DOI: https://doi.org/10.24959/ophcj.19.962

The synthesis of novel spirocyclic N-aryl-substituted 2-thiopyrimidine-4,6-diones

N. I. Kobyzhcha, V. M. Holovatiuk, V. V. Rozhkov, V. I. Kashkovsky

Abstract


A convenient and efficient method for the synthesis of new unsaturated spiro-annulated N-aryl-4,6-dioxopyrimidine-2-thione derivatives has been developed. The resulting compounds can be potential biological active molecules or precursors for further chemical modification.

Aim. To develop the methods for the synthesis of new unsaturated spiro-annulated 2-thiopyrimidine-4,6-dione derivatives, which can be used as potentially biological active molecules or precursors for their formation.

Results and discussion. By condensation of N-aryl-substituted thioureas and allylmalonic acid using acetic anhydride or acetyl chloride the series of 5-allyl-substituted 2-thiopyrimidinediones has been synthesized. Their further alkylation with allyl bromide or metallyl chloride led to formation of 5,5-dialkenyl derivatives, which were converted to the corresponding unsaturated spirocyclic dioxopyrimidine-2-thiones by ring-closing metathesis. 

Experimental part. The synthesis of the starting compounds and title products was performed by preparative chemical methods, TLC and column chromatography, elemental analysis, NMR-spectroscopy.

Conclusions. The efficient three-step synthetic route of new unsaturated spiro-annulated N-aryl-4,6-dioxopyrimidine-2-thione derivatives from the starting N-arylsubstituted thioureas and allylmalonic acid has been developed. The spiro-annulated products obtained can find application in biological and pharmaceutical science or as starting substrates for further chemical modification.

Keywords


nitrogen heterocycles; spiro-annulation; thiopyrimidine-4,6-dione; metathesis; Grubbs catalyst

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References


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GOST Style Citations


1. Synthesis, hypnotic properties and molecular modeling studies of 1,2,7,9–tetraaza–spiro[4.5]dec–2–ene–6,8,10-triones / A. S. Girgis, H. Farag, N. S. Ismail, R. F. George // Eur. J. Med. Chem. – 2011. – Vol. 46 (10). – P. 4964–4969. https://doi.org/10.1016/j.ejmech.2011.07.058

 

2. US Pat. Appl., 2725380 A. Spiro barbituric acids / Arthur C. Cope. – declared 13.08.1949 ; published 29.11.1955.

 

3. Lee W. C. Comparative depression of several short acting barbiturates and spiro-barbiturates / W. C. Lee // Jap. J. Pharmacol. – 1953. – Vol. 2. – P. 123–126. https://doi.org/10.1254/jjp.2.123

 

4. Synthesis and anticonvulsant activity of certain spiro compounds derived from barbituric and thiobarbituric acids / A. N. Osman, M. M. Kandeel, M. M. Saidand, E. M. Ahmed // Ind. J. Chem. – 1996. – Vol. 35B. – P. 1073–1078. https://doi.org/10.1002/chin.199652179

 

5. Studies on spiroheterocycles Part–II : Heterocyclization of the spiro compounds containing cyclohexanone and thiobarbituric acid with different bidentate nucleophilic reagents / R. K. Behera, A. K. Behera, R. Pradhan et al. // Synth. Commun. – 2006. – Vol. 36. – P. 3729–3742. https://doi.org/10.1080/00397910600946231

 

6. Design, synthesis and anticancer activity of functionalized spiro–quinolines with barbituric and thiobarbituric acids / R. K. Bhaskarachar, V. G. Revanasiddappa, S. Hegde et al. // Med. Chem. Res. – 2015. – Vol. 24. – P. 3516–3528. https://doi.org/10.1007/s00044-015-1408-7

 

7. Studies on spiroheterocycles part-I: Installation of biologically active heterocyclic nuclei into spiro compounds derived from cyclohexanone and diphenyl thiobarbituric acid / R. K. Behera, A. K. Behera, R. Pradhan, M. Patra // Ind. J. Chem. – 2006. – Vol. 45B. – P. 933–942.

 

8. Green Synthesis and Urease Inhibitory Activity of Spiro–Pyrimidinethiones / Spiro–Pyrimidinones-Barbituric Acid Derivatives / M. Ziarani, S. Asadi, S. Faramarzi, M. Amanlou // Iran. J. Pharm. Res. – 2015. – Vol. 14 (4). – P. 1105–1114.

 

9. Synthesis and CNS depressant of newer spirobarbiturates / B. Goel, S. Sharma, K. Bajaj et al. // Ind. J. Pharm. Sci. – 2005. – Vol. 67. – P. 194–199.

 

10. Cope, A. Spirobarbituric Acids Containing a Six–membered Carbocyclic Ring / A. Cope, P. Kovacic, M. Burg // J. Am. Chem. Soc. – 1949. – Vol. 71 (11). – P. 3658–3662. https://doi.org/10.1021/ja01179a023

 

11. Kotha, S. Spiro-annulation of barbituric acid derivatives and its analogs by ring–closing metathesis reaction / S. Kotha, A. Deb, R. Kumar // Bioorg. Med. Chem. Lett. – 2005. – Vol. 15 (4). – P. 1039–1043. https://doi.org/10.1016/j.bmcl.2004.12.034

 

12. Kotha, S. Design and synthesis of spiro-heterocycles by ring–closing metathesis / S. Kotha, A. Deb // Ind. J. Chem. – 2008. – Vol. 47B. – P. 1120–1134.

 

13. Synthesis of new N,N’–disubstituted 5–spirocyclopenten–3–yl 2,4,6–trioxyhexahydropy–rimidines / N. I. Kobyzhcha, V. M. Holovatiuk, Yu.V. Bezugly, V. I. Kashkovsky // J. of Org. and Pharm. Chem. – 2013. – Vol. 11 (4). P. 42–47. https://doi.org/10.24959/ophcj.13.770

 

14. Synthesis of mono– and N,N–disubstituted thioureas and N–acylthioureas / A. R. Katritzky, N. Kirichenko, B. V. Rogovoy et al. // Synthesis. – 2004. – Vol. 11. – P. 1799–1805. https://doi.org/10.1055/s-2004-829127

 

15. A Recyclable Ru–Based Metathesis Catalyst / J. S. Kingsbury, J. P. Harrity, P. J. Bonitatebus, A. H. Hoveyda // J. Am. Chem. Soc. –1999. – Vol. 121 (4). – P. 791–799. https://doi.org/10.1021/ja983222u





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