A practical and green approach towards synthesis of dihydropyrimidinones: Using heteropoly acids as efficient catalysts

Article abstract of DOI:10.1016/j.bmcl.2006.01.087

A simple and green chemistry procedure for the synthesis of dihydropyrimidinones using heteropoly acid mediated cyclocondensation reaction is described. This method provides an efficient and much improved modification of the original Biginelli reaction re

Full text of DOI:10.1016/j.bmcl.2006.01.087

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2463–2466
A practical and green approach towards synthesis
of dihydropyrimidinones: Using heteropoly acids
as efficient catalysts
Ezzat Rafiee* and Hadi Jafari
Department of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Received 4 January 2006; revised 20 January 2006; accepted 23 January 2006
Available online 7 February 2006
Abstract—A simple and green chemistry procedure for the synthesis of dihydropyrimidinones using heteropoly acid mediated cyclo-
condensation reaction is described. This method provides an efficient and much improved modification of the original Biginelli reac-
tion reported in 1893, in terms of high yields, and short reaction times. It has the ability to allow a wide variety of substitutions in all
three components.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Multicomponent reactions (MCRs) are of increasing
importance in organic and medicinal chemistry.1–6 In a
time when a premium is put on speed, diversity and effi-
ciency in the drug discovery process,4,5 MCR strategies
offer significant advantages over conventional linear-
type syntheses.1–6 In such reactions, three or more reac-
tants come together in a single reaction vessel to form
new products that contain portions of all the compo-
nents. The search and discovery for new MCRs on
one hand,7 and the full exploitation of the already
known multicomponent reactions on the other hand, is
therefore of considerable current interest. One such
MCR that belongs to the latter category is the Biginelli;
dihydropyrimidine (DHPM) synthesis.
have been found to be potent HIV gp-120-CD4
inhibitors.14
The Biginelli reaction, first reported more than a century
ago and recently reviewed,8 involves the acid-catalyzed
cyclocondensation reaction of ethyl acetoacetate, benz-
aldehyde and urea. A number of synthetic procedures
based on the modifications of the classical Biginelli’s ap-
proach have been developed during past few years.6,8
Basically, these methods are all similar, using different
Lewis acid catalysts.15–29 Obviously, many of these cat-
alysts and solvents are not acceptable in the context of
green synthesis. Thus, as a part of our programme to-
wards green synthesis,30 and continuing our studies on
the application of heteropoly acids (HPAs) in organic
synthesis,31 our new approach reported herein involves
the use of HPAs as catalysts for the synthesis of
DHPMs.
3,4-Dihydropyrimidin-2(1H)-ones, named Biginelli
compounds, are known to exhibit a wide range of bio-
logical activities such as antiviral, antitumour, antibac-
terial and anti-inflammatory actions.6,8,9 More
recently, appropriately functionalized DHPMs have
emerged as potent calcium channel blockers,10 antihyper-
tensive agents,11 a1a adrenergic antagonists12 neuropep-
tide Y (NPY) antagonists.13 Several marine alkaloids
containing the DHPM core unit have shown interesting
biological properties. In particular, batzelladine alkaloids
Heteropoly acids have been extensively studied as acid
catalysts for many reactions and found industrial appli-
cations in several processes.32 The Keggin-type HPAs
typically represented by the formula H8Àx[XM12O40],
where X is the heteroatom (e.g., P5+ or Si4+), x is its oxi-
dation state and M is the addenda atom ( usually Mo6+
or W6+), are the most important catalysts, especially
H3PW12O40
(PW),
H3PMo12O40
(PMo)
and
H4SiW12O40 (SiW).33 They are more active than the con-
ventional catalysts, such as mineral acids, ion-exchange
resins, zeolites, SiO2/Al2O3 and H3PO4/SiO2.32,34 HPAs
have several advantages over liquid acid catalysts,
Keywords: Dihydropyrimidinones or thiones (DHPMs); Heteropoly
acid; Multicomponent reactions (MCR); Biginelli reaction.
*
Corresponding author. Tel./fax: +98 831 4274559; e-mail:
e.rafiei@razi.ac.ir
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.087

