Synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by nafion-H under ultrasound irradiation and solvent-free conditions

Article abstract of DOI:10.1007/BF03246016

A novel synthesis of 3,4-dihydropyrimidin-2-(1H)-ones by one-pot cyclocondensation of aldehydes, 1,3-dicarbonyl compounds and urea or thiourea using nafion-H as the catalyst under ultrasound irradiation and solvent-free conditions was developed. Compared

Full text of DOI:10.1007/BF03246016

J. Iran. Chem. Soc., Vol. 7, No. 2, June 2010, pp. 318-321.
JOUIRrNaAnLiaOnF THE
Chemical Society
Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Nafion-H Under
Ultrasound Irradiation and Solvent-Free Conditions
Q. Wang and W. Pei
College of Chemical Engineering and Materials, Zhejiang University of Technology, Hangzhou 310014, China
(Received 2 April 2009, Accepted 23 May 2009)
A novel synthesis of 3,4-dihydropyrimidin-2-(1H)-ones by one-pot cyclocondensation of aldehydes, 1,3-dicarbonyl
compounds and urea or thiourea using nafion-H as the catalyst under ultrasound irradiation and solvent-free conditions was
developed. Compared with the classical Biginelli reactions, this method consistently enjoys the advantages of mild reaction
conditions, excellent yields, easy work up and short reaction time.
Keywords: One-pot, Nafion-H, Biginelli condensation, Ultrasound irradiation, Solvent-free
INTRODUCTION
reaction [9] involving acid-catalyzed three-component
condensation of 1,3-dicarbonyl compound, aldehyde, and
urea, have been developed during the past few years.
Basically, these methods are all similar, using different Lewis
acid catalysts such as BF3 [10], FeCl3 [11], InCl3 [12], BiCl3
[13], LaCl3 [14], LiClO4 [15], in a solvent such as CH3CN,
CH2Cl2, or THF. In addition, several ionic liquids [16],
microwave irradiation [17], and combinatorial approaches
[18] to 3,4-dihydropyrimidin-2-(1H)-ones have also been
employed. Obviously, many of these catalysts and solvents are
not at all acceptable in the context of green synthesis. Thus, as
a part of our program towards green synthesis, we have
discovered that Biginelli’s reaction proceeds very efficiently
by ultrasound irradiation, requiring no solvent, and producing
3,4-dihydropyrimidin-2(1H)-ones in high yields (Scheme 1).
Ultrasound has increasingly been used in organic synthesis
in the last three decades [1]. Compared with traditional
methods, this technique is more convenient and easily
controlled. A large number of organic reactions can be carried
out in higher yields, shorter reaction time and milder
conditions under ultrasound irradiation. Perfluorinated resin
sulfonic acid (nafion-H) [2], an acid catalyst, is extensively
used for alkylation [3], acylation [4], nitration [5], acetal
synthesis, [6] and in Diels-Alder reaction [7]. The Nafion-H
catalyst, an insoluble resin, is inert to corrosive environments,
stable up to 201 °C, easy to recover and to reuse.
3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) are of
considerable interest in industry as well as in academia
because of their promising biological activities as calcium
channel blockers, antihypertensive agents, and anticancer
drugs [8]. Thus, the synthesis of this heterocyclic nucleus is of
high importance, and quite a number of synthetic procedures
based on the modifications of the century-old Biginelli’s
EXPERIMENTAL
Liquid aldehydes were purified by distillation prior to use.
All compounds were identified by comparison of their spectral
data and physical properties with those of the authentic
samples. The nafion-H catalyst (beads, 7-9 mesh) was
*Corresponding author. E-mail: qinwang99@hotmail.com

