Advertisement

Synthesis and process optimization of symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles

  • João L. Serrano
  • Pedro F. Soeiro
  • Melani A. Reis
  • Renato E. F. Boto
  • Samuel Silvestre
  • Paulo AlmeidaEmail author
Original Article
  • 56 Downloads

Abstract

Benzisoxazoles represent an important pharmacophore in medicinal chemistry. Recently, an unexpected formation of symmetric 3-substituted 2,1-benzisoxazoles through reduction of 5-(2-nitrobenzylidene)barbiturates has been described. This reductive intramolecular heterocyclization probably involves a nitroso intermediary. To improve the previous reaction conditions, the nature of the reducing agent and additives, reaction time and solvents were evaluated. By applying the optimized conditions, several symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles were prepared with an yield of 52–87%. From this set, seven compounds were novel and the unsymmetric nature of the (thio)barbituric acid moiety was explored. For that, the total synthesis, starting from the respective urea or thiourea, was successfully performed, and 11 thiobarbiturates, benzylidene barbiturate and thiobarbiturate precursors are described.

Graphical abstract

Keywords

2,1-Benzisoxazoles Anthranils Barbituric acid derivatives Nitroaromatic reduction Process optimization 

Notes

Acknowledgements

This work is supported by FEDER funds through the POCI-COMPETE 2020-Operational Programme Competitiveness and Internationalization in Axis I-Strengthening research, technological development and innovation (Project No. 007491) and National Funds by FCT-Foundation for Science and Technology (Project UID/Multi/00709). J. L. Serrano is thankful to Santander-Totta/UBI for the fellowship (BID/ICI-UID FC/Santander Universidades-UBI/2017).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11030_2019_9937_MOESM1_ESM.docx (1.5 mb)
Supplementary material 1 (DOCX 1490 kb)

