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Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180 001, India
Department of Chemistry, University of Jammu, Jammu 180 004, India
e-mail: bashir_15_dar@yahoo.com
b
1. Introduction
3, 4-Dihydropyrimidone scaffold displays a captivating
assortment of pharmacological and therapeutic properties 1 have emerged as an integral part of several calcium
channel blockers, 2,3 antihypertensive agents 25 and neuropeptide Y (NPY) antagonists. 1 Moreover, several
alkaloids containing the 3, 4-dihydropyrimidone scaffold have been isolated from marine sources, which also
exhibit interesting biological properties. 6,7 Synthesis of
these 3, 4-dihydropyrimidones via Biginelli reaction is
one of the most efficient methods. Classical Biginelli
reaction faces major drawback of poor to moderate
yields, when substituted aromatic or aliphatic aldehydes
and thiourea are employed. 8,9 Various catalytic process
involving catalysis like AlCl3 , 10 [Al (H2 O)6 ](BF4 )3 , 11
ZnCl2 , 12 CuCl2 .2H2 O, 13 FeCl3 .6H2 O, 14 ZieglerNatta
catalyst, 15 polyphosphate ester, 16 Bakers yeast, 17
LaCl3 7H2 O, 18 and LiClO4 , 19 and heteropoly acids 20
have been developed but most of these catalysts are
expensive, non-recoverable and generate strong acidic
wastes. 21 This problem has been addressed to some
extent by different heterogeneous methods using zeolites, 22 KSF clay with dry acetic acid under microwave
irradiations, 23 Nafion-H, 24 montmorilonite K10, 25,26
HCl4 /SiO2 , 27 amberlyst-15, 28 etc. The disadvantages
of poor yield, long reaction time, highest, complexity,
For
correspondence
2. Experimental
2.1 Catalyst preparation
FeAl/clay composite was prepared by dissolving
equal mole proportion of AlCl3 and FeCl3 in ethanol
and adding a known amount of H+ montomorillonite
KSF to the solution in small portions to form 5 wt%
of each metal on clay surface. The mixture was stirred
and refluxed for 15 h, dried under vacuum and kept
overnight in hot air oven at 120 C then calcined at
425 C for 3 h. The catalyst so formed was labelled as
Fe-Al/clay. The other catalysts like FeZn/clay composite, FeCu clay composite, AlZn/clay composite, CuZn/clay composite and AlCu/clay composite
were prepared in similar way.
545
546
O
O
NH2
+
NH2
FeAl/Clay
100C, 3-5 h
NH
N
H
1j
4j
600
500
Lin (Counts)
400
300
d = 4.47079
200
d = 3.34158
d = 2.70080
d = 2.56511
d = 1.69582
d = 1.54185
d = 2.51702
d = 1.48610
100
0
2
10
20
30
40
50
2-Theta - Scale
60
70
80
Synthesis of 3,4-dihydropyrimidones
547
Catalyst
Time (hrs)
Yield % [ref.]
Temp. C
Solvent
FeAl/clay
AlZn/clay
FeZn/clay
CuAl/clay
CuFe/clay
CuZn/clay
[Al(H2 O)6 ](BF4 )3
ZnCl2
CuCl2 .2H2 O
FeCl3 .6H2 O
AlCl3
3
3
3
5
5
5
20
20
16
24
20
98
93
93
89
88
83
81 11
52 12
71 13
71 14
90 10
100
100
100
100
100
100
Reflux
80
Microwaves
Reflux
Reflux
No solvent
No solvent
No solvent
No solvent
No solvent
No solvent
CH3 CN
No solvent
No solvent
Ethanol
CH3 CN
Table 2. Effect of ammonia desorption value of catalyst on the yield of product for
the Biginelli reaction.
Entry
FACC at 250 C
FACC at 425 C
NH3 desorbed
(mol/g)
Weak/ 207/40400
Medium/ 580/ 400630
Strong/ 682/ 6301000
Weak/ 105/ 40360
Medium/ 494/ 360585
Strong/ 627/ 5851000
395
186
201
1486
1322
793
Yield %
87%
98%
548
Table 3.
reaction.