2464
Ezzat Rafiee, H. Jafari / Bioorg. Med. Chem. Lett. 16 (2006) 2463–2466
Table 2. Heteropoly acids catalyzed synthesis of dihydropyrimidin-
2(1H)-ones and thiones (DHPMs)
including being noncorrosive and environmentally be-
nign. Thus, they present fewer disposal problems and
more economically and environmentally attractive.35
Furthermore, HPA catalysis lacks side reactions, such
as sulfonation, chlorination, etc., that frequently occur
with mineral acids.
R1
O
X
O
HPA
O
R1CHO
+
NH
+
R2
R2
CH3CN, 80oC, 1h
H2N
NH2
N
X
Me
H
1
4
2
3
Recently, our own work found HPAs to be very efficient
catalyst for three-component coupling reactions.31 We
wish to report here another remarkable catalytic activity
of HPAs for the one-pot condensation of 1,3-dicarbonyl
compound (1), aldehyde (2) and urea or thiourea (3) to
DHPMs (4).
Entry R1
R2
X
Yielda (%)
PWb PMoc SiWd
Ref.e
1
2
C6H5
3-NO2C6H4
4-NO2C6H4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
92
89
90
96
91
90
91
95
52
73
94
68
57
50
90
87
80
86
91
89
90
87
92
57
70
90
61
55
47
89
93
90
91
92
89
87
92
94
60
71
96
65
54
52
88
25
25
25
25
25
25
25
25
19
25
19
20
19
20
25
3
4
4-CH3OC6H4
2-ClC6H4
3-ClC6H4
5
After some experimentation with respect to the catalytic
amount of several HPAs (Table 1, entries 2–10), differ-
ent solvents (Table 1, entries 10–13) and reaction tem-
perature (Table 1, entry 14), the optimal conditions
have been established.36 However, in the absence of
HPA, the reaction did not yield the desired product (Ta-
ble 1, entry 1).
6
7
4-ClC6H4
8
4-CH3C6H4
2-HOC6H4
3-HOC6H4
9
10
11
12
13
14
15
4-N(Me)2–C6H4 OEt
C–C6H11
n-C3H7
n-C5H11
OEt
OEt
OEt
OEt
To study the generality of this process, a variety of
substituted aromatic, carrying either electron-donating
or -withdrawing substituents, aliphatic and heterocyclic
aldehydes were examined (Table 2). Many of the phar-
macologically relevant substitution patterns on the aro-
matic ring could be introduced with high efficiency.
Aliphatic aldehydes such as propanal and pentanal also
reacted well (Table 2, entries 12–14). Such aldehydes
normally show extremely poor yields in the Biginelli
reaction. It is interesting to note that in the case of the
acid-sensitive aldehydes such as furfural and cinnamal-
dehyde, DHPMs were achieved in excellent yields with-
out the formation of any side products, which are
normally observed in the presence of protic acids (Table
PhCH@CH
16
17
18
OEt
OEt
OEt
O
O
O
95
93
77
90
91
79
91
92
70
25
25
19
O
S
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
C6H5
OMe
OMe
OMe
OMe
OMe
OMe
O
O
O
O
O
O
O
O
O
O
S
93
88
90
97
75
96
88
93
91
71
94
97
71
85
86
96
85
83
85
90
69
94
80
89
87
70
86
91
68
81
80
93
86
90
91
95
73
96
82
90
86
72
91
93
62
80
87
94
25
18
22
25
25
25
26
21
21
21
25
25
29
25
25
25
3-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-NO2C6H4
4-CH3C6H4
Table 1. Effect of catalysts under different reaction conditions for
condensation of benzaldehyde, ethyl acetoacetate and urea
4-N(Me)2–C6H4 OMe
C6H5
Me
Me
4-CH3OC6H4
4-NO2C6H4
C6H5
O
O
O
O
CHO
+
Me
Catalyst
EtO
Me
NH
+
OEt
OEt
OEt
OEt
OEt
OEt
OEt
H2N
NH2
Solvent , 1h
4-CH3OC6H4
3-HOC6H4
4-ClC6H4
4-NO2C6H4
4-CH3C6H4
S
N
O
H
S
S
Entry
Catalyst
(mol %)
Temperature
(ꢁC)
Solvent
Yielda
(%)
S
S
1
2
—
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
C2H5OH
C6H5CH3
CHCl3
0b
70
89
87
79
93
95
81
95
92
53
41
59
68
35
OEt
S
89
85
84
25
PMo (5)
PMo (10)
PMo (8)
SiW (2)
SiW (5)
SiW (8)
PW (2)
PW (8)
PW (5)
PW (5)
PW (5)
PW (5)
PW (5)
S
3
a Isolated yield.
4
b The mole ratio of aldehyde to dicarbonyl compound to urea or
thiourea to PW is 1:1:1.5:0.05.
5
6
c The mole ratio of aldehyde to dicarbonyl compound to urea or
thiourea to PMo is 1:1:1.5:0.08.
7
8
d The mole ratio of aldehyde to dicarbonyl compound to urea or
thiourea to SiW is 1:1:1.5:0.05.
9
10
11
12
13
14
e Products were characterised by comparison of their spectroscopic
data with those reported in the literature.
CH3CN
2, entries 15–17). Furthermore, the experimental results
showed that besides ethyl acetoacetate, acetylacetate
and methyl acetoacetate could also be used, and the
a Isolated yield.
b After 10 h.

