Synthesis of new pyrimidine-containing compounds: 5-(2-(alkylamino)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives

  • Khudaidad Kochia
  • Mohammad BayatEmail author
  • Shima Nasri
  • Aref Mohammadi
Original Article


In this study, the one-pot reaction between primary amines, 1,1-bis-(methylthio)-2-nitroethene, ninhydrin, and barbituric acid as an enolizable C–H-activated compound provides a simple method for the preparation of 5-(2-(alkylamino)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives with potential synthetic and pharmacological interest. This reaction shows attractive characteristics, such as substrate availability, good yields, existence of numerous hydrogen-bonding possibilities in product, and its mild conditions in ethanol media.

Graphic abstract


Pyrimidine Barbituric acid Ninhydrin Nitroketene dithioacetals Indene 



Financial support of this research from Imam Khomeini International University, Iran, is gratefully acknowledged.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interest.

Supplementary material

11030_2019_10009_MOESM1_ESM.doc (12.8 mb)
Supplementary material 1 (DOC 13142 kb)


  1. 1.
    Li B, Webster TJ (2018) Bacteria antibiotic resistance: new challenges and opportunities for implant-associated orthopedic infections. J Orthop Res 36:22–32PubMedGoogle Scholar
  2. 2.
    Ajani OO, Isaac JT, Owoeye TF, Akinsiku AA (2015) Exploration of the chemistry and biological properties of pyrimidine as a privilege pharmacophore in therapeutics. Int J Biol Chem 9:148–177CrossRefGoogle Scholar
  3. 3.
    Lagoja IM (2005) Pyrimidine as constituent of natural biologically active compounds. Chem Biodivers 2:1–50CrossRefGoogle Scholar
  4. 4.
    Sharma P, Rane N, Gurram VK (2004) Synthesis and QSAR studies of pyrimido [4,5-d] pyrimidine-2, 5-dione derivatives as potential antimicrobial agents. Bioorg Med Chem Lett 14:4185–4190CrossRefGoogle Scholar
  5. 5.
    Basavaraja HS, Sreenivasa GM, Jayachandran E (2005) Synthesis and biological activity of novel pyrimidino imidazolines. Indian J Heterocycl Chem 15:69Google Scholar
  6. 6.
    Kaldrikyan MA, Grigoryan LA, Geboyan VA, Arsenyan FG, Stepanyan GM, Garibdzhanyan BT (2000) Synthesis and antitumor activity of some disubstituted 5-(3-methyl-4-alkoxybenzyl) pyrimidines. Pharm Chem J 34:521–524CrossRefGoogle Scholar
  7. 7.
    Nezu Y, Miyazaki M, Sugiyama K, Kajiwara I (1996) Dimethoxypyrimidines as novel herbicides. Part 1. Synthesis and herbicidal activity of dimethoxyphenoxyphenoxypyrimidines and analogues. Pestic Sci 47:103–113CrossRefGoogle Scholar
  8. 8.
    Wannachaiyasit S, Chanvorachote P, Nimmannit U (2008) A novel anti-HIV dextrin–zidovudine conjugate improving the pharmacokinetics of zidovudine in rats. AAPS PharmSciTech 9:840CrossRefGoogle Scholar
  9. 9.
    Hannah DR, Stevens MF (2003) Structural studies on bioactive compounds. Part 38.1 reactions of 5-aminoimidazole-4-carboxamide: synthesis of imidazo[1,5-a]quinazoline-3-carboxamides. J Chem Res 2003:398–401CrossRefGoogle Scholar
  10. 10.
    Balzarini J, McGuigan C (2002) Bicyclic pyrimidine nucleoside analogues (BCNAs) as highly selective and potent inhibitors of varicella-zoster virus replication. J Antimicrob Chemother 50:5–9CrossRefGoogle Scholar
  11. 11.
    Lee HW, Kim BY, Ahn JB, Kang SK, Lee JH, Shin JS, Yoon SS (2005) Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione. Eur J Med Chem 40:862–874CrossRefGoogle Scholar
  12. 12.
    Gupta AK, Kayath HP, Ajit S, Geeta S, Mishra KC (1994) Anticonvulsant activity of pyrimidine thiols. Indian J Pharmacol 26:227Google Scholar
  13. 13.
    Abu-Hashem A, El-Shehry M, Badria F (2010) Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents. Acta Pharm 60:311–323CrossRefGoogle Scholar
  14. 14.
    Rahaman SA, Pasad YR, Kumar P, Kumar B (2009) Synthesis and anti-histaminic activity of some novel pyrimidines. Saudi Pharm J 17:255–258CrossRefGoogle Scholar