References

  1. 1.
    Banerjee B (2017) Recent developments on ultrasound-assisted one-pot multicomponent synthesis of biologically relevant heterocycles. Ultrason Sonochem 35((A)):15–35.  https://doi.org/10.1016/j.ultsonch.2016.10.010 CrossRefGoogle Scholar
  2. 2.
    Williams DA, Lemke TL (2008) Foye’s principles of medicinal chemistry 7th edn. Lippincott Williams and Wilkins, Philadelphia, Baltimore, New York, pp 489–569Google Scholar
  3. 3.
    Figueiredo J, Serrano JL, Cavalheiro E, Keurulainen L, Yli-Kauhaluoma J, Moreira VM, Ferreira S, Domingues FC, Silvestre S, Almeida P (2018) Trisubstituted barbiturates and thiobarbiturates: synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents. Eur J Med Chem 143:829–842.  https://doi.org/10.1016/j.ejmech.2017.11.070 CrossRefGoogle Scholar
  4. 4.
    Shaker Raafat M, Ishak Esam A (2011) Barbituric acid utility in multi-component reactions. Z Naturforsch B 66(12):1189–1201.  https://doi.org/10.1515/znb-2011-1201 CrossRefGoogle Scholar
  5. 5.
    Mohammadi Ziarani G, Aleali F, Lashgari N (2016) Recent applications of barbituric acid in multicomponent reactions. RSC Adv 6(56):50895–50922.  https://doi.org/10.1039/C6RA09874F CrossRefGoogle Scholar
  6. 6.
    Lopez-Munoz F, Ucha-Udabe R, Alamo C (2005) The history of barbiturates a century after their clinical introduction. Neuropsych Dis Treat 1(4):329–343Google Scholar
  7. 7.
    Ling T, Maier J, Das S, Budhraja A, Bassett R, Potts MB, Shelat A, Rankovic Z, Opferman JT, Rivas F (2019) Identification of substituted 5-membered heterocyclic compounds as potential anti-leukemic agents. Eur J Med Chem 164:391–398.  https://doi.org/10.1016/j.ejmech.2018.12.059 CrossRefGoogle Scholar
  8. 8.
    Keerthi Krishnan K, Ujwaldev SM, Saranya S, Anilkumar G, Beller M (2019) Recent advances and perspectives in the synthesis of heterocycles via zinc catalysis. Adv Synth Catal 361(3):382–404.  https://doi.org/10.1002/adsc.201800868 CrossRefGoogle Scholar
  9. 9.
    Ma C, Jiang F, Sheng F-T, Jiao Y, Mei G-J, Shi F (2018) Design and catalytic asymmetric construction of axially chiral 3,3′-bisindole skeletons. Angew Chem Int Edit.  https://doi.org/10.1002/anie.201811177 Google Scholar
  10. 10.
    Varvounis G, Gerontitis IE, Gkalpinos V (2018) Metal-catalyzed synthesis of five-membered ring N-heterocycles: a recent update. Chem Heterocycl Compd 54(3):249–268.  https://doi.org/10.1007/s10593-018-2260-8 CrossRefGoogle Scholar
  11. 11.
    Ma C, Zhou J-Y, Zhang Y-Z, Jiao Y, Mei G-J, Shi F (2018) Synergistic-catalysis-enabled reaction of 2-indolymethanols with oxonium ylides for the construction of 3-indolyl-3-alkoxy oxindole frameworks. Chem-Asian J 13(17):2549–2558.  https://doi.org/10.1002/asia.201800620 CrossRefGoogle Scholar
  12. 12.
    Mei G-J, Shi F (2018) Catalytic asymmetric synthesis of spirooxindoles: recent developments. Chem Commun 54(50):6607–6621.  https://doi.org/10.1039/C8CC02364F CrossRefGoogle Scholar
  13. 13.
    Jorge ARS, Rui MAP, Samuel MS (2009) Recent advances of bismuth(III) salts in organic chemistry: application to the synthesis of heterocycles of pharmaceutical interest. Curr Org Synth 6(4):426–470.  https://doi.org/10.2174/157017909789108701 CrossRefGoogle Scholar
  14. 14.
    Yoshikazu U (2016) 1,2-Benzisoxazole: a privileged structure with a potential for polypharmacology. Curr Pharm Des 22(21):3201–3211.  https://doi.org/10.2174/1381612822666160224142648 CrossRefGoogle Scholar
  15. 15.
    Rakesh KP, Shantharam CS, Sridhara MB, Manukumar HM, Qin H-L (2017) Benzisoxazole: a privileged scaffold for medicinal chemistry. MedChemComm 8(11):2023–2039.  https://doi.org/10.1039/C7MD00449D CrossRefGoogle Scholar
  16. 16.
    Serrano JL, Cavalheiro E, Barroso S, Romão MJ, Silvestre S, Almeida P (2017) A synthetic route to novel 3-substituted-2,1-benzisoxazoles from 5-(2-nitrobenzylidene)(thio)barbiturates. CR Chim 20(11):990–995.  https://doi.org/10.1016/j.crci.2017.10.002 and references cited therein CrossRefGoogle Scholar
  17. 17.
    Wiȩcław M, Bobin M, Kwast A, Bujok R, Wróbel Z, Wojciechowski K (2015) General synthesis of 2,1-benzisoxazoles (anthranils) from nitroarenes and benzylic C–H acids in aprotic media promoted by combination of strong bases and silylating agents. Mol Divers 19(4):807–816.  https://doi.org/10.1007/s11030-015-9627-x CrossRefGoogle Scholar
  18. 18.
    Friedländer P, Henriques R (1882) Zur reduktion des orthonitrobenzaldehyds. Ber Dtsch Chem Ges 15(2):2105–2110.  https://doi.org/10.1002/cber.188201502147 CrossRefGoogle Scholar
  19. 19.
    Budruev AV, Dzhons DY (2016) Synthesis of 2,1-benzisoxazoles (microreview). Chem Heterocycl Compd 52(7):441–443.  https://doi.org/10.1007/s10593-016-1908-5 CrossRefGoogle Scholar
  20. 20.
