Ultrasound-assisted synthesis of novel 4-(2-phenyl-1,2,3-triazol-4-yl)-3,4- dihydropyrimidin-2(1H)-(thio)ones catalyzed by sm(ClO4)3

Article abstract of DOI:10.3390/molecules15042087

An efficient synthesis of novel 4-(2-phenyl-1,2,3-triazol-4-yl)-3,4- dihydropyrimidin2(¹H)-(thio)ones from 1,3-dicarbonyl compounds, 2-phenyl-1,2,3-triazole-4carbaldehyde and urea or thiourea under ultrasound irradiation and using samarium perc

Full text of DOI:10.3390/molecules15042087

Molecules 2010, 15, 2087-2095; doi:10.3390/molecules15042087
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Ultrasound-Assisted Synthesis of Novel 4-(2-Phenyl-1,2,3-
Triazol-4-yl)-3,4-Dihydropyrimidin-2(1H)-(Thio)ones Catalyzed
by Sm(ClO4)3
Chen-Jiang Liu 1,2 and Ji-De Wang 1,2,
*
1
School of Science, Xi'an Jiaotong University, 710049 Xi'an, China; E-Mail: pxylcj@126.com
School of Chemistry and Chemical Engineering, Xinjiang University, Key Laboratory of Oil and
Gas Fine Chemicals, Ministry of Education, 830046 Urumqi, China
2
* Author to whom correspondence should be addressed; E-Mail: cjliuxj@126.com;
Tel.: +86-9918581211; Fax: +86-9918582807.
Received: 28 January 2010; in revised form: 15 March 2010 / Accepted: 24 March 2010 /
Published: 24 March 2010
Abstract: An efficient synthesis of novel 4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydro-
pyrimidin-2(1H)-(thio)ones from 1,3-dicarbonyl compounds, 2-phenyl-1,2,3-triazole-4-
carbaldehyde and urea or thiourea under ultrasound irradiation and using samarium
perchlorate as catalyst is described. Compared with conventional methods, the main
advantages of the present methodology are milder conditions, shorter reaction times and
higher yields.
Keywords: Biginelli reaction; dihydropyrimidinone; triazole; Sm(ClO4)3; ultrasound
Introduction
3,4-Dihydropyrimidin-2(1H)-ones and their derivatives have attracted increasing interest owing to
their therapeutic and pharmaceutical properties, such as antiviral, antibacterial, anti-inflammatory and
antitumour activities [1–3]. Recently, functionalized dihydropyrimidinones have been successfully
used as antihypertensive agents, calcium channel blockers, adrenergic and neuropeptide Y (NPY)
antagonists [4–5]. In addition, some alkaloids containing the dihydropyrimidine core unit which also
exhibit interesting biological properties have been isolated from marine sources. Most notably, among
these are the batzelladine alkaloids, which were found to be potent HIV gp-120-CD4 inhibitors [6,7].

