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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

by
Chen-Jiang Liu
1,2 and
Ji-De Wang
1,2,*
1
School of Science, Xi'an Jiaotong University, 710049 Xi'an, China
2
School of Chemistry and Chemical Engineering, Xinjiang University, Key Laboratory of Oil and Gas Fine Chemicals, Ministry of Education, 830046 Urumqi, China
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(4), 2087-2095; https://doi.org/10.3390/molecules15042087
Submission received: 28 January 2010 / Revised: 15 March 2010 / Accepted: 24 March 2010 / Published: 24 March 2010
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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.

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 [1,2,3]. 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].
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.

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.
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 Table 2. It was found that all the reactions proceeded smoothly to give the corresponding 4-(2-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.

Experimental

General

All compounds were characterized by IR, 1H-NMR spectra and elemental analysis. The IR spectra were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, USA). The 1H-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 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 Table 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.
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, 679 cm-1; 1H-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. IR: ν 3291, 3177, 3072, 2980, 1681, 1643, 1560, 1336, 1205, 1145, 959, 762, 670 cm-1; 1H-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, 696 cm-1; 1H-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.

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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Sample Availability: Available from the authors
Molecules 15 02087 sch001 550
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.
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.
Molecules 15 02087 sch001
Molecules 15 02087 sch002 550
Scheme 2. Mechanism of Biginelli reaction catalyzed by Sm(ClO4)3.
Scheme 2. Mechanism of Biginelli reaction catalyzed by Sm(ClO4)3.
Molecules 15 02087 sch002
Table
Table 1. Effects of different catalysts on the formation of 4a under conventional conditions. a
Table 1. Effects of different catalysts on the formation of 4a under conventional conditions. a
No.CatalystCatalyst (mol %)Time (h)Yield of 4ab (%)
1HCl102442
2Zn(ClO4)2101251
3Mg(ClO4)2101270
4Sm(ClO4)310988
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
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.
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.
EntryR1R2XTime (h)aYield (%)bMp ( °C)
AcBcAcBc
4aCH3OCH2CH3O938895176-177
4bCH3OCH3O937178215-218
4cCH3CH3O628994245-246
4dCH3PhO627885244-246
4ePhOCH2CH3O937280203-206
4fCH3OCH2CH3S937077203-205
4gCH3OCH3S936976219-222
4hCH3OC(CH3)3S938689200-203
4iCH3CH3S627684269-270
4jCH3PhS629095259-261
4kPhOCH2CH3S938086204-206
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.

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Liu, C.-J.; Wang, J.-D. 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. Molecules 2010, 15, 2087-2095. https://doi.org/10.3390/molecules15042087

AMA Style

Liu C-J, Wang J-D. 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. Molecules. 2010; 15(4):2087-2095. https://doi.org/10.3390/molecules15042087

Chicago/Turabian Style

Liu, Chen-Jiang, and Ji-De Wang. 2010. "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" Molecules 15, no. 4: 2087-2095. https://doi.org/10.3390/molecules15042087

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