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Biginelli reaction using thiourea; N,N'-(4,4'-(ethane-1,2-diyl)bis(4,1-phenylene))bis(4-(3-bromo-4-hydroxy-5-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide)

SyntheticPage 812
DOI: 10.1039/SP812
Submitted Nov 25, 2016, published Nov 28, 2016
Sirin Gulten (siringulten@hotmail.com), Ezgi Arslan (zg_moncal@hotmail.com)
A contribution from Sirin Gülten, Çanakkale Onsekiz Mart University


			Reaction Scheme: Biginelli reaction using thiourea

Chemicals Used

3-Oxo-N-[4-[4-(3-oxobutanoylamino)phenyl]ethylphenyl]butanamide, Gulten, S, SyntheticPages, 2011, 498

5-Bromovanillin (Aldrich)

Thiourea (Acros Organics)

37% HCl (Merck)

 

Procedure

A mixture of 3-oxo-N-[4-[4-(3-oxobutanoylamino)phenyl]ethylphenyl]butanamide (300 mg, 0.789 mmol), thiourea (180 mg, 2.37 mmol), 5-bromovanilin (460 mg, 1.97 mmol) and catalytic amount of conc. HCl (4 drops) in EtOH (10 mL) was heated at reflux for 3 days. After the completion of reaction, the mixture was allowed to cool. The solid product formed was filtered, washed with water (5 mL) and cold ether (3x5 mL) and dried. The title compound was obtained as a mustard yellow coloured solid (650 mg, 89% yield).

Author's Comments

This reaction was carried out with catalytic amount of pTSA to give the corresponding bis Biginelli product in 43% yield.

The authors thank the Çanakkale Onsekiz Mart University Scientific Research Projects Coordination Department (BAP, FYL-2014-178) for financial support.

 

Data

IR-ATR: 3249, 3195, 3119, 2970, 2934, 1674, 1633, 1575, 1495, 1280, 1180, 1042, 680 cm-1. 1H NMR (300 MHz, DMSO-d6): ppm = 10.02 (s, 2H, NH), 9.73 (s, 2H, NH), 9.52 (br s, 2H, OH), 9.40 (s, 2H, NH), 7.48 (d, 4H, J = 10.17 Hz, CHAr), 7.15 (d, 4H, J = 8.45 Hz, CHAr), 6.99 (s, 2H, CHAr), 6.87 (s, 2H, CHAr), 5.36 (s, 2H, CH), 3.77 (s, 6H, OCH3), 2.81 (s, 4H, CH2CH2), 2.10 (s, 6H, CH3).
13C NMR (75 MHz, DMSO-d6): ppm = 175.13, 165.26, 148.76, 143.77, 137.15, 137.07, 135.71, 135.24, 128.92, 122.40, 120.20, 110.41, 110.07, 107.44, 56.52, 54.91, 37.02, 16.97.


Lead Reference

Vijay Virsodia, Raghuvir R.S. Pissurlenkar, Dinesh Manvar, Chintan Dholakia, Priti Adlakha, Anamik Shah, Evans C. Coutinho, Synthesis, screening for antitubercular activity and 3D-QSAR studies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides, Eur. J. Med. Chem., 43, 2008, 2103-2115. doi:10.1016/j.ejmech.2007.08.004

 

Other References

B.R. Prashantha Kumar, Gopu Sankar, R.B. Nasir Baig, Srinivasan Chandrashekaran, Novel Biginelli dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study, Eur. J. Med. Chem., 44, 2009, 4192-4198. doi:10.1016/j.ejmech.2009.05.014

Supplementary Information

Proton NMR (Proton NMR.jpg)
Carbon NMR (Carbon NMR.jpg)

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Keywords: addition, amines, aromatics/arenes, Biginelli dihydropyrimidine, heterocyclic compounds, nucleophilic, thermal

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