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The original protocol for the synthesis of dihydropyrimidinones, reported by Biginelli in 1893,
involves a one-pot reaction of benzaldehyde, ethyl acetoacetate and urea in ethanol under strongly
acidic conditions [8]. However, this method suffers from drawbacks such as low yields (20–40%) of
the desired products, particularly in case of substituted aldehydes, and loss of acid sensitive functional
groups during the reaction. This has led to multi-step synthetic strategies that produce somewhat better
yields, but which lack the simplicity of the original one-pot Biginelli protocol [9]. The search for more
suitable preparation of dihydropyrimidinones continues today.
Recently, many synthetic methods for preparing these compounds have been developed to improve
and modify this reaction by using Lewis acid catalysts as well as protic acids including FeCl3·6H2O,
NiCl2·6H2O [10], lanthanide triflate [11], H3BO3 [12], VCl3 [13], Sr(OTf)2 [14], PPh3 [15], Indium(III)
halides [16], LiBr [17], Silicasulfuric acid [18], Mn(OAc)3·2H2O [19], Y(NO3)3·6H2O [20], In(OTf)3
[21], TaBr5 [22], Ce(NO3)3·6H2O [23], silica chloride [24], HCOOH [25], SrCl2·6H2O-HCl[26],
Yb(OTf)3 [27], Bi(NO3)3·5H2O [28], tungstate sulfuric acid [29], HClO4-SiO2 [30] and so on. In
addition, ionic liquids [31], microwave irradiation [32] and ultrasound irradiation [33] were also
utilized as the catalytic condition. However, in spite of their potential utility, many of these methods
involve expensive reagents, strong acidic conditions and long reaction times.
As environmental consciousness has increased in chemical research and industry, the challenge for
a sustainable environment calls for clean procedures. Ultrasound has gradually been introduced in
organic synthesis as a green synthetic approach over the last three decades. Compared with traditional
methods, this technique is more convenient and easily controlled. A large number of organic reactions
can be carried out under milder conditions, in shorter reaction times and providing higher yields under
ultrasound irradiation [34].
Due to their unique biological properties, 1,2,3-triazole derivatives have attracted much attention
[35]. In continuation of our interest in Lewis acid applications for dihydropyrimidinones and
ultrasound-assisted synthesis [36], herein we report the preparation of 4-(2-phenyl-1,2,3-triazol-4-yl)-
3,4-dihydropyrimidin-2(1H)-(thio)ones from 1,3-dicarbonyl compounds, 2-phenyl-1,2,3-triazole-4-
carbaldehyde and urea or thiourea in the presence of Sm(ClO4)3 under ultrasound irradiation
(Scheme 1). In this work, an efficient method for the synthesis of target compounds is described and
none of them have been reported yet in the literature.
Scheme 1. The synthesis of 4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimdin-2(1H)-
(thio)ones catalyzed by Sm(ClO4)3.
X
HN
NH
R1
CHO
+
O
O
X
3
10 mol%, Sm(ClO4)3
NH2
EtOH, U. S.
+
N
N
R1
R2
H2N
N
N
N
N
R2
O
Ph
Ph
1
2
4

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Results and Discussion
To begin this study, different catalysts were tested in the condensation reactions of ethyl
acetoacetate (2 mmol), 2-phenyl-1,2,3-triazole-4-carbaldehyde (2 mmol) and urea (3 mmol) in
refluxing ethanol, affording 5-ethoxycarbonyl-6-methyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydro-
pyrimidin-2(1H)-one (4a) in various yields (Table 1). These results show that samarium perchlorate
was the most efficient of the four catalysts studied. In order to identify the best molar ratio of reagents,
we next did the experiment with different ratios of 1,3-dicarbonyl compounds, 2-phenyl-1,2,3-triazole-
4-carbaldehyde, urea or thiourea and Sm(ClO4)3 in EtOH refluxing at 75–80 °C under ultrasonic
irradiation. We found that a 1:1:1.5:0.1 molar ratio of reactants gave the best results.
Table 1. Effects of different catalysts on the formation of 4a under conventional conditions. a
No.
Catalyst
Catalyst (mol %) Time (h)
Yield of 4ab (%)
1
2
3
HCl
10
10
10
10
24
12
12
9
42
51
70
88
Zn(ClO4)2
Mg(ClO4)2
Sm(ClO4)3
4
a
Reaction conditions: 2-phenyl-1,2,3-triazole-4-carbaldehyde (2 mmol), ethyl acetoacetate (2
mmol), urea (3 mmol), EtOH (10 mL), 75-80 °C; b Isolated yield.
Table 2. Sm(ClO4)3-catalyzed one-pot three-component synthesis of 4-(2-phenyl-1,2,3-
triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-(thio)ones.
Time (h)a
Yield (%)b
Entry R1
R2
X
Mp ( °C)
Ac
9
Bc
3
3
2
2
3
3
3
3
2
2
3
Ac
88
71
89
78
72
70
69
86
76
90
80
Bc
95
78
94
85
80
77
76
89
84
95
86
4a
4b
4c
4d
4e
4f
CH3
OCH2CH3
OCH3
O
O
O
O
O
S
176-177
215-218
245-246
244-246
203-206
203-205
219-222
200-203
269-270
259-261
204-206
CH3
CH3
CH3
Ph
9
CH3
6
Ph
6
OCH2CH3
OCH2CH3
OCH3
9
CH3
CH3
CH3
CH3
CH3
Ph
9
4g
4h
4i
S
9
OC(CH3)3
CH3
S
9
S
6
4j
Ph
S
6
4k
OCH2CH3
S
9
a Reactions were continued until the TLC shown the starting materials disappeared; b Isolated yield;
c
Method A: Sm(ClO4)3 as catalyst in refluxing EtOH at 75–80 °C without ultrasound; Method B:
Sm(ClO4)3 as catalyst in refluxing EtOH at 75–80 °C under ultrasound irradiation.
Using these optimized reaction conditions, the reaction of various 1,3-dicarbonyl compounds, 2-
phenyl-1,2,3-triazole-4-carbaldehyde and urea or thiourea using Sm(ClO4)3 as catalyst under both
ultrasound irradiation and conventional conditions were investigated. The results are summarized in
Tables 2. It was found that all the reactions proceeded smoothly to give the corresponding 4-(2-

