Facile and highly diastereo and regioselective synthesis of novel octahydroacridine-isoxazole and octahydroacridine-1,2,3-triazole molecular hybrids from citronella essential oil

  • Mauricio Acelas
  • Vladimir V. Kouznetsov
  • Arnold R. Romero BohórquezEmail author
Original Article


A novel and highly efficient synthetic approach for the expedite construction of new octahydroacridine-isoxazole- and octahydroacridine-1,2,3-triazole-based molecular hybrids is first reported. Rapid access to the octahydroacridine core was achieved in a highly diastereoselective fashion via cationic Povarov reaction of N-propargyl anilines and citronella essential oil (Cymbopogon nardus). The subsequent 1,3-dipolar and Cu (I) catalyzed alkyne-azide cycloaddition reaction of the terminal alkyne fragment with the corresponding oxime or azide affords the desired 3,5-isoxazoles and 1,2,3-triazoles, respectively, as interesting molecular hybrid models for pharmacological studies.


Octahydroacridines Isoxazoles Triazoles Molecular hybrids Cationic Povarov reaction Citronella essential oil 



This work was supported by Patrimonio Autónomo Fondo Nacional de Financiamiento para la Ciencia, la Tecnología y la Innovación, Francisco José de Caldas (Contract RC-0572-2012). We want to thank Laboratorio de Espectrometria de Masas—Parque Tecnológico Guatiguará for data collection. We also wish to acknowledge Prof. Elena E. Stashenko, Research Director CROM-MASS–CENIVAM, Industrial University of Santander, Colombia, for the generous donation and characterization of the EO of citronella.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

11030_2018_9863_MOESM1_ESM.docx (3.1 mb)
Supplementary material 1 (DOCX 3218 kb)