  15. 15.
    Rodrigues ALS, Rosa JM, Gadotti VM, Goulart EC, Santos MM, Silva AV, Santos ARS (2005) Antidepressant-like and antinociceptive-like actions of 4-(4′-chlorophenyl)-6-(4″-methylphenyl)-2-hydrazinepyrimidine Mannich base in mice. Pharmacol Biochem Behav 82:156–162CrossRefGoogle Scholar
  16. 16.
    Choi Y, Kim H, Park SB (2019) A divergent synthetic pathway for pyrimidine-embedded medium-sized azacycles through an N-quaternizing strategy. Chem Sci 10:569–575CrossRefGoogle Scholar
  17. 17.
    Jain KS, Chitre TS, Miniyar PB, Kathiravan MK, Bendre VS, Veer VS, Shishoo CJ (2006) Biological and medicinal significance of pyrimidines. Curr Sci 90:793Google Scholar
  18. 18.
    Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS (1982) Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections. Drugs 23:405–430CrossRefGoogle Scholar
  19. 19.
    Millan MJ, Cussac D, Milligan G, Carr C, Audinot V, Gobert A, Nicolas JP (2001) Antiparkinsonian agent piribedil displays antagonist properties at native, rat, and cloned, human α2-adrenoceptors: cellular and functional characterization. J Pharmacol Exp Ther 297:876–887PubMedGoogle Scholar
  20. 20.
    Moffett BS, Weingarten MM, Galati M, Placencia JL, Rodman EA, Riviello JJ, Kayyal SY (2018) Phenobarbital population pharmacokinetics across the pediatric age spectrum. Epilepsia 59:1327–1333CrossRefGoogle Scholar
  21. 21.
    Ahmed N (2016) Synthetic advances in the indane natural product scaffolds as drug candidates: a review. Stud Nat Prod Chem 51:383–434CrossRefGoogle Scholar
  22. 22.
    Catto M, Aliano R, Carotti A, Cellamare S, Palluotto F, Purgatorio R, Campagna F (2010) Design, synthesis and biological evaluation of indane-2-arylhydrazinylmethylene-1, 3-diones and indol-2-aryldiazenylmethylene-3-ones as β-amyloid aggregation inhibitors. Eur J Med Chem 45:1359–1366CrossRefGoogle Scholar
  23. 23.
    Prabhakar KR, Veerapur VP, Bansal P, Vipan KP, Reddy KM, Barik A, Unnikrishnan MK (2006) Identification and evaluation of antioxidant, analgesic/anti-inflammatory activity of the most active ninhydrin–phenol adducts synthesized. Bioorg Med Chem 14:7113–7120CrossRefGoogle Scholar
  24. 24.
    Ziarani GM, Lashgari N, Azimian F, Kruger HG, Gholamzadeh P (2015) Ninhydrin in synthesis of heterocyclic compounds. ARKIVOK 6:1–139Google Scholar
  25. 25.
    ElKalyoubi S, Fayed E (2016) Synthesis and evaluation of antitumour activities of novel fused tri-and tetracyclic uracil derivatives. J Chem Res 40:771–777CrossRefGoogle Scholar
  26. 26.
    Naguib BH, El-Nassan HB, Abdelghany TM (2017) Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors. J Enzyme Inhib Med Chem 32:457–467CrossRefGoogle Scholar
  27. 27.
    Squarcialupi L, Betti M, Catarzi D, Varano F, Falsini M, Ravani A, Varani K (2017) The role of 5-arylalkylamino-and 5-piperazino-moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles. J Enzyme Inhib Med Chem 32:248–263CrossRefGoogle Scholar
  28. 28.
    Elkanzi NAA (2013) Synthesis of pyrimidine and pyrimidinthione. Heterocycl Lett 3:247–268Google Scholar
  29. 29.
    Kidder GW, Dewey VC (1949) The biological activity of substituted pyrimidines. J Biol Chem 178:383–387PubMedGoogle Scholar
  30. 30.
    Zhang L, Dong J, Xu X, Liu Q (2016) Chemistry of ketene N, S-acetals: an overview. Chem Rev 116:287–322CrossRefGoogle Scholar
  31. 31.
    Mohammadi A, Bayat M, Nasri S (2019) Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds. RSC Adv 9:16525–16533CrossRefGoogle Scholar
  32. 32.
    Alizadeh A, Zarei A, Rezvanian A (2011) A novel and one-pot multicomponent approach to the synthesis of dihyroindeno[1,2-b]pyrroles and indeno[2′,1′:4,5]pyrrolo[1,2-a]-fused 1, 3-diazaheterocycles. Synthesis 2011:497–501CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceImam Khomeini International UniversityQazvinIran

Personalised recommendations