Supramolecular synthesis of 3,4-dihydropyrimidine-2(1H)-one/thiones under neat conditions

Article abstract of DOI:10.1016/j.cclet.2010.09.030

An efficient solvent free method for the synthesis of various 3,4-dihydropyrimidin-2(1H)-one/thiones in excellent yields using sulfonated β-cyclodextrine as recyclable catalyst is described. Sulfonated β-cyclodextrine was found to be efficient, recyclable

Full text of DOI:10.1016/j.cclet.2010.09.030

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 127–130
www.elsevier.com/locate/cclet
Supramolecular synthesis of 3,4-dihydropyrimidine-2(1H)-one/
thiones under neat conditions
a
Sekineh Asghari , Mahmood Tajbakhsh ,
a,
*
a
Behnam Jafarzadeh Kenari , Samad Khaksar
b
a
Department of Chemistry, University of Mazandaran, Babolsar, Iran
b
Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, Amol, Iran
Received 17 June 2010
Abstract
An efficient solvent free method for the synthesis of various 3,4-dihydropyrimidin-2(1H)-one/thiones in excellent yields using
sulfonated b-cyclodextrine as recyclable catalyst is described. Sulfonated b-cyclodextrine was found to be efficient, recyclable
heterogeneous catalyst and showed rate enhancements, high yields and short reaction times in this transformation.
#
2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Cyclodextrine; Recyclable catalyst; Heterogeneous; Dihydropyrimidine
The Biginelli dihydropyrimidine synthesis [1], first described in 1891, consists of the condensation of urea, an
aldehyde, and a 1,3-ketoester. This condensation reaction has been used for the synthesis of dihydropyrimidin-2-
ones, which have attracted considerable interest because of their wide applications as calcium channel blockers,
antihypertensive agents, a-1a-antagonists and neuropeptide Y (NPY) antagonists [2,3]. Moreover, some bioactive
alkaloids such as batzelladine B containing the dihydropyrimidine unit have been isolated from marine sources,
which show anti-HIV activity [4]. However, this method suffers from the drawbacks such as the lower yields of
the desired products (20–40%) particularly in case of substituted aldehydes and loss of sensitive functional groups
during the reaction. Therefore, in the recent years several improved methodologies mainly using BF ÁOEt /CuCl
3
2
[
5], lanthanide triflate [6], indium trichloride [7], vanadium(III) chloride [8], cupric chloride [9], LiBr [10],
zirconium(IV) chloride [11], lithium perchlorate [12], and polymer-supported ytterbium(II) reagent [13], as well
as Bronsted acids, such as p-toluene sulfonic acid [14], silica sulfuric acid [15], KHSO [16], H PMo O [17],
4
3
12 40
montmorillonite KSF [18], natural HEU-type zeolite [19], and HY-zeolite [20], have been employed as
heterogeneous catalyst for the synthesis of dihydropyrimidinones. Recently ionic liquids have also been used as
catalysts for Biginelli reaction [21–23]. However, most of these methods require expensive reagents, long reaction
time, harsh reaction conditions, tedious work-up procedure, give unsatisfactory yields and moreover use of
homogeneous catalysts which are difficult in separation from reaction mixture for reuse. Furthermore, ionic
*
Corresponding author.
E-mail address: tajbaksh@umz.ac.ir (M. Tajbakhsh).
1001-8417/$ – see front matter # 2010 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2010.09.030

