Skip to main content
Log in

Synthesis of aminouracil-tethered tri-substituted methanes in water by iodine-catalyzed multicomponent reactions

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

An efficient, mild and environmentally benign protocol has been developed for the synthesis of aminouracil-tethered tri-substituted methane derivatives. The three-component reaction of 2-hydroxy-1,4-naphthaquinone, 6-amino-1,3-dimethyluracil and aldehydes in the presence of molecular iodine as catalyst under reflux conditions resulted in aminouracil-tethered tri-substituted methane derivatives 4 in aqueous medium. Similarly, the four-component reaction of 2-hydroxy-1,4-naphthaquinone, o-phenylenediamine, aldehydes and aminouracil derivatives resulted in aminouracil-tethered tri-substituted methane derivatives 6 under the same reaction conditions. The notable features of this protocol are simple experimental procedure, cheap catalyst, readily available starting materials, moderate-to-good yields of the products having biologically active important moieties such as aminouracil, hydroxy-naphthaquinone/benzophenazine.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2

Similar content being viewed by others

References

  1. Parker WB (2009) Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev 109:2880–2893. https://doi.org/10.1021/cr900028p

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bradshaw TK, Hutchinson DW (1977) 5-Substituted pyrimidine nucleosides and nucleotides. Chem Soc Rev 6:43–62. https://doi.org/10.1039/CS9770600043

    Article  CAS  Google Scholar 

  3. Noia JD, Neuberger MS (2002) Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419:43–48. https://doi.org/10.1038/nature00981

    Article  CAS  PubMed  Google Scholar 

  4. Dinner AR, Blackburn GM, Karplus M (2001) Uracil-DNA glycosylase acts by substrate autocatalysis. Nature 413:752–755. https://doi.org/10.1038/35099587

    Article  CAS  PubMed  Google Scholar 

  5. Isobe Y, Tobe M, Inoue Y, Isobe M, Tsuchiya M, Hayashi H (2003) Structure and activity relationships of novel uracil derivatives as topical anti-inflammatory agents. Bioorg Med Chem 11:4933–4940. https://doi.org/10.1016/j.bmc.2003.09.012

    Article  CAS  PubMed  Google Scholar 

  6. Zhi C, Long Z-Y, Gambino J, Xu W-C, Brown NC, Barnes M, Butler M, LaMarr W, Wright GE (2003) Synthesis of substituted 6-aminouracils and their inhibition of DNA polymerase IIIC and gram-positive bacterial growth. J Med Chem 46:2731–2739. https://doi.org/10.1021/jm020591z

    Article  CAS  PubMed  Google Scholar 

  7. Muller CE, Shi D, Manning M, Daly JW (1993) Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure-activity relationships at adenosine receptors. J Med Chem 36:3341–3349. https://doi.org/10.1021/jm00074a015

    Article  CAS  PubMed  Google Scholar 

  8. Bills CW, Gebura SE, Meek JS, Sweeti OJ (1962) New synthesis of uric acid and dimethyluric acid. J Org Chem 27:4633–4635. https://doi.org/10.1021/jo01059a501

    Article  CAS  Google Scholar 

  9. Wells JN, Garst JE, Kramer GL (1981) Inhibition of separated forms of cyclic nucleotide phosphodiesterase from pig coronary arteries by 1,3-disubstituted and 1,3,8-trisubstituted xanthines. J Med Chem 24:954–958. https://doi.org/10.1021/jm00140a008

    Article  CAS  PubMed  Google Scholar 

  10. Buckle DR, Arch JRS, Connolly BJ, Fenwick AE, Foster KA, Murray KJ, Readshaw SA, Smallridge M, Smith DG (1994) Inhibition of cyclic nucleotide phosphodiesterase by derivatives of 1,3-bis (cyclo propylmethyl)xanthine. J Med Chem 37:476–485. https://doi.org/10.1021/jm00030a007

    Article  CAS  PubMed  Google Scholar 

  11. Azizian J, Mohammadizadeh MR, Teimouri F, Mohammadi AA, Karimi AR (2006) Reactions of 6-aminouracils: the first simple, fast, and highly efficient synthesis of bis(6-Amino pyrimidonyl)methanes (BAPMs) using thermal or microwave-assisted solvent-free methods. Synth Commun 36:3631–3638. https://doi.org/10.1080/00397910600943832

