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Short Note

Methyl 6-Methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

by
Qing Chen
,
Qingjian Liu
* and
Haiping Wang
College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Engineering Research Center of Pesticide and Medicine Intermediate Clean Production, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
*
Author to whom correspondence should be addressed.
Molbank 2012, 2012(2), M752; https://doi.org/10.3390/M752
Submission received: 20 December 2011 / Accepted: 9 April 2012 / Published: 17 April 2012
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Abstract

:
Methyl 6-methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate has been synthesized via the modified Biginelli reaction from benzaldehyde, p-tolylurea, and methyl acetoacetate, promoted with microwave irradiation and catalyzed by TsOH under solvent-free conditions in high yield.

Graphical Abstract

Recently, dihydropyrimidinones (DHPMs) and their derivatives have draw intensive interest because of their biological and pharmaceutical properties [1,2]. So, the synthesis of DHPMs has been revalued. The classical synthesis of dihydropyrimidinone was the Biginelli reaction of aldehyde, ethyl acetoacetate, and urea under acidic conditions [3]. In the last few decades, many improvements and modifications have been developed, including microwave promotion [4,5,6], ultrasound irradiation [7,8], ionic liquids [9,10,11] and the use of Lewis acid catalysts, such as NbCl5/QN-NH2 [12], BF3·OEt2/CuCl [13], formic acid [14], Yb(OTf)3 [15], InCl3 [16], NH4Cl [17], Cu(OTf)2 [18], Cu(ClO4)2·6H2O [19], etc.
Chiral DHPMs via Biginelli condensation reaction have been realized [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37].
A variety of substitutients including N-substituted urea [38] and β-acylpyruvates [39] in the components have been investigated to produce differently substitued DHPMs for searching for DHPMs with distinguished biological and medicinal activities.
Microwave-assisted chemistry [40,41,42] and solvent-free reactions [42,43] have received a considerable attention. Application of microwave irradiation in organic synthesis is becoming an increasingly popular technology because of its rapid reaction rates, cleaner reaction conditions and ease of manipulation [43,44,45,46,47,48,49,50,51].
Herein, we report the synthesis of methyl 6-methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate from benzaldehyde, methyl acetoacetate, and p-tolylurea via the modified Biginelli reaction promoted with microwave irradiation and catalyzed by p-toluenesulfonic acid (TsOH) under solvent-free conditions in high yield (Scheme 1). This procedure had the advantages of short reaction time, simple and easy work-up, and it is environmentally benign. The product has been characterized by NMR (1H and 13C), IR, MS, and elemental analysis.

Experimental Procedure

Benzaldehyde (2 mmol), methyl acetoacetate (3.6 mmol), p-tolylurea (2 mmol) and TsOH (anhydrous, 5% of aldehyde based) were irradiated in a microwave reactor (600 W) at 60 °C for 15 min and monitored by TLC. After completion of the reaction, the reaction mixture was poured into crushed ice with stirring and was filtrated, washed with ethanol (95%) to obtain the crude product. Recrystallization from ethanol afforded the pure target compound as white crystals, 0.59 g, yield of 87.7%, m.p. 159.5–162 °C.
Accordingly, our investigation showed that the best results were observed when the molar ratio of aldehyde, p-tolylurea and methyl acetoacetate was 1:1:1.8. Different catalysts including HCl, H2SO4, H3PO4, formic acid, acetic acid, TsOH, tartaric acid and iodine had been tested and it was found that TsOH was the best and that the yields were not obviously affected by the concentration of TsOH.
In summary, methyl 6-methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate has been synthesized from benzaldehyde, methyl acetoacetate, and p-tolylurea catalyzed by TsOH and promoted with microwave irradiation under solvent-free conditions in high yield and characterized by NMR (1H and 13C) and IR spectra. The preparation is characteristic of short reaction time, simple and easy work-up, and it is environmentally benign. This protocol developed a facile and green synthesis of N-substituted 1,2,3,4-tetrahydropyrimidin-2-one and extended the utility of subtituted urea in the venerable Biginelli reaction.

Structural Characterization

1H NMR (Bruker 300 MHz, DMSO-d6): δH 8.13 (br s, 1 H, N-H), 7.42–7.05 (m, 9 H, Ar-H), 5.26 (br s, 1 H, 4-CH), 3.58 (s, 3 H, OCH3), 2.33 (s, 3 H, ArCH3), 2.02 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, DMSO-d6): δC 166.5, 152.7, 149.8, 144.4, 137.9, 135.6, 130.0, 129.9, 129.1, 128.0, 126.6, 103.9, 53.4, 51.6, 21.1, 18.5 ppm. IR (Bruker Tensor 27, KBr): νmax 3472, 1694, 1211, 1076 cm−1. HRMS (Bruker maXis, ESI): m/z 337.1535 ([M + H]+), C20H20N2O3 required: 337.1547 (M + H). Anal. calcd. (PE2400 II CHONS): calcd. for C20H20N2O3: C 71.41, H 5.99, N 8.33; found: C 71.68, H 5.82, N 8.53.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

Acknowledgments

Thanks go to College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University.

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Molbank 2012 m752 sch001 550
Scheme 1. The synthesis of the title compound via the modified Biginelli reaction.
Scheme 1. The synthesis of the title compound via the modified Biginelli reaction.
Molbank 2012 m752 sch001

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MDPI and ACS Style

Chen, Q.; Liu, Q.; Wang, H. Methyl 6-Methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate. Molbank 2012, 2012, M752. https://doi.org/10.3390/M752

AMA Style

Chen Q, Liu Q, Wang H. Methyl 6-Methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate. Molbank. 2012; 2012(2):M752. https://doi.org/10.3390/M752

Chicago/Turabian Style

Chen, Qing, Qingjian Liu, and Haiping Wang. 2012. "Methyl 6-Methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate" Molbank 2012, no. 2: M752. https://doi.org/10.3390/M752

APA Style

Chen, Q., Liu, Q., & Wang, H. (2012). Methyl 6-Methyl-1-(4-methylphenyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate. Molbank, 2012(2), M752. https://doi.org/10.3390/M752

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