Yielda %
Solvent-free
Methanol
Ethanol
Dimethylsulphide
Butanol
H2 O
Acetonitrile
Dimethylformamide
Xylene
Toluene
98
85
70
68
50
45
90
65
55
77
Entry
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
a
during the reaction process. Clays hybridized with polymeric inorganic oxocations are perspective catalysts
due to high stability, microporosity, larger surface area
and existence of acid sites. 32 Almost all the catalysts
proved good and were unexpectedly found to have better catalytic activity than their parent metal halides.
FeAl/clay was found to be most active and showed
better catalytic activity than some reported catalysts
(table 1). This catalyst was prepared in bulk and calcined at two different temperatures to study the effect of
calcinations on the activity of the catalyst. FeAl/clay
calcined at 425 C was found to be more effective
catalyst than that calcined at 250 C for the one-pot synthesis of dihydropyrimidin-2(1H )-ones. This increase
in activity may be attributed to the increase in the number of acidic sites (by three to four-folds) of all the
three types (weak, medium, strong) as determined by
NH3 TPD (table 2). Increase in calcination temperature
not only increases the acidity of the catalyst but also
decreases the metal leaching as observed with the catalysts calcined at lower temperatures. It may be due to
the availability of sufficient energy at higher temperature for strong interaction between the support and
the metals deposited. The most efficient catalyst thus
obtained was further characterized by XRD, SEM and
BET and explored for different substrates; it provided
good to excellent yields as shown in table 2.
Solvent-free
Acetonitrile
98
90
98
89
96
87
97
87
96
87
Synthesis of 3,4-dihydropyrimidones
Table 5.
O
+
549
NH2
+
O
NH2
Fe-Al/Clay
100oC, 3 h
NH
N
H
Entry
Aldehyde
3
X
1.
x = o,s
Yielda %
Product
CHO
NH
H 3C
1a
N
H
87
4a
CHO
2.
NH
O
H 3C
1b
N
H
88
4b
Cl
CHO
O
3.
NH
93
Cl
H 3C
1c
N
H
4c
Cl
CHO
O
4.
NH
92
Cl
H 3C
1d
N
H
4d
CHO
Br
5.
1e
Br
O
O
H 3C
NH
N
H
92
550
(Continued).
Entry
Aldehyde
CHO
Br
Br
6.
Yielda %
Product
NH
O
H 3C
1f
N
H
92
4f
F
CHO
Br
7.
Br
NH
O
H 3C
N
H
95
1g
4g
F
CHO
Br
8.
Br
NH
93
F
H 3C
1h
N
H
4h
O
O
CHO
OCH3
9.
H3CO
OCH3
O
H 3C
1i
86
NH
N
H
4i
NO2
CHO
O
10.
NH
NO2
1j
H 3C
4j
N
H
98
Synthesis of 3,4-dihydropyrimidones
Table 5.
Entry
551
(Continued).
Aldehyde
Yielda %
Product
NO2
CHO
O
11.
NH
95
NO2
H 3C
1k
N
H
4k
OH
CHO
O
12.
NH
89
OH
H 3C
1l
N
H
4l
OH
CHO
O
13.
NH
87
OH
H 3C
1m
N
H
4m
CHO
O
14.
1n
90
NH
H 3C
N
H
CHO
O
15.
1o
NH
H 3C
4o
N
H
91
552
(Continued).
Entry
Aldehyde
Yielda %
Product
O
O
CHO
17.
NH
H 3C
1s
N
H
88
4s
O
CHO
18.
1t
O
H 3C
1u
NH
O
H 3C
N
H
CHO
20.
N
H
79
CHO
19.
NH
1v
81
O
NH
O
H 3C
N
H
53
CHO
21.
1w
44
NH
O
H 3C
N
H
a HPLC yield
4. Conclusions
In conclusion, this one-pot protocol for synthesis of
3,4dihydropyrimidone is solvent-free, highly efficient,
economical and safe. The Fe-Al/clay composite is
leaching-free, easy to prepare, easy to handle, environment friendly and can be recycled several times without significant loss of catalytic activity; thus it will be
highly useful for economical synthesis of 3,4dihydro-
Acknowledgement
BAD thanks the Council of Scientific and Industrial Research (CSIR) for Senior Research Fellowship.
Authors are thankful to the authorities of Indian Institute of Integrated Medicine (IIIM), Jammu for providing necessary facilities and good support to carry out
the research work.
Synthesis of 3,4-dihydropyrimidones
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