[()TD$FIG]
1
28
S. Asghari et al. / Chinese Chemical Letters 22 (2011) 127–130
R1
O
O
X
O
O
X= O, S
CD-SO H (0.04 g)
R2
3
NH
R1
+
+
H C
R
2
H
H N
NH2
1
2
3
R = Aryl or Alkyl R = CH , OC H
2
3
2
5
Solvent free- 100 C
H C
N
X
3
H
3
Scheme 1. CD–SO H-catalyzed Biginelli reaction.
liquids with imidazole as the cation are relatively expensive, which hinders their industrial applications.
À
À
À
Moreover, typical ionic liquids consist of halogen containing anions (such as [PF ] , [BF ] , [CF SO ] and
6
4
3
3
À
(CF SO ) N] ) which in some regard limit their ‘‘greenness’’ [24–26]. Therefore, in spite of a large number of
3 2 2
[
methods reported for this transformation, there is still need to develop a more efficient, simple, milder and high
yielding protocol using reusable and environmentally friendly catalyst. Biopolymers have some properties, which
make them attractive alternative for conventional organic or inorganic supports for catalytic applications.
Recently, science and technology are shifting emphasis on environmentally friendly and sustainable resource and
processes. In this regard, biopolymers are attractive candidates to explore for supported catalysis [27,28]. Several
interesting biopolymers have been utilized as a support for catalytic applications, such as alginate [29], gelatin
[
30], starch [31,32], and chitosan derivatives [33]. Cyclodextrins (CDs) are cyclic oligomers of D-glucose and are
named a-, b- and g-CD for hexamer, heptamer and octamer, respectively [34]. They have a toroidal cyclic
structure with secondary hydroxyl glucose C-2 and C-3 on their more open face and the primary C-6 hydroxyl on
the opposite secondary face [35]. Their ability to bind organic molecules in the hydrophobic central cavity has
provided a basis for the construction of receptor models [36]. It is widely accepted that the binding forces
involved in the inclusion-complex formation are van der Waals interactions, hydrophobic interactions, hydrogen
bonding and electrostatic interactions between charged parts of guest molecule and CDs [37]. In this letter, we
would like to report a simple effective approach to the Biginelli reaction products using sulfonated b-
cyclodextrine as the catalyst under solvent free conditions (Scheme 1).
Sulfonated b-cyclodextrine was readily prepared by reaction of CD with chlorosulfonic acid.
1
. Experimental
Synthesis of sulfonated b-cyclodextrine: To a magnetically stirred mixture of b-cyclodextrine (5.00 g, 4.5 mmol) in
CHCl (20 mL), chlorosulfonic acid (1.00 g, 9 mmol) was added dropwise at 0 8C during 2 h. After addition was
3
completed, the mixture was stirred for 2 h to remove HCl from reaction vessel. Then, the mixture was filtered and
washed with methanol (30 mL) and dried at room temperature to obtain sulfonated b-cyclodextrine as white powder
(
5.28 g). The –SO H content was measured by titration method and showed 0.52 mequiv./g.
3
General procedure: A mixture of aldehyde (2 mmol), b-dicarbonyl compound (2 mmol), urea or thiourea
3 mmol), and b-cyclodextrine–SO H (0.04 g), was heated with stirring at 100 8C for 2 h. The reaction was followed
(
by TLC. Then, the reaction mixture dissolved in ethanol and filtered off to remove the catalyst. Evaporation of the
3
ethanolic solution gave a solid which recrytallised to afford pure product. Products were identified by comparison
1 13
with authentic samples and by H and C NMR and their melting points.
Spectroscopic data for selected products.
1
Entry 1: Mp 228–230; H NMR (300 MHz, DMSO-d ): d 9.16 (br s, 1 H, NH), 7.78 (br s, 1 H, NH), 7.22–7.36
6
1
m, 5H), 5.25 (d, 1H, J = 2.4 Hz), 2.24 (s, 3H), 2.07 (s, 3H); C NMR: d 194.4, 158.5, 152.1, 147.8, 136.9, 127.7,
3
(
1
1
NH), 7.78 (br s, 1 H, NH), 7.16 (d, 2H, J = 8.7 Hz), 6.88 (d, 2H, J = 8.7 Hz), 5.20 (d, 1H, J = 3.0 Hz), 3.72 (s, 3H),
13.9, 109.6, 55.1, 53.3, 30.18, 18.8. Entry 2: Mp 165–167 8C; H NMR (300 MHz, DMSO-d ): d 9.16 (br s, 1 H,
6
1
.28 (s, 3H), 2.07 (s, 3H); C NMR: d 194.4, 158.5, 152.1, 147.8, 136.4, 127.7, 113.9, 109.6, 55.1, 53.3, 30.2,
3
2
1
1
8.8. Entry 3: Mp 226–228; H NMR (300 MHz, DMSO-d ): d 9.40 (br s, 1 H, NH), 8.21 (d, 2H, J = 8.4 Hz), 7.93
6
1
3
s, 1H), 7.51 (d, 2H, J = 8.7 Hz), 5.39 (s, 1H), 2.32 (s, 3H), 2.19 (s, 3H); C NMR: d 194.0, 152.0, 151.6, 149.1,
(
1
1
46.7, 127.7, 123.8, 109.5, 53.1, 30.7, 19.1. Entry 10: Mp 192–194 8C; H NMR (300 MHz, DMSO-d ): d 8.86
6
(
br s, 1H, NH), 7.26 (br s, 1 H, NH), 4.04 (m, 2H), 3.96 (t, 1H, J = 3.6 Hz), 2.18 (s, 3H), 1.68 (m, 1H), 1.19 (t, 3H,
1
3
J = 7.1 Hz), 0.82 (d, 3H, J = 6.9 Hz), 0.74 (d, 3H, J = 6.8 Hz); C NMR: d 165.8, 153.2, 148.4, 98.2, 59.1, 55.5,
4.6, 18.5, 17.7, 16.0, 14.2.
3