    Article  CAS  Google Scholar 

  12. Das S, Thakur AJ (2011) A clean, highly efficient and one-pot green synthesis of aryl/alkyl/heteroaryl-substituted bis(6-amino-1,3-dimethyluracil-5-yl)methanes in Water. Eur J Org Chem 2011:2301–2308. https://doi.org/10.1002/ejoc.201001581

    Article  CAS  Google Scholar 

  13. Brahmachari G, Banerjee B (2015) Ceric ammonium nitrate (CAN): an efficient and eco-friendly catalyst for the one-pot synthesis of alkyl/aryl/heteroaryl-substituted bis(6-aminouracil-5-yl)methanes at room temperature. RSC Adv 5:39263–39269. https://doi.org/10.1039/c5ra04723d

    Article  CAS  Google Scholar 

  14. Emmadi NR, Atmakur K, Bingi C, Godumagadda NR, Chityal GK, Nanubolu JB (2014) Regioselective synthesis of 3-benzyl substituted pyrimidino chromen-2-ones and evaluation of anti-microbial and anti-biofilm activities. Bioorg Med Chem Lett 24:485–489. https://doi.org/10.1016/j.bmcl.2013.12.038

    Article  CAS  PubMed  Google Scholar 

  15. Lu G-P, Cai C (2014) A one-pot, efficient synthesis of polyfunctionalized pyrido[2,3-d]pyrimidines and uncyclized adducts by aldehydes, 1,3-dicarbonyl compounds, and 6-aminouracil. J Heterocycl Chem 51:1595–1602. https://doi.org/10.1002/jhet.1704

    Article  CAS  Google Scholar 

  16. Pérez-Sacau E, Díaz-Peñate RG, Estévez-Braun A, Ravelo AG, García-Castellano JM, Pardo L, Campillo M (2007) Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line. J Med Chem 50:696–706. https://doi.org/10.1021/jm060849b

    Article  CAS  PubMed  Google Scholar 

  17. Berghot MA, Kandeel EM, Abdel-Rahman AH, Abdel-Motaal M (2014) Synthesis, antioxidant and cytotoxic activities of novel naphthoquinone derivatives from 2,3-dihydro-2,3-epoxy-1,4- naphthoquinone. Med Chem 4:381–388. https://doi.org/10.4172/2161-0444.1000169

    Article  CAS  Google Scholar 

  18. Moorthy NSHN, Karthikeyan C, Trivedi P (2009) Synthesis, cytotoxic evaluation and in silico pharmacokinetic prediction of some benzo[a] phenazine-5-sulfonic acid derivatives. Med Chem 5:549–557. https://doi.org/10.2174/157340609790170533

    Article  CAS  Google Scholar 

  19. Lavaggi ML, Cabrera M, de los Ángeles Aravena M, Olea-Azar C, de Ceráin AL, Monge A, Pachón G, Cascante M, Bruno AM, Pietrasanta LI, González M, Cerecetto H (2010) Study of benzo[a]phenazine 7,12-dioxide as selective hypoxic cytotoxin-scaffold. Identification of aerobic-antitumoral activity through DNA fragmentation. Bioorg Med Chem 18:4433–4440. https://doi.org/10.1016/j.bmc.2010.04.074

    Article  CAS  PubMed  Google Scholar 

  20. Sasada T, Kobayashi F, Sakai N, Konakahara T (2009) An unprecedented approach to [4,5-d] pyrimidine derivatives by a ZnCl2-Catalyzed three-component coupling reaction. Org Lett 11:2161–2164. https://doi.org/10.1021/ol900382j

    Article  CAS  PubMed  Google Scholar 

  21. Gopalsamy A, Yang H, Ellingboe JW, Tsou HR, Zhang N, Honores E, Powell D, Miranda M, McGinnis JP, Robindran SP (2005) Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel anti-proliferative agents: parallel synthesis for lead optimization of amide region. Bio Org Med Chem 15:1591–1594. https://doi.org/10.1016/j.bmcl.2005.01.066

