) in Et
2
O
(
70.0 mL). The mixture was concentrated and the residue was
heated at 100 ºC for 72 h under vacuum to furnish MFRH as a
free flowing powder.
All the products are characterized by comparing their IR,
13
H NMR, C NMR, MS and melting points with those reported
Preparation of dihydropyrimidinone compounds
1
7
-26
Conventional method (methodA):A mixture of aromatic
aldehyde (1 mmol), the β-dicarbonyl compound (1 mmol),
urea or thiourea (1.5 mmol) and MFRH (0.05 g, equal to 0.6
in literature
.
Spectral data for selected product: Compound 5: IR
-1
1
(KBr, νmax, cm ): 3215, 1731, 1707, 1641; H NMR (DMSO-
+
3
d ): δ 1.07 (3H, t, J 6.8 Hz, CH ), 2.26 (3H, s, CH ), 3.97
mmol H ) was magnetically stirred in a round-bottomed flask
6
H
3
3
3
(2H, q, J 5.4 Hz, OCH ), 5.27 (1H, s, CH), 7.50 (2H, d, J 7.3
3
at 80 ºC for the appropriate time according to Table-1. The
progress of the reaction was monitored by TLC, upon completion
of the reaction;the mixture was cooled to room temperature.
Reaction mixture was washed with cold water to remove excess
urea or thiourea and then filtered. The remaining solid material
was washed with hot ethyl acetate. The filtrate was concentrated
2
3
Hz, arom.), 7.87 (1H, s, NH), 8.20 (2H, d, J 7.2 Hz, arom),
13
9.33 (1H, s, NH); C NMR: δ 14.5, 18.3, 54.2, 59.8, 98.7,
C
124.2, 128.1, 147.2, 149.8, 152.2, 152.5, 165.5; MS (m/z, %)
+
305 (M , 25), 276 (M -C H , 92), 260 (M -C H CO , 20),
+
+
2
5
2
5
2
183 (100).

4
590 Rezaei et al.
Asian J. Chem.
In conclusion, we have described use of melamine-form-
+
aldehyde resin supported H (MFRH) as an efficient catalyst
RESULTS AND DISCUSSION
This method not only preserved the simplicity of
for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and
thione analogs by multicomponent Biginelli reactions under
solvent-free conditions, using both conventional heating and
microwave irradiation. The advantages of this procedure over
earlier reported processes include its simplicity, fast and clean
reactions, high yield and the absence of organic solvent. It
was found that the reactions under microwave irradiation were
proceeded more rapidly and in higher yields. Further work is
in progress to extend the catalytic activity of melamine-form-
Biginelli's one-pot condensation but also remarkably improved
the yields (>70 %) of dihydropyrimidinones in shorter reaction
times (15-25 min) as against the longer reaction times required
for other catalysts after the addition of a low catalyst concen-
tration. The procedure gives the products in good yields and
avoids problems associated with solvent use (cost, handling,
safety and pollution). Decreased reaction times were also
realized because of the increased reactivity of the reactant in
the solid state. In order to improve the yields, we started to
study the three-component Biginelli condensation catalyzed with
MFRH by examining the conditions required for the reaction
involving ethyl acetoacetate, benzaldehyde and urea to afford
the DHPM1 [R1 = Me, R2 = OEt, R3 = H, X = O, S (Table-1)].
Reactions at different conditions and various molar ratios
of substrates in the presence of MFRH, were revealed that the
best result was achieved by carry out the reaction (with 1:1:1.5
mol ratio of ethyl acetoacetate, benzaldehyde and urea) in the
+
aldehyde resin supported H to other organic transformations.
ACKNOWLEDGEMENTS
The authors gratefully thank the Chemical Research Center
of IslamicAzad University, Firoozabad Branch for their valu-
able help of this work.
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