    Kotov AD, Prokaznikov MA, Antonova EA, Rusakov AI (2014) Synthesis of nitrogen-containing heterocycles from nitroarenes (minireview). Chem Heterocycl Compd 50(5):647–657.  https://doi.org/10.1007/s10593-014-1517-0 CrossRefGoogle Scholar
  21. 21.
    Krüger S (2013) Meier C (2013) Synthesis of site-specific damaged DNA strands by 8-(acetylarylamino)-2′-deoxyguanosine adducts and effects on various DNA polymerases. Eur J Org Chem 6:1158–1169.  https://doi.org/10.1002/ejoc.201200984 CrossRefGoogle Scholar
  22. 22.
    Ren P-D, Pan X-W, Jin Q-H, Yao Z-P (1997) Reduction of nitroarenes to n-arylhydroxylamines with KBH4/BiCl3 system. Synth Commun 27(20):3497–3503.  https://doi.org/10.1080/00397919708007070 CrossRefGoogle Scholar
  23. 23.
    Bordwell FG, Liu W-Z (1996) Equilibrium acidities and homolytic bond dissociation energies of N–H and/or O–H bonds in N-phenylhydroxylamine and its derivatives. J Am Chem Soc 118(37):8777–8781.  https://doi.org/10.1021/ja960152n CrossRefGoogle Scholar
  24. 24.
    Wurz RP, Charette AB (2004) An expedient and practical method for the synthesis of a diverse series of cyclopropane α-amino acids and amines. J Org Chem 69(4):1262–1269.  https://doi.org/10.1021/jo035596y CrossRefGoogle Scholar
  25. 25.
    Lin Y-I, Lang SA (1980) Selective reduction of nitro-heterocycles with sodium sulfide in aqueous p-dioxane. J Heterocycl Chem 17(6):1273–1275.  https://doi.org/10.1002/jhet.5570170625 CrossRefGoogle Scholar
  26. 26.
    Padiya KJ, Gavade S, Kardile B, Tiwari M, Bajare S, Mane M, Gaware V, Varghese S, Harel D, Kurhade S (2012) Unprecedented “in water” imidazole carbonylation: paradigm shift for preparation of urea and carbamate. Org Lett 14(11):2814–2817.  https://doi.org/10.1021/ol301009d CrossRefGoogle Scholar
  27. 27.
    Whiteley MA (1907) CXXIII.—Studies in the barbituric acid series. I. 1: 3-Diphenylbarbituric acid and some coloured derivatives. J Chem Soc Trans 91:1330–1350.  https://doi.org/10.1039/CT9079101330 CrossRefGoogle Scholar
  28. 28.
    Ramisetti SR, Pandey MK, Lee SY, Karelia D, Narayan S, Amin S, Sharma AK (2018) Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells. Eur J Med Chem 143:1919–1930.  https://doi.org/10.1016/j.ejmech.2017.11.006 CrossRefGoogle Scholar
  29. 29.
    Wang F, Zhao P, Xi C (2011) Copper-catalyzed one-pot synthesis of 2-thioxo-2, 3-dihydroquinazolin-4 (1H)-ones from ortho-bromobenzamides and isothiocyanates. Tetrahedron Lett 52(2):231–235.  https://doi.org/10.1016/j.tetlet.2010.11.010 CrossRefGoogle Scholar
  30. 30.
    Gonçalves IL, Davi L, Rockenbach L, das Neves GM, Kagami LP, Canto RFS, Figueiró F, Battastini AMO, Eifler-Lima VL (2018) Versatility of the Biginelli reaction: synthesis of new biphenyl dihydropyrimidin-2-thiones using different ketones as building blocks. Tetrahedron Lett 59(28):2759–2762.  https://doi.org/10.1016/j.tetlet.2018.06.006 CrossRefGoogle Scholar
  31. 31.
    Singh K, Sharma S (2017) An isocyanide based multi-component reaction under catalyst- and solvent-free conditions for the synthesis of unsymmetrical thioureas. Tetrahedron Lett 58(3):197–201.  https://doi.org/10.1016/j.tetlet.2016.11.082 CrossRefGoogle Scholar
  32. 32.
    Koshti VS, Thorat SH, Gote RP, Chikkali SH, Gonnade RG (2016) The impact of modular substitution on crystal packing: the tale of two ureas. Cryst Eng Commun 18(37):7078–7094.  https://doi.org/10.1039/C6CE01324D CrossRefGoogle Scholar
  33. 33.
    Mohammadi L, Zolfigol MA, Khazaei A, Yarie M, Ansari S, Azizian S, Khosravi M (2018) Synthesis of nanomagnetic supported thiourea–copper(I) catalyst and its application in the synthesis of triazoles and benzamides. Appl Organomet Chem 32(1):e3933.  https://doi.org/10.1002/aoc.3933 CrossRefGoogle Scholar
  34. 34.
    Nakashima K (1977) The coloration reaction mechanism of 6-aminouracil derivatives with Ehrlich reagent and its application to the colorimetric determination method. II (author’s transl). Yakuga Zasshi 97 (8):906–910.  https://doi.org/10.1248/yakushi1947.97.8_906
  35. 35.
    Manick A-D, Berhal F, Prestat G (2018) Development of a one-pot four C–C bond-forming sequence based on palladium/ruthenium tandem catalysis. Org Lett 20(1):194–197.  https://doi.org/10.1021/acs.orglett.7b03556 CrossRefGoogle Scholar
  36. 36.
    Botsi S, Tsolomitis A (2007) One or two step acid mediated cyclocondensation process for the preparation of 5-carbethoxy-2-thiouracils from diethyl ethoxymethylenemalonate and thioureas. Heterocycl Commun 13(4):229–234.  https://doi.org/10.1515/HC.2007.13.4.229 CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.CICS-UBI - Health Sciences Research CenterUniversity of Beira InteriorCovilhãPortugal
  2. 2.Department of ChemistryUniversity of Beira InteriorCovilhãPortugal
  3. 3.CNC - Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal

Personalised recommendations