Microwave-induced perchloric acid catalyzed novel solvent-free synthesis of 4-aryl-3,4-dihydropyrimidones via biginelli condensation

Article abstract of DOI:10.1002/jhet.5570440439

(Chemical Equation Presented) We report here domestic microwave-induced perchloric acid-catalyzed solvent-free synthesis of various 4-aryl-3,4- dihydropyrimidones for the first time. In all the cases the yields are excellent and the mechanism follows a si

Full text of DOI:10.1002/jhet.5570440439

Jul-Aug 2007
Microwave-induced Perchloric Acid Catalyzed Novel Solvent-free
979
Synthesis of 4-Aryl-3,4-dihydropyrimidones Via Biginelli Condensation
a
a
b
Chhanda Mukhopadhyay, * Arup Datta and Bimal K. Banik
a
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata-700009, India
E.mail: csm@vsnl.net; Telephone: 91-33-23371104
b
Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg,
TX 78541, USA
Received October 8, 2006
O
Ar
H
HClO (0.05ml)
4
X
O
O
4 3
5
NH
ArCHO
+
+
Microwaves
solvent -free
conditions
1
2
H N
NH2
R
2
6
X
N
H
(
R=Me. OMe.OEt)
(X=O, S)
We report here domestic microwave-induced perchloric acid-catalyzed solvent-free synthesis of various 4-
aryl-3,4-dihydropyrimidones for the first time. In all the cases the yields are excellent and the mechanism
follows a simple Biginelli condensation to produce the dihydropyrimidones in a few seconds. This procedure
has been successfully employed to synthesize the mitotic kinesin EG5 inhibitor Monastrol (Figure I).
J. Heterocyclic Chem., 44, 979 (2007).
INTRODUCTION
agents, alpha-1a-antagonists [2] and neuropeptide Y
NPY) antagonists [3]. Therefore, new method for the
(
Microwave-assisted synthesis has been investigated
extensively using organic solvents in open vessels. High-
boiling microwave-absorbing solvents have shown a great
promise for this purpose. But, the use of solvents has
limited the advantages in relation to product isolation. On
this basis, designing of solvent-free reaction in microwave
oven would be ideal. The protection of the environment is
a major requirement in our overcrowded world of
increasing demands. One of the very promising
approaches to this effect is the employment of solvent-
free techniques in Organic Synthesis [1]. The effects of
microwave-induced reaction under solvent-free conditions
have several advantages. This method would be
economical, convenient and simple. Herein we report an
expeditious solvent-free Biginelli condensation method
for the synthesis of 4-aryl-3,4-dihydropyrimidones with
catalytic amounts of perchloric acid in a domestic
microwave oven including that of the mitotic kinesin EG5
inhibitor Monastrol.
synthesis of the dihydropyrimidone nucleus is important.
The first synthesis was carried out by Biginelli in low
yield (20-50%) [4] following a condensation reaction of
ethylacetoacetate with aldehydes and urea in presence of
strong mineral acid. Subsequently, other improved
procedures have been reported [5], but they suffer serious
drawbacks. Strong Lewis acids [6,7,8] or costly
lanthanide compounds [9] in the presence of use of toxic
organic solvents are used in some of the recent results. On
this basis, a high yielding, cost effective, rapid synthesis
of the dihydropyrimidone nucleus is necessary. The
simplicity of the procedure can be enhanced using the
application of “Microwave induced Organic Reaction
Enhancement” (MORE) [10] techniques. For example, the
reaction of benzaldehyde, acetylacetone and urea required
almost 10 hours for completion in an oil bath at 100 °C. In
a detailed study, we prepared several dihydropyrimidones
in excellent yield and within minutes using catalytic
amounts of perchloric acid (0.05 ml) in a domestic
microwave oven in the absence of any solvents. Higher
quantity of perchloric acid led to charring of the reaction
mixture. The use of microwave oven resulted in not only
higher reaction rates, but also the formation of cleaner
products. The crude reaction products solidified as soon
as they were taken out of the microwave oven. A medium
power level was used (10-20% of a 1200 watt microwave
oven system). The reaction was very rapid and completed
OH
O
O
NH
N
S
H
Figure-I
Monastrol
(entry 29, Table)
Scheme I
O
Ar
H
RESULTS AND DISCUSSION
X
O
O
HClO (0.05ml)
4
4
5
3
NH
2
ArCHO
+
+
H
2
N
NH
2
R
1
The dihydropyrimidone nucleus exhibits wide potenti-
ality as calcium channel blockers, antihypertensive
Microwaves
solvent -free
conditions
6
N
X
(
R=Me, OMe, OEt)
(X=O, S)
H