Ezzat Rafiee, H. Jafari / Bioorg. Med. Chem. Lett. 16 (2006) 2463–2466
2465
13. Bruce, M. A.; Pointdexter, G. S.; Johnson, G. PCT Int.
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corresponding DHPMs were produced in high to excel-
lent yields (Table 2, entries 19–28). Thiourea has been
used with similar success to provide the corresponding
dihydropyrimidin-2(1H)-thiones which are also of much
interest with regard to biological activity8 (Table 2, en-
tries 29-35). Noteworthy is the recently identified lead
compound, monastrol (Table 2, entry 31), of a new class
of anticancer agents that act as cell division (mitosis)
blockers.37 Thus, variations in all three compounds have
been accommodated very comfortably. It is pleasing to
observe the remarkable stability of a variety of function-
al groups such as ether, nitro, hydroxyl, halides, hetero-
cyclic moieties and conjugated C@C double bond under
the reaction conditions. The authors investigated the
mechanism of the Biginelli reaction in the literature38
and proposed an N-acyliminium ion formed in situ
by reaction of the aldehyde with urea as the key
intermediate.
14. Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, A. J.; Debrossi, C.; Mai, S.; Truneh, A.; Faulkner,
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15. Bose, D. S.; Sudharshan, M.; Chavhan, S. W. ARKIVOC
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16. Russowsky, D.; Lopes, F. A.; da Silva, V. S. S.; Canto, K.
F. S.; Montes D’Oca, M. G.; Godoi, M. N. J. Brazil.
Chem. Soc. 2004, 15, 165.
17. Reddy, Y. T.; Rajitha, B.; Reddy, P. N.; Kumar, B. S.;
Rao, V. P. Synth. Commun. 2004, 34, 3821.
18. Paraskar, A. S.; Dewkar, G. K.; Sudalai, A. Tetrahedron
Lett. 2003, 44, 3305.
19. Lu, J.; Bai, Y. Synthesis 2002, 466.
20. Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. Synthesis 2001, 1341.
21. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000,
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In conclusion, this report discloses a simple modifica-
tion of the Biginelli DHPM synthesis. Excellent yields,
enhanced reaction rates, compatibility with various
functional groups, environmentally friendly procedure,
timesaving process, low cost and easy availability of
the catalyst are some of the salient features of this reac-
tion. This procedure will offer an easy access to substi-
tuted dihydropyrimidin-2(1H)-ones and thiones with
different substitution patterns in high to excellent
yields.
23. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270.
24. Reddy, C. V.; Mahesh, M.; Raju, P. V. V. K.; Babu, T. R.;
Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657.
25. Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J.
T.; Peppe, C. Tetrahedron 2002, 58, 4801.
26. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem.
2003, 68, 587.
27. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
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Acknowledgments
28. Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1799.
29. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M.
A. Tetrahedron Lett. 2003, 44, 2889.
The authors thank the Razi University Research Coun-
cil and Kermanshah Refinery Company for support of
this work.
30. (a) Rafiee, E.; Tangestaninejad, S.; Habibi, M. H.;
Mikhani, V. Bioorg. Med. Chem. Lett. 2004, 14, 3611;
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Ezzat Rafiee, H. Jafari / Bioorg. Med. Chem. Lett. 16 (2006) 2463–2466
36. Typical procedure for the synthesis of 3,4-dihydropyrim-
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appropriate b-dicarbonyl compound (2 mmol), corre-
sponding aldehyde (2 mmol), urea or thiourea (3 mmol)
and appropriate amount of catalyst (Table 2) in acetoni-
trile (5 mL) was stirred rapidly and heated at 80 ꢁC in a
preheated oil bath for one hour (completion of the
reaction was monitored by TLC). The reaction mixture
was then filtered to remove the catalyst, and the filtrate
was poured into crushed ice. Stirring was continued for
several minutes. The solid product was filtered, washed
with cold water (2· 30 mL) and recrystallized from ethyl
acetate/n-hexane or ethanol to afford pure product. All
products were identified by comparing their spectral and
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