Molecules 2010, 15
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phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-(thio)ones in good yields. Compared to the
conventional heating method, the achieved yields under ultrasound irradiation increase six or eight
percent and only one-third of the reaction time need. According to the mechanism suggested by Kappe
[37], a proposed reaction mechanism of Biginelli condensation via acyl imine intermediate 5 is
presented in Scheme 2, this intermediate is formed by the reaction of the 2-phenyl-1,2,3-triazole-4-
carbaldehyde 1 and urea or thiourea 3 and then stabilized by Sm(ClO4)3 through a coordinate bond
owing to its empty orbital. Subsequent addition of the iminium ion to ethyl acetoactate in the presence
of Sm(ClO4)3 as catalyst produces an open chain ureide 6 which subsequently undergo cyclization and
dehydration to afford the corresponding dihydropyrimidinone 4.
Scheme 2. Mechanism of Biginelli reaction catalyzed by Sm(ClO4)3.
OH
X
CHO
X
N
H
NH2
-H2O
+
N
N
H2N
N
N
NH2
N
N
Ph
1
Ph
3
X
Sm3+
O
H
X
H
N
NH2
O
O
N
NH2
R1
R2
N
N
R1
-H+
N
N
N
N
R2
X
O
Ph
Ph
5
6
X
HN
NH
R2
HN
NH
OH
R1
-H2O
R1
H
C
O
R2
N
N
N
N
N
N
O
Ph
Ph
4
Experimental
General
1
All compounds were characterized by IR, H-NMR spectra and elemental analysis. The IR spectra
1
were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, USA). The H-
NMR spectra were obtained on a Varian Inova-400 spectrometer using CDCl3 or DMSO-d6 as solvent
(details given below) and TMS as an internal standard; chemical shifts are given in ppm. Elemental
analyses (C, H, N) were performed on a Perkin-Elmer Analyzer 2400. Melting points were determined

