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

SyntheticPage 811
DOI: 10.1039/SP811
Submitted Nov 25, 2016, published Nov 29, 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

Chemicals Used

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

5-Bromovanillin (Aldrich)

Urea (Merck)

37% HCl (Merck) 

Procedure

A mixture of 3-oxo-N-[4-[4-(3-oxobutanoylamino)phenyl]ethylphenyl]butanamide (300 mg, 0.789 mmol), urea (140 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 1 day. 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 brown solid (640 mg, 81% yield).

Author's Comments

This reaction was carried out with catalytic amount of pTSA to give the corresponding bis Biginelli product in 34% yield.

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

 

Data

IR-ATR: 3330, 3231, 3116, 2936-2866, 1663, 1596, 1498, 1458, 1280, 1230, 1177, 1041, 681 cm-1. 1H NMR (300 MHz, DMSO-d6): ppm = 9.54 (s, 2H, NH), 9.43 (s, 2H, NH), 8.73 (s, 2H, NH), 7.69 (s, 2H, CHAr), 7.55-7.46 (m, 4H, CHAr), 7.14 (d, 2H, J = 8.47 Hz, CHAr), 7.01 (s, 2H, CHAr), 6.87 (s, 2H, CHAr), 5.46 (br s, 2H, OH), 5.36 (s, 2H, CH), 3.75 (s, 6H, OCH3), 2.80 (s, 4H, CH2CH2), 2.07 (s, 6H, CH3).
13C NMR (75 MHz, DMSO-d6): ppm = 165.66, 152.92, 149.00, 143.44, 138.47, 137.39, 136.84, 136.56, 128.86, 122.17, 120.13, 109.67, 109.48, 105.67, 56.49, 54.97, 37.05, 17.50.

 

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, amides, aromatics/arenes, Biginelli dihydropyrimidine, heterocyclic compounds, nucleophilic, thermal