S. Asghari et al. / Chinese Chemical Letters 22 (2011) 127–130
129
Table 1
Effect of solvent under different reaction conditions for Biginelli reaction.
Entry
Solvent
Time (h)
Yield (%)
1
2
3
Toluene
Ethanol
None
3
3
3
Trace
Trace
83
Table 2
b-Cyclodextrine–SO H-catalyzed synthesis of dihydropyrimidinones/thiones.
3
1
R
2
R
a,b
Entry
X
Yield (%)
Mp (8C) found
Mp (8C) reported
1
2
3
4
5
6
7
8
9
C
6
H
5
CH
CH
CH
OC
OC
OC
OC
OC
OC
OC
OC
OC
OC
OC
3
3
3
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
S
83
80
91
89
93
89
88
92
89
73
86
74
85
71
228–230
165–167
226–228
200–202
205–207
196–198
210–212
190–192
212–214
192–194
205–207
146–148
190–192
193–195
223–236 [42]
168–170 [42]
230 [42]
4-MeO–C
6 4
H
4-O NC
2
6
H
4
C
6
H
5
H
H
H
H
H
H
H
H
H
H
H
5
5
5
5
5
5
5
5
5
5
5
201–203 [42]
207–210 [42]
199–201 [42]
210–212 [42]
193–195 [42]
215–216 [42]
194–195 [42]
208–210 [43]
150–152 [43]
192–194 [43]
192–194 [43]
4-O
2
N–C
6
H
4
4-MeO–C
6
H
4
4-Cl–C
3-Cl–C
6
H
H
4
4
6
4-Me–C
(CH
6
H
4
1
1
1
1
1
0
1
2
3
4
3
)
2
CH
6 5
C H
4-MeO–C
4-Me–C
4-Cl–C
6
H
4
S
6
H
4
S
6
H
4
S
a
Yields refer to isolated products.
b
All the reactions completed within 2 h.
2
. Results and discussion
We first examined the reaction of benzaldehyde, acetyl acetone and urea in toluene, ethanol and also under solvent free
conditions at 100 8C. The results showed that the highest yield of the products was achieved under solvent free conditions
(Table 1).
Using these optimized reaction conditions, the scope and efficiency of this solvent free approach was explored for the
synthesis ofawidevariety ofsubstituted 3,4-dihydropyrimidin-2(1H)-ones and resultsare summarizedinTable 2. Allthe
aforementioned reactions (Table 2) proceeded expeditiously, delivered excellent product yields and accommodated a
widerangeofaromaticaldehydes bearingboth, electron-donatingandelectron-withdrawingsubstituents;substrateswith
electron-withdrawing groups gave relatively higher yields. These three-component condensation reactions also
proceeded smoothly with thiourea (Table 2, entries 11–14) and were completed within 120 min. In all cases, the pure
product was isolated by simple filtration, without any chromatography or cumbersome work-up procedure. After the
reaction, thecatalystcanbeeasilyseparatedfromtheproductandreusedwithoutanydecreaseinitsactivity. Forexample,
the reaction of benzaldehyde, acetyl acetone and urea afforded the corresponding 3,4-dihydropyrimidine-2(1H)-one
in 83, 80, and 80% isolated yield over three cycles. In order to show the merit of the present work in comparison with
some reported protocols, we compared the results of the synthesis of 5-ethoxycarbonyl-4-phenyl-6-methyl-3,4-
Table 3
Comparison of the synthesis of 5-ethoxycarbonyl-4-phenyl-6-methyl-3,4-dihidropyrimidine-2(1H)-one using different catalysts.
Entry
Catalyst
Time (h)
Yield (%)
Reference
1
2
3
4
5
6
7
Montmorillonite KSF
Sulfuric acid
48
18
12
6
82
71
80
91
71
80
89
[18]
[1]
Zeolite
[20]
Silica sulfuric acid
[15]
BF
PMo12
CD–SO
3
ÁOEt
2
/CuCl
18
5
[5]
H
3
O
40
[17]
3
H
2
This work