Molecules 2010, 15
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using a Büchi B-540 instrument. Sonication was performed in a Kunshan ultrasonic cleaner
(KQ5200B, Kunshan Ultrasonic Instrument Co. Ltd.) with a frequency of 40 KHz and a nominal
power of 200W. The reaction flask was located in the maximum energy area of the cleaner, where the
surface of reactants is slightly lower than the level of the water. All melting points are uncorrected.
2-Phenyl-1,2,3-triazole-4-carbaldehyde was synthesized according to previous literature [38].
General procedure for the synthesis of 4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-
(thio)ones 4a-4k
2-Phenyl-1,2,3-triazole-4-carbaldehyde (1 mmol), 1,3-dicarbonyl compound (1 mmol), urea or
thiourea (1.5 mmol), Sm(ClO4)3 (10 mol %) and absolute EtOH (10 mL) were placed in a Pyrex flask
(50 mL). The mixture was irradiated in the water bath of the ultrasonic cleaner at 75–80 °C for a
specified period. Sonication was continued until the starting material had disappeared as indicated by
TLC using ethyl acetate/petroleum ether (1:3) as eluent. After completion of the reaction, the mixture
was cooled to room temperature and filtered. The collected solid was washed with a little amount of
ethanol, and then dried. The products were pure enough without further purification. The results are
summarized in Tables 2. Data of the compounds are shown below:
5-Ethoxycarbonyl-6-methyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-one
(4a):
White solid. IR: ν 3296, 3179, 3079, 2984, 1679, 1643, 1600, 1452, 1370, 1144, 966, 761, 689 cm-1;
1H-NMR (CDCl3) δ: 10.32 (bs, 1H, NH), 9.55 (bs, 1H, NH), 7.63 (s, 1H, Tr-H), 7.32-8.02 (m, 5H, Ph),
5.72 (s, 1H, CH), 4.18 (q, J = 7.2 Hz, 2H, OCH2), 2.38 (s, 3H, CH3), 1.25 (t, J = 7.2 Hz, 3H,
*
CH3 CH2O); Anal. calcd. for C16H17N5O3: C, 58.71; H, 5.23; N, 21.39. Found: C, 58.83; H, 5.20; N,
21.28.
6-Methyl-5-methoxycarbonyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-one
(4b):
White solid. IR: ν 3307, 3182, 3090, 2972, 1667, 1638, 1611, 1449, 1389, 1128, 963, 770, 695 cm-1;
1H-NMR (CDCl3) δ: 10.31 (bs, 1H, NH), 9.29 (bs, 1H, NH), 7.86 (s, 1H, Tr-H), 7.39-7.95 (m, 5H, Ph),
5.44 (s, 1H, CH), 3.61 (s, 3H, OCH3), 2.26 (s, 3H, CH3); Anal. calcd. for C15H15N5O3: C, 57.50; H,
4.83; N, 22.35. Found: C, 57.65; H, 4.79; N, 22.46.
5-Acetyl-6-methyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-one (4c): White solid.
IR: ν 3290, 3166, 3071,2983, 1683, 1645, 1552, 1335, 1145, 955, 753, 692 cm-1; 1H-NMR (DMSO-d6)
δ: 10.49 (bs, 1H, NH), 9.57 (bs, 1H, NH), 7.84 (s, 1H, Tr-H), 7.40-7.97 (m, 5H, Ph), 5.54 (s, 1H, CH),
2.28 (s, 3H, CH3CO), 2.27 (s, 3H, CH3); Anal. calcd. for C15H15N5O2: C, 60.60; H, 5.09; N, 23.56.
Found: C, 60.51; H, 5.15; N, 23.62.
6-Methyl-5-benzoyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-one (4d): White solid.
IR: ν 3287, 3172, 3076, 2984, 1688, 1640, 1601, 1333, 1149, 973, 763,700 cm-1; 1H-NMR (DMSO-d6)
δ: 10.45 (bs, 1H, NH), 9.73 (bs, 1H, NH), 7.95 (s, 1H, Tr-H), 7.42-7.98 (m, 10H, Ph), 5.58 (s, 1H,
CH), 1.67 (s, 3H, CH3CO); Anal. calcd. for C20H17N5O2: C, 66.84; H, 4.77; N, 19.49. Found: C, 66.94;
H, 4.83; N, 19.38.