    Article  CAS  Google Scholar 

  22. Kandhasamy S, Ramanathan G, Muthukumar T, Thyagarajan S, Umamaheshwari N, Santhanakrishnan VP, Sivagnanam UT, Perumal PT (2017) Nanofibrous matrixes with biologically active hydroxybenzophenazine pyrazolone compound for cancer theranostics. Mater Sci Eng C 74:70–85. https://doi.org/10.1016/j.msec.2017.01.001

    Article  CAS  Google Scholar 

  23. Paengsri W, Lee VS, Chong WL, Wahab HA, Baramee A (2012) Synthesis, antituberculosis activity and molecular docking studies for novel naphthoquinone derivatives. Int J Biol Chem 6:69–88. https://doi.org/10.3923/ijbc.2012.69.88

    Article  CAS  Google Scholar 

  24. Dömling A (2005) In: Zhu J, Bienayme H (eds) Multicomponent reactions. Wiley-VCH, Weinheim, pp 76–94

    Chapter  Google Scholar 

  25. Tejedor D, Garcia-Tellado F (2007) Chemo-differentiating ABB′ multicomponent reactions. Privileged building blocks. Chem Soc Rev 36:484–491. https://doi.org/10.1039/B608164A

    Article  CAS  PubMed  Google Scholar 

  26. Ibarra IA, Islas-Jácome A, González-Zamora E (2018) Synthesis of polyheterocycles via multicomponent reactions. Org Biomol Chem 16:1402–1418. https://doi.org/10.1039/C7OB02305G

    Article  CAS  PubMed  Google Scholar 

  27. Ismaili L, Carreiras MC (2017) Multicomponent reactions for multitargeted compounds for Alzheimer’s disease. Curr Top Med Chem 17:3319–3327. https://doi.org/10.2174/1568026618666180112155424

    Article  CAS  PubMed  Google Scholar 

  28. Cioc RC, Ruijter E, Orru RVA (2014) Multicomponent reactions: advanced tools for sustainable organic synthesis. Green Chem 16:2958–2975. https://doi.org/10.1039/C4GC00013G

    Article  CAS  Google Scholar 

  29. Boukis AC, Reiter K, Frölich M, Hofheinz D, Meier MAR (2018) Multicomponent reactions provide key molecules for secret communication. Nat Commun 9:1439. https://doi.org/10.1038/s41467-018-03784-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Azizi N, Ahooie TS, Hashemi MM (2017) Multicomponent domino reactions in deep eutectic solvent: an efficient strategy to synthesize multisubstituted cyclohexa-1,3-dienamines. J Mol Liq 246:221–224. https://doi.org/10.1016/j.molliq.2017.09.049

    Article  CAS  Google Scholar 

  31. Felluga F, Benedetti F, Berti F, Drioli S, Regin G (2018) Efficient Biginelli synthesis of 2-aminopyrimidines under microwave irradiation. Synlett 29:1047–1054. https://doi.org/10.1055/s-0036-1591900

    Article  CAS  Google Scholar 

  32. Narayan S, Muldoon J, Finn MG, Fokin VV, Kolb HC, Sharpless KB (2005) “On water”: unique reactivity of organic compounds in aqueous suspension. Angew Chem Int Ed 44:3275–3279. https://doi.org/10.1002/anie.200590069

    Article  CAS  Google Scholar 

  33. Das P, McLeod D, McNulty J (2011) A direct synthesis of functionalized styrenes and terminal 1,3-dienes via aqueous Wittig chemistry with formalin. Tetrahedron Lett 52:199–201. https://doi.org/10.1016/j.tetlet.2010.10.090

    Article  CAS  Google Scholar 

  34. Yi-M Ren, Cai C, Yang R-C (2013) Molecular iodine-catalyzed multicomponent reactions: an efficient catalyst for organic synthesis. RSC Adv 3:7182–7204. https://doi.org/10.1039/c3ra23461d

    Article  CAS  Google Scholar 

  35. Parvatkar PT, Parameswaran PS, Tilve SG (2012) Recent developments in the synthesis of five- and six-membered heterocycles using molecular iodine. Chem Eur J 18:5460–5489. https://doi.org/10.1002/chem.201100324