130
S. Asghari et al. / Chinese Chemical Letters 22 (2011) 127–130
dihydropyrimidin-2(1H)-one (Table 2, entry 4) in the presence of montmorillonite KSF, sulfuric acid, zeolite, silica
sulfuric acid, BF ÁOEt /CuCl, H PMo O and CD–SO H with respect to the reaction times (Table 3). The yield of
3
2
3
12 40
3
product in the presence of CD–SO H is comparable with these catalysts. However, other catalysts in Table 3 required
3
longer reaction times than CD–SO H.
3
3
. Conclusion
In summary, we have developed a simple and new procedure for the synthesis of 3,4-dihydropyrimidine-2(1H)-one/
thiones by three-component condensation in one pot using b-cyclodextrine–SO H as catalyst under solvent free
3
condition. This method offers several advantages such as catalyst recyclability, inexpensive catalyst, environmental
friendly procedure, short reaction time, high yields, simple work-up procedure and easy isolation.
Acknowledgment
Financial support of this work from the Research Council of Mazandaran University is gratefully acknowledged.
References
[1] For the first account of this reaction, see:
(
(
(
a) P. Biginelli, Gazz. Chim. Ital. 21 (1981) 497, for reviews, see:;
b) C.O. Kappe, Acc. Chem. Res. 33 (2000) 879;
c) C.O. Kappe, QSAR Comb. Sci. 22 (2003) 630.
[2] (a) C.O. Kappe, Eur. J. Med. Chem. 35 (2000) 1043;
(
(
b) C.O. Kappe, O.V. Shishkin, J. Uray, P. Verdino, Tetrahedron 56 (2000) 1859;
c) K.S. Atwal, G.C. Rovnyak, S.D. Kimball, et al. J. Med. Chem. 33 (1990) 2629.
[
[
[
[
[
[
[
3] G.C. Rovnyak, S.D. Kimball, B. Beyer, et al. J. Med. Chem. 38 (1995) 119.
4] A.D. Patil, N.V. Kumar, W.C. Kokke, et al. J. Org. Chem. 60 (1995) 1182.
5] E.H. Hu, D.R. Sidler, U.H. Dolling, J. Org. Chem. 63 (1998) 3454.
6] Y. Ma, C.T. Qian, L.M. Wang, et al. J. Org. Chem. 65 (2000) 3864.
7] A. Brindban, J.U. Jana, J. Org. Chem. 65 (2000) 6270.
8] G. Salitha, G.S.K. Reddy, et al. Tetrahedron Lett. 44 (2003) 6497.
10] M. Gohain, D. Prajapati, J.S. Sandhu, Synlett (2004) 235.
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
11] G. Maiti, P. Kundu, C. Guin, Tetrahedron Lett. 44 (2003) 2757.
12] C.V. Reddy, M. Mahesh, P.V.K. Raju, et al. Tetrahedron Lett. 43 (2002) 2657.
13] J.S. Yadav, B.V.S. Reddy, R. Srinivas, et al. Synthesis (2001) 1341.
14] A. Dondoni, A. Massi, Tetrahedron Lett. 42 (2001) 7975.
15] T. Jin, S. Zhang, T. Li, Synth. Commun. 32 (2002) 1847.
16] P. Salehi, M. Dabiri, M.A. Zolfigol, et al. Tetrahedron Lett. 44 (2003) 2889.
17] S. Tu, F. Fang, S.L. Zhu, T.X. Zhang, Q. Zhuang, Synlett (2004) 537.
18] M.M. Heravi, K. Bakhtiari, F.F. Bamoharram, Catal. Commun. 7 (2006) 373.
19] F. Bigi, S. Carloni, B. Frullanti, et al. Tetrahedron Lett. 40 (1999) 3465.
20] M. Tajbakhsh, B. Mohajerani, et al. J. Mol. Catal. 236 (2005) 216–219.
21] J.J. Peng, Y.Q. Deng, Tetrahedron Lett. 42 (2001) 5917.
22] M. Li, W.S. Guo, L.R. Wen, et al. J. Mol. Catal. A: Chem. 258 (2006) 133.
23] R.W. Zheng, X.X. Wang, H. Xu, J.X. Du, Synth. Commun. 36 (2006) 1503.
¨
24] P. Wasserscheid, R. Hal, A. Bosmann, Green Chem. 4 (2002) 400.
25] J. Fraga-Dubreuil, K. Bourahla, et al. J. Catal. Commun. 3 (2002) 185.
26] V.R. Rani, N. Srinivas, M.R. Kishan, et al. Green Chem. 3 (2001) 305.
27] R. Breslow, Acc. Chem. Res. 13 (1980) 170.
28] J.H. Clark, D.J. Macquarrie, Green Chemistry and Technology, Blackwell, Abingdon, 2002.
29] W.L. Wei, H.W. Zhu, C.L. Zhao, et al. React. Funct. Polym. 59 (2004) 33.
30] C. Creechio, P. Ruggiero, M.D.R. Pizzigallo, Biotechnol. Bioeng. 48 (1995) 585.
31] H. Gliemann, U. Nickel, S. Schneider, J. Raman Spectosc. 29 (1998) 89.
32] K. Huang, L. Xue, Y.C. Hu, M.Y. Huang, Y.Y. Jiang, React. Funct. Polym. 50 (2002) 199.
33] E. Guibal, Prog. Polym. Sci. 30 (2005) 71.
34] J. Szejtli, Cyclodextrin Technology, Kluwer Academic Publishers, Dordrecht, 1988.
35] Y. Cao, X. Xiao, R. Lu, Q. Guo, J. Mol. Struct. 660 (2003) 73.
36] S. Li, W.C. Purdy, Chem. Rev. 92 (1992) 1457.
37] J. Szeitli, Chem. Rev. 98 (1998) 1743.