9
80
C. Mukhopadhyay, A. Datta and B. K. Banik
Vol 44
within 4-5 minutes. Several products were synthesized in
gram scale. This method was applied to ꢀ-keto esters and
microwave oven (Scheme-I). This method is very
general and tolerates different types of functional
groups. Considering the simplicity and environ-
ꢀ
-diketones and a variety of substituted aryl aldehydes.
Table
Perchloric Acid catalysed “solvent free” synthesis of 4-aryl-3,4-dihydropyrimidones in the microwave oven.
Time
(seconds)
Power
(watt)
Yield
( %)
Entry
Ar
R
X
References
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Me
OMe
OEt
Me
OEt
OMe
OEt
Me
OMe
Me
OEt
OMe
Me
OEt
OEt
OMe
Me
OEt
OMe
OEt
Me
OEt
OMe
OEt
Me
OEt
OMe
OEt
OEt
OEt
Me
O
O
O
S
S
S
30
120
120
140
180
180
60
120
240
240
120
120
120
240
120
240
240
120
120
120
120
240
240
120
240
240
240
240
120
600
600
240
240
240
240
600
120
240
600
720
240
94
92
95
90
93
89
87
93
95
90
92
82
90
85
91
94
94
82
93
92
92
83
88
84
86
83
90
93
92
84
85
89
87
90
5, 7
6, 7
6, 7
7
7, 12
13
14
15
16
Ph
4 OH-3OMe-C
4 OH-3OMe-C
4 OH-3OMe-C
6
6
6
H
H
H
3
3
3
O
O
O
S
O
O
O
S
O
O
O
S
O
O
O
S
O
O
O
O
O
O
S
O
O
O
O
S
30
60
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
2Cl- C
6
H
4
180
180
240
180
30
300
300
120
210
300
180
30
110
240
180
150
90
120
180
300
50
4OMe-C
4OMe-C
4OMe-C
4OMe-C
6
6
6
6
H
4
8, 17
8, 17
8
17, 18
14, 19
17
20
17
7, 21
6, 7
22
H
H
H
4
4
4
3NO
3NO
3NO
3NO
2
2
2
2
-C
-C
-C
-C
6
6
6
6
H
H
H
H
4
4
4
4
4OH-C
4OH-C
4OH-C
4OH-C
4Cl-C
4Cl-C
4Cl-C
6
6
6
6
H
H
H
H
4
4
4
4
23
6
6
6
H
H
H
4
6, 7, 8,17
6, 7, 8,17
22
4
4
4NMe
4NMe
2
-C
-C
6
H
4
4
14
16
7
24
21
17
8, 17
8, 17
25
2
6
H
3OH-C
3OH-C
furanyl
6
H
H
4
6
4
4NO
4NO
4NO
2
2
2
-C
-C
-C
6
6
6
H
H
H
4
4
4
180
300
180
30
OMe
OEt
OMe
6 3
4OH-3OMe-C H
Nitro, chloro, hydroxy, methoxy, and N,N-dimethyl-
amino groups on the aryl nucleus posed no problem. Both
urea and thiourea were equally effective in this reaction
mentally benign process, this method may find useful
application in the near future.
(
table). Although we have not investigated the mechanism
EXPERIMENTAL
of the reaction, it may follow a path proposed by Folkers
and Johnson [11]. Perchloric acid may stabilize the
initially formed acylimine intermediate. Subsequently, the
Typical Experimental Procedure. 4 mmol of aldehyde,
mmol of ꢀ-diketone or ꢀ-keto ester, 6 mmol of urea or thiourea
and 0.05 ml of perchloric acid were mixed thoroughly. The
mixture was taken in a 50 ml Erlenmeyer flask, placed in an
alumina bath inside a microwave oven (BPL Sanyo, BMO-
5
ꢀ
-diketone or the ꢀ-keto ester (enolate) may add to the
acylimine intermediate. A cyclization and dehydration
route may follow to produce the dihydropyrimidone.
7
00T, 2450 MHz, 1200 W) and irradiated at a specified power
CONCLUSION
level for the specified time period (Table). The crude mass was
removed from the oven, poured into crushed ice, stirred for
several minutes and filtered. The solid residue was washed with
cold water several times and crystallized from hot ethanol.
In conclusion, in this paper a catalytic amount of
perchloric acid has been used very effectively for the
first time for a solvent-free high yielding rapid
synthesis of 4-aryl, 3,4-dihydropyrimidones including
that of Monastrol in a one-pot operation in a domestic
1
13
The products were characterized by mp, IR, H NMR and
C
NMR data. The compounds were also compared with respect to
authentic compound available in literature. The melting point,

Jul-Aug 2007
Microwave Induced Perchloric Acid Catalysed Biginelli Condensation
981
spectral and analytical data of the new compound (entry 10 in
the Table) is presented below:
[6] Hu, E.H.; Sidler, D.R.; Dolling, U.-H. J .Org. Chem., 1998,
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[
7] Ranu, B.C.; Hazra, A.; Jana, U. J. Org. Chem., 2000, 65,
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5
-Acetyl-4-(2-Chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-
6
270.
tetrahydropyrimidine (entry10). (yellow crystalline solid) mp:
[
1
1
ꢀ
86-188°C ( ethanol), ir (potassium bromide): 3315, 3187, 1611,
-1 1
65, 3864.
454, 1327, 1198 and 760cm ; H NMR (300MHz, DMSO-d ):
6
[
9] Robert, H.; Garrigues, B.; Dubac, J. Tetrahedron Lett., 1998,
10.34(s, 1H, NH), 9.62 ( s, 1H, NH), 7.40-7.48 ( m, 1H,
3
9, 1161.
aromatic C -H), 7.29-7.36 ( m 2H, aromatic C -H and C -H),
3
4
5
[10a] Caddick, S. Tetrahedron, 1995, 51, 10403. [b] Hayes, B.L. In
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7
.23-7.27 (m, 1H, aromatic C -H), 5.69 ( d, 1H, J=3.60Hz, C -
6 4
13
H), 2.37 ( s, 3H, -COCH ), 2.11 ( s, 3H, C -CH ); C NMR
3
6
3
(
1
DMSO-d ): ꢀ 195.04, 174.40, 145.32, 140.16, 132.33, 130.19,
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3
4
2
784.
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5
1
3
13
2
[
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205.
Acknowledgement. One of the authors (A.D.) thank the
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(
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