Molecules 2010, 15
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5-Ethoxycarbonyl-6-phenyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-one
(4e):
White solid. IR: ν 3292, 3164, 3079, 2980, 1673, 1641, 1591, 1550, 1454, 1375, 1147, 958, 761, 701
cm-1; 1H-NMR (DMSO-d6) δ: 10.43 (bs, 1H, NH), 9.70 (bs, 1H, NH), 8.00 (s, 1H, Tr-H), 7.33-7.98 (m,
*
10H, Ph), 5.56 (s, 1H, CH), 3.79 (q, J = 7.2 Hz, 2H, OCH2), 0.77 (t, J = 7.2 Hz, 3H, CH3 CH2O);
Anal. calcd. for C21H19N5O3: C, 64.77; H, 4.92; N, 17.98. Found: C, 64.69; H, 4.86; N, 18.10.
5-Ethoxycarbonyl-6-methyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-thione
(4f):
White solid. IR: ν 3298, 3174, 3081, 2980, 1680, 1650, 1601, 1457, 1373, 1200, 1140, 960, 756, 696
cm-1; 1H-NMR (DMSO-d6) δ: 10.39 (bs, 1H, NH), 9.61 (bs, 1H, NH), 7.88 (s, 1H, Tr-H), 7.54-7.94 (m,
5H, Ph), 5.47 (s, 1H, CH), 4.07 (q, J = 7.2 Hz, 2H, OCH2), 2.30 (s, 3H, CH3), 1.13 (t, J = 7.2 Hz, 3H,
*
CH3 CH2O); Anal. calcd. for C16H17N5O2S: C, 55.96; H, 4.99; N, 20.39. Found: C, 55.85; H, 5.02; N,
20.30.
6-Methyl-5-methoxycarbonyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-thione (4g):
White solid. IR: ν 3279, 3139, 3070, 2973, 1675, 1641, 1603, 1472, 1369, 1206, 1129, 951, 767, 687
cm-1; 1H-NMR (DMSO-d6) δ: 10.45 (bs, 1H, NH), 9.69 (bs, 1H, NH), 7.89 (s, 1H, Tr-H), 7.40-7.95 (m,
5H, Ph), 5.47 (s, 1H, CH), 3.62 (s, 3H, OCH3), 2.32 (s, 3H, CH3); Anal. calcd. for C15H15N5O2S: C,
54.70; H, 4.59; N, 21.26. Found: C, 54.58; H, 4.65; N, 21.33.
5-(tert-Butoxycarbonyl)-6-methyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-thione
(4h): White solid. IR: ν 3283, 3149, 3076, 2969, 1683, 1643, 1606, 1461, 1362, 1201, 1133, 949, 770,
1
679 cm-1; H-NMR (DMSO-d6) δ: 10.40 (bs, 1H, NH), 9.66 (bs, 1H, NH), 7.89 (s, 1H, Tr-H), 7.41-
7.96 (m, 5H, Ph), 5.43 (s, 1H, CH), 2.29 (s, 3H, CH3), 1.38 (s, 9H, OC(CH3)3); Anal. calcd. for
C18H21N5O2S: C, 58.20; H, 5.70; N, 18.85. Found: C, 58.37; H, 5.63; N, 18.76.
5-Acetyl-6-methyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-thione (4i): White solid.
1
IR: ν 3291, 3177, 3072, 2980, 1681, 1643, 1560, 1336, 1205, 1145, 959, 762, 670 cm-1; H-NMR
(DMSO-d6) δ: 10.52 (bs, 1H, NH), 9.63 (bs, 1H, NH), 7.84 (s, 1H, Tr-H), 7.40-7.94 (m, 5H, Ph), 5.56
(s, 1H, CH), 2.33 (s, 3H, CH3CO), 2.28 (s, 3H, CH3); Anal. calcd. for C15H15N5OS: C, 57.49; H, 4.82;
N, 22.35. Found: C, 57.39; H, 4.77; N, 22.24.
6-Methyl-5-benzoyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-thione (4j): White
solid. IR: ν 3290, 3169, 3077, 2985, 1688, 1639, 1601, 1334, 1203, 1136, 965, 750, 671 cm-1; 1H-NMR
(DMSO-d6) δ: 10.36 (bs, 1H, NH), 9.71 (bs, 1H, NH), 7.94 (s, 1H, Tr-H), 7.39-7.97 (m, 10H, Ph), 5.59
(s, 1H, CH), 1.72 (s, 3H, CH3); Anal. calcd. for C20H17N5OS: C, 63.98; H, 4.56; N, 18.65. Found: C,
64.08; H, 4.53; N, 18.76.
5-Ethoxycarbonyl-6-phenyl-4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-thione (4k):
White solid. IR: ν 3294, 3174, 3079, 2979, 1679, 1643, 1599, 1554, 1456, 1372, 1201, 1140, 964, 757,
1
696 cm-1; H-NMR (CDCl3) δ: 10.38 (bs, 1H, NH), 9.67 (bs, 1H, NH), 7.78 (s, 1H, Tr-H), 7.35-8.08
*
(m, 10H, Ph), 5.86 (s, 1H, CH), 3.57 (q, J = 7.2 Hz, 2H, OCH2), 0.91 (t, J = 7.2 Hz, 3H, CH3 CH2O);
Anal. calcd. for C21H19N5O2S: C, 62.21; H, 4.72; N, 17.27. Found: C, 62.11; H, 4.79; N, 17.36.

Molecules 2010, 15
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Conclusions
In conclusion, we have successfully demonstrated an efficient protocol for the synthesis of 4-(2-
phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidin-2(1H)-(thio)ones by the Sm(ClO4)3-catalyzed reaction
of 1,3-dicarbonyl compounds, 2-phenyl-1,2,3-triazole-4-carbaldehyde and urea or thiourea under
ultrasound irradiation. The protocol offers several advantages such as mild reaction conditions, short
reaction times, easy isolation and good yields. Hence, it is an important supplement to the existing
methods for the synthesis of dihydroprimidiones and their corresponding thio-derivatives.
Acknowledgements
We gratefully acknowledge support from the National Natural Science Foundation of China (No.
20662009).
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