    Article  CAS  PubMed  Google Scholar 

  36. Jereb M, Vrazic D, Zupan M (2011) Iodine-catalyzed transformation of molecules containing oxygen functional groups. Tetrahedron 67:1355–1387. https://doi.org/10.1016/j.tet.2010.11.086

    Article  CAS  Google Scholar 

  37. Reddy GR, Reddy TR, Joseph SC, Reddy KS, Pal M (2012) Iodine catalyzed four-component reaction: a straightforward one-pot synthesis of functionalized pyrroles under metal-free conditions. RSC Adv 2:3387–3395. https://doi.org/10.1039/C2RA00982J

    Article  CAS  Google Scholar 

  38. Ramachandran G, Karthikeyan NS, Giridharan P, Sathiyanarayanan KI (2012) Efficient iodine catalyzed three components domino reaction for the synthesis of 1- ((phenylthio)(phenyl)methyl)pyrroli din-2-one derivatives possessing anticancer activities. Org Biomol Chem 10:5343–5346. https://doi.org/10.1039/C2OB25530H

    Article  CAS  PubMed  Google Scholar 

  39. Bharti R, Kumari P, Parvin T, Choudhury LH (2018) Recent advances of aminopyrimidines in multicomponent reactions. Curr Org Chem 22:417–445. https://doi.org/10.2174/1385272822666171212152406

    Article  CAS  Google Scholar 

  40. Panday AK, Mishra R, Jana A, Parvin T, Choudhury LH (2018) Synthesis of pyrimidine fused quinolines by ligand-free copper catalyzed domino reactions. J Org Chem 83:3624–3632. https://doi.org/10.1021/acs.joc.7b03272

    Article  CAS  PubMed  Google Scholar 

  41. Jana A, Panday AK, Mishra R, Parvin T, Choudhury LH (2017) Synthesis of thio and selenoethers of cyclic β-hydroxy carbonyls and amino uracils: a metal-free regioselective I2/DMSO mediated reaction. ChemistrySelect 2:9420–9424. https://doi.org/10.1002/slct.201702066

    Article  CAS  Google Scholar 

  42. Choudhury LH, Parvin T (2011) Recent advances in the chemistry of imine-based multicomponent reactions (MCRs). Tetrahedron 67:8213–8228. https://doi.org/10.1016/j.tet.2011.07.020

    Article  CAS  Google Scholar 

  43. Bharti R, Parvin T (2015) One-pot synthesis of highly functionalized tetrahydropyridines: a camphoresulfonic acid catalyzed multicomponent reaction. J Heterocycl Chem 52:1806–1811. https://doi.org/10.1002/jhet.2268

    Article  CAS  Google Scholar 

  44. Bharti R, Parvin T (2015) Diversity oriented synthesis of tri-substituted methane containing aminouracil and hydroxynaphthoquinone/hydroxycoumarin moiety using organocatalysed multicomponent reactions in aqueous medium. RSC Adv 5:66833–66839. https://doi.org/10.1039/c5ra13093j

    Article  CAS  Google Scholar 

  45. Bharti R, Kumari P, Parvin T, Choudhury LH (2017) Molecular diversity from the three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes and 6-aminouracils: a reaction condition dependent MCR. RSC Adv 7:3928–3933. https://doi.org/10.1039/c6ra18828a

    Article  CAS  Google Scholar 

  46. Bharti R, Parvin T (2016) Multicomponent synthesis of diverse pyrano-fused benzophenazines using bifunctional thiourea-based organocatalyst in aqueous medium. Mol Divers 20:867–876. https://doi.org/10.1007/s11030-016-9681-z

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are thankful to NIT Patna and Department of Science and Technology, India, for financial support with Sanction No. EMR/2016/000960. We are also grateful to SAIF-Panjab University and SAIF-IIT Patna for providing analytical facilities.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tasneem Parvin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 13042 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumari, P., Bharti, R. & Parvin, T. Synthesis of aminouracil-tethered tri-substituted methanes in water by iodine-catalyzed multicomponent reactions. Mol Divers 23, 205–213 (2019). https://doi.org/10.1007/s11030-018-9862-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-018-9862-z

Keywords

Navigation