Wang & Pei
O
C
R1
X
R2
NH
O
O
Nafion-H
U.S.
+
+
R1 CHO
1
X
N
H
R2
H2N NH2
2
3
4
X=O or S
Scheme 1. The synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by nafion-H under ultrasound irradiation
1
4H, Ar-H), 5.62 (d, J = 2.5 Hz, 1H, H-4), 3.48 (s, 3H,
COOCH3), 2.30 (s, 3H, C6-CH3); 13C NMR ꢀ: 165.4, 151.3,
149.2, 141.4, 131.6, 129.3, 129.0, 128.6, 127.6, 97.8, 51.3,
50.6, 17.6; IR (KBr) ꢁ: 3367, 3221, 3103, 2948, 1713, 1696
cm-1; MS m/z (%): 280 (M+, 5.13).
provided by Shanghai Institute of Organic Chemistry. H
NMR spectra were recorded on a BRUKER AVANCE (400
MHz) spectrometer using TMS as internal standard and CDCl3
or DMSO as solvent. IR spectra were recorded on Mattson
1000 FT-IR spectrometer using KBr pellets. Melting points
are uncorrected. Soniation was performed in Shanghai
Branson-CQX ultrasonic cleaner (with a frequency of 25 KHz
and a nominal power 250 W).
1
Entry 14: m.p.: 251-253 °C, H NMR (DMSO-d6, 400
MHz) ꢀ: 9.20 (s, 1H, NH), 7.62 (s, 1H, NH), 7.26-7.43 (m,
4H, Ar-H), 5.67 (s, 1H, H-4), 2.33 (s, 3H, COCH3), 2.04 (s,
3H, C6-CH3); 13C NMR ꢀ: 193.8, 151.2, 148.7, 140.6, 131.6,
129.5, 129.2, 128.6, 127.6, 108.4, 51.4, 30.0, 18.7; IR (KBr)
ꢁ: 3243, 3093, 2940, 1704, 1621 cm-1; MS m/z (%): 265 (M+,
2.04).
General Procedure for the Synthesis of 3,4-
Dihydropyrimidin-2-(1H)-ones
Combinaitons of aldehyde 1 (50 mmol), 1,3-dicarbonyl
compound 2 (50 mmol), urea (thiourea) 3 (75 mmol) and
nafion-H (100 wt% of the reactants) were mixed together on a
desk-top. Then, the mixture was irradiated in the water-bath of
the ultrasonic cleaner for some time. After the completion of
the reaction (indicated by TLC), the mixture was dissolved in
ethanol and poured into ice cold water. The resulting
precipitate was filtered and recrystallized from ethanol. All
products were confirmed by comparing their melting points,
1H NMR and IR spectral data with literature data. Some of the
representative compounds are given below:
RESULTS AND DISCUSSION
The results are summarized in Table 1. It can easily be seen
that the condensation of a series of aldehydes with 1, 3-
dicarbonyl compound and urea/thiourea leading to 3,4-
dihydropyrimidin-2(1H)-ones gives good yields under
ultrasound irradiation and solvent-free conditions.
As shown in Table 1, various aromatic aldehydes carrying
either electron-releasing or electron-withdrawing substituents
can obtain high yields. It is pleasing to observe the remarkable
stability of a variety of functional group such as nitro,
hydroxyl, and conjugated carbon-carbon double bound under
the reaction conditions. Acid-sensitive aldehyde such as
cinnamaldehyde was adopted well without the formation of
any side products (entry 11). However, when the aliphatic
aldehydes were used as the starting materials, the yield
dropped because of the lower activity of carbonyl group in
aliphatic aldehydes (entry 10). 3,4-Dihydropyrimidin-2(1H)-
thiones (entries 17-21), which were also of considerable
interest with regard to biological activity, were successfully
synthesized under similar conditions. 3, 4-Dihydropyrimidin-
2-(1H)-ones were achieved in excellent yields without the
1
Entry 1: m.p.: 202-204 °C, H NMR (DMSO-d6, 400
MHz) ꢀ: 9.18 (s, 1H, NH), 7.73 (s, 1H, NH), 7.23-7.24 (m,
5H, Ar-H), 5.14 (d, 1H, J = 2.6 Hz, H-4), 3.96 (q, 2H, J = 7.0
Hz, OCH2CH3), 2.25 (s, C6-CH3), 1.07 (t, J = 7.0 Hz, 3H,
OCH2CH3); IR (KBr) ꢁ: 3244, 3112, 2979, 1724, 1699, 1651
cm-1.
1
Entry 2: m.p.: 206-208 °C, H NMR (DMSO-d6, 400
MHz) ꢀ: 9.20 (s, 1H, NH), 7.74 (s, 1H, NH), 7.22-7.33 (m,
5H, Ar-H), 5.13 (d, J = 3.2 Hz, 1H, H-4), 3.52 (s, 3H,
COOCH3), 2.24 (s, 3H, C6-CH3). IR (KBr) ꢁ: 3334, 3223,
3106, 2951, 1700, 1666 cm-1.
1
Entry 13: m.p.: 227-229 °C, H NMR (DMSO-d6, 400
MHz) ꢀ: 9.26 (s, 1H, NH), 7.59 (s, 1H, NH), 7.25-7.40 (m,
319

Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
Table 1. Synthesis of 3,4-Dihydropyrimidin-2-(1H)-ones Catalyzed by Nafion-H under Ultrasound Irradiation
and Solvent-Free Conditions
m.p. (°C)
Entry
R1
R2
X
Yield (%)a
Found
Reported
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
3-O2NC6H4
4-HOC6H4
4-O2NC6H4
3-ClC6H4
4-CH3OC6H4
4-ClC6H4
CH3
OEt
OMe
Me
O
O
O
O
O
O
O
O
O
O
O
95
91
90
91
90
88
89
92
92
80
90
202-204
206-208
235-236
226-228
227-228
206-208
192-193
201-203
212-215
188-189
232-234
(203-204 [19])
(207-210 [19])
(233-236 [19])
(227-229 [20])
(227-228 [20])
(207-209 [20])
(192-193 [20])
(201-203 [20])
(212-215 [20])
(189-190 [21])
(232-235 [11])
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
9
10
11
C6H5CH=CH
12
13
14
15
OEt
OMe
Me
O
O
O
O
85
87
85
89
202-204
227-229
251-253
236-238
(202-204 [22])
O
2-ClC6H4
2-ClC6H4
4-HOC6H4
Me
(236-238 [23])
(239-241 [19])
16
4-O2NC6H4
Me
O
91
239-241
17
18
19
C6H5
C6H5
C6H5
OEt
Me
OMe
S
S
S
88
85
84
205-206
219-221
220-222
(205-206 [24])
(220-222 [12])
(222 [25])
20
21
4-CH3OC6H4
4-ClC6H4
OEt
OEt
S
S
87
87
135-137
183-185
(136-138 [26])
(180-182 [26])
aYield of isolated product.
formation of any side products, which are normally observed
in the presence of other traditional methods. The catalyst
could be easily isolated by filtration.
ACKNOWLEDGEMENTS
We gratefully acknowledge the financial support of the
open foundation of the Key Discipline of Industrial Catalysis.
In summary, we have developed a simple and efficient
procedure for the synthesis of dihydropyrimidinones or
thiones, using nafion-H as catalyst. The crude products
REFERENCES
1
obtained are of high purity (>95% by H NMR) and do not
require any chromatographic separation. Most significantly,
the whole operation does not involve any organic solvent at
any stage. The mild reaction conditions, rapid conversion,
high yields, simple experimental procedure, and catalyst
reusability are notable advantages of the present method.
[1]
[2]
[3]
K.S. Suslick, P.F. Schubert, J.W. Goodale, J. Am.
Chem. Soc. 18 (1986) 5641.
G.A. Olah, P.S. Iyer, G.K.S. Prakash, Synthesis 7
(1986) 513.
G.A. Olah, J. Kaspi, J. Bukala, J. Org. Chem. 42 (1977)
320

Wang & Pei
4187.
[16] J.J. Peng, Y. Deng, Tetrahedron Lett. 42 (2001) 5917.
[17] V.R. Choudhary, V.H. Tillu, V.S. Narkhede, H.B.
Borate, R.D. Wakharkar, Catal. Commun. 4 (2003)
449.
[18] G.A. Gross, H. Wurziger, A. Schober, J. Comb. Chem.
8 (2006) 153.
[4]
G.A. Olah, R. Malhotra, S.C. Narang, J.A. Olah,
Synthesis (1978) 672.
G.A. Olah, S.C. Narang, Synthesis (1978) 690.
G.A. Olah, S.C. Narang, D. Meidar, G.F. Salem,
Synthesis (1981) 282.
[5]
[6]
[7]
G.A. Olah, D. Meidar, A.P. Fung, Synthesis (1979)
270.
[19] Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem. 65
(2000) 3864.
[8]
[9]
C.O. Kappe, Tetrahedron 49 (1993) 6937.
P. Biginelli, Gazz. Chim. Ital. 23 (1893) 360.
[20] T.S. Jin, H.X. Wang, C.Y. Xing, X.L. Li, T.S. Li,
Synth. Commun. 34 (2004) 3009.
[10] E.H. Hu, D.R. Sidler, U.H. Dolling, J. Org. Chem. 63
(1998) 3454.
[21] K. Folkers, H.J. Harwood, T.B. Johnson, J. Am. Chem.
Soc. 54 (1932) 3751.
[11] J. Lu, Ma, H. Synlett. (2000) 63.
[12] B.C. Rannu, A. Hajra, U. Jana, J. Org. Chem. 65 (2000)
6270.
[22] J. Lu, Y. Bai, Synthesis (2002) 466.
[23] S.J. Tu, F. Fang, S. Zhu, T. Li, X. Zhang, Q. Zhuang,
Synlett 3 (2004) 537.
[13] K. Ramalinga, P. Vijayalakshmi, T.N.B. Kaimal,
Synlett (2001) 863.
[14] J. Lu, Y. Bai, Z. Wang, B. Yang, H. Ma, Tetrahedron
Lett. 41 (2000) 9075.
[15] J.S. Yadav, B.V.S. Reddy, R. Srinivas, C. Venugopal,
T. Ramalingam, Synthesis (2001) 1341.
[24] C.O. Kappe, J. Org. Chem. 62 (1997) 7201.
[25] K.M. Anup, A. Geetanjali, K.M. Soni, Indian J. Chem.,
Sect. B 43 (2004) 2018.
[26] S. Xue, Y.C. Shen, Y.L. Li, X.M. Shen, Q.X. Guo,
Chin. J. Chem. 20 (2002) 385.
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