  1. 1.
    Beruvé G (2016) An overview of molecular hybrids in drug discovery. Expert Opin Drug Discov 11:281–305. CrossRefGoogle Scholar
  2. 2.
    Akhtar J, Khan AA, Ali Z, Haider R, Yar MS (2017) Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur J Med Chem 125:143–189. CrossRefPubMedGoogle Scholar
  3. 3.
    Xiao ZP, Wang XD, Wang PF, Zhou Y, Zhang JW, Zhang L, Zhou J, Zhou SS, Ouyang H, Lin XY, Mustapa M, Reyinbaike A, Zhum HL (2014) Design, synthesis, and evaluation of novel fluoroquinolone–flavonoid hybrids as potent antibiotics against drug-resistant microorganisms. Eur J Med Chem 80:92–100. CrossRefPubMedGoogle Scholar
  4. 4.
    Ozkay Y, Incesu Z, Onder NI, Tunali Y, Karaca H, Isikdag I, Ucucu Ü (2013) Antimicrobial and anticancer effects of some 2-(substitutedsulfanyl)-N-(5-methyl-isoxazol-3-yl) acetamide derivatives. Med Chem Res 22:211–218. CrossRefGoogle Scholar
  5. 5.
    Bartlett RR, Schleyerbach R (1985) Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity–I. Disease modifying action on adjuvant arthritis of the rat. Int J Immunopharmacol 7:7–18. CrossRefPubMedGoogle Scholar
  6. 6.
    Murata M, Hasegawa K, Kanazawa I, Japan Zonisamide on PD Study Group (2007) Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology 68:45–50. CrossRefPubMedGoogle Scholar
  7. 7.
    Sahu JK, Ganguly S, Kaushik A (2013) Triazoles: a valuable insight into recent developments and biological activities. Chin J Nat Med 11:456–465. PubMedCrossRefGoogle Scholar
  8. 8.
    Müller-Schiffmann A, Sticht H, Korth C (2012) Hybrid compounds: from simple combinations to nanomachines. BioDrugs 26:21–31. CrossRefPubMedGoogle Scholar
  9. 9.
    Mao J, Yuan H, Wang Y, Wan B, Pak D, He R, Franzblau SG (2010) Synthesis and antituberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs. Bioorg Med Chem 20:1263–1268. CrossRefGoogle Scholar
  10. 10.
    Shekhar AC, Lingaiah BPV, Rao PS, Narsaiah B, Allanki AD, Sijwali PS (2015) Design, synthesis and biological evaluation of novel fluorinated heterocyclic hybrid molecules based on triazole & quinoxaline scaffolds lead to highly potent antimalarials and antibacterials. Lett Drug Des Discov 12:393–407. CrossRefGoogle Scholar
  11. 11.
    Lokanatha Rai KM, Linganna N, Hassner A, Anjanamurthy C (1992) A convenient method for the generation of nitrile oxide and its application to the synthesis of 2-isoxazolines. Org Prep Proc Int 24:91–93. CrossRefGoogle Scholar
  12. 12.
    Kim JN, Ryu EK (1990) A convenient synthesis of nitrile oxides from aldoximes by 1-chlorobenzotriazole. Synth Commun 20:1373–1377. CrossRefGoogle Scholar
  13. 13.
    Hassner A, Lokanatha Rai KM (1989) A new method for the generation of nitrile oxides and its application to the synthesis of 2-isoxazolines. Synthesis 1:57–59. CrossRefGoogle Scholar
  14. 14.
    Grundmann C, Dean JM (1965) Nitrile oxides. V. Stable aromatic nitrile oxides. J Org Chem 30:2809–2812. CrossRefGoogle Scholar
  15. 15.
    Himo F, Lovell T, Hilgraf R, Rostovtsev VV, Noodleman L, Sharpless KB, Fokin VV (2005) Copper (I)-catalized synthesis of azoles. DFT study predicts unprecedent reactivity and intermediates. J Am Chem Soc 127:210–216. CrossRefPubMedGoogle Scholar
  16. 16.
    Hein JE, Fokin VV (2010) Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and beyond: new reactivity of Copper (I) acetylides. Chem Soc Rev 39:1302–1315. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Del Giudice MR, Borioni A, Mustazza C, Gatta F (1997) Synthesis of 9-amino-, 9-aminomethyl-1,2,3,4-tetrahydro-and 1,2,3,4,5,6,7,8-octahydroacridine derivatives. J Heterocyclic Chem 34:1661–1667. CrossRefGoogle Scholar
  18. 18.
    Ermolaeva VG, Yashunskii VG, Polezhaeva AI, Mashkovskii MD (1968) Synthesis and pharmacological properties of certain derivatives of octahydroacridines. Pharm Chem J 2:310–312. CrossRefGoogle Scholar
  19. 19.
    Canas-Rodriguez A, Canas RG, Mateo-Bernardo A (1987) Tricyclic inhibitors of gastric acid secretion. Part V. Octahydroacridines. An Quim Ser C 83:24–27Google Scholar
  20. 20.
    Mayekar NV, Nayak SK, Chattopadhyay S (2004) Two convenient one-pot strategies for the synthesis of octahydroacridines. Synth Commun 34:3111–3119. CrossRefGoogle Scholar
  21. 21.
    Laschat S, Noe R, Riedel M (1993) Novel (Imino-η6-arene)chromium complexes and their diastereoselective intramolecular hetero-Diels-Alder reactions. Organometallics 12:3738–3742. CrossRefGoogle Scholar
  22. 22.
    Schulte JL, Laschat S, Kotila S, Hecht J, Frölich R, Wibbeling B (1996) Synthesis of η6-(octahydroacridine)-chromiumtricarbonyl complexes with nonpolar tails via molecular sieves-catalized cyclization of N-arylimines and subsequent diastereoselective complexation. Heterocycles 43:2713–2724. CrossRefGoogle Scholar
  23. 23.
    Acelas M, Romero Bohórquez AR, Kouznetsov VV (2017) Highly diastereoselective synthesis of new trans-fused octahydroacridines via intramolecular cationic imino Diels-Alder reaction of N-protected anilines and citronellal or citronella essential oil. Synthesis 49:2153–2162. CrossRefGoogle Scholar
  24. 24.
    Rodríguez YA, Gutiérrez M, Ramírez D, Alzate-Morales J, Bernal CC, Güiza FM, Romero Bohórquez AR (2016) Novel N-allyl/propargyl tetrahydroquinolines: synthesis via three-component cationic imino Diels-Alder reaction, binding prediction and evaluation as cholinesterase inhibitors. Chem Biol Drug Des 88:498–510. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Van Berkel GJ, McLuckey SA, Glish GL (1992) Electrochemical origin of radical cations observed in electrospray ionization mass spectra. Anal Chem 64:1586–1593. CrossRefGoogle Scholar
  26. 26.
    Crotti AEM, Vessecchi R, Callegari JLC, Lopes NP (2006) Electrospray ionization mass spectrometry: chemical processes involved in the ion formation from low molecular weight organic compounds. Quím Nova 29:287–292. CrossRefGoogle Scholar
  27. 27.
    Zenobi R, Knochenmuss R (1998) Ion formation in MALDI mass spectrometry. Mass Spectrom Rev 17:337–366.;2-S CrossRefGoogle Scholar
  28. 28.
    Stephen O, Nwaukwa MK, Philip MK (1989) Ring chlorination of benzenoid compounds using calcium hypochlorite [Ca(OCl)2]. Synth Commun 19:799–804. CrossRefGoogle Scholar
  29. 29.
    Easton CJ, Hughes CM, Tiekink ERT, Lubin CE, Savage GP, Simpson GW (1994) Reversal of regiochemistry in the synthesis of isoxazoles by nitrile oxide cycloadditions. Tetrahedron Lett 35:3589–3592. CrossRefGoogle Scholar
  30. 30.
    Colombano G, Albani C, Ottonello G, Ribeiro A, Scarpelli R, Tarozzo G, Daglian J, Jung KM, Piomelli D, Bandiera T (2015) O-(triazolyl)methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors. Chem Med Chem 10:380–395. CrossRefPubMedGoogle Scholar
  31. 31.
    Shao C, Wang X, Zhang Q, Luo S, Zhao J, Hu Y (2011) Acid-base jointly promoted copper(I)-catalized azide-alkyne cycloaddition. J Org Chem 76:6832–6836. CrossRefPubMedGoogle Scholar
  32. 32.
    Urankar D, Steinbücher M, Kosjek J, Kosmrlj J (2010) N-(propargyl)diazenecarboxamides for ‘click’ conjugation and their 1,3-dipolar cycloadditions with azidoalkylamines in the presence of Cu(II). Tetrahedron 66:2602–2613. CrossRefGoogle Scholar
  33. 33.
    Jwad RS, Mohammed AI, Shihab MS (2012) Synthesis of 1,2,3-triazoles based on phenacyl azide derivatives via click chemistry. Iraqi J Sci 53:487–494Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Mauricio Acelas
    • 1
  • Vladimir V. Kouznetsov
    • 1
  • Arnold R. Romero Bohórquez
    • 2
    Email author
  1. 1.Laboratorio de Química Orgánica y Biomolecular (LQOBio), CMNUniversidad Industrial de Santander, Parque Tecnológico GuatiguaráPiedecuestaColombia
  2. 2.Grupo de Investigación en Compuestos Orgánicos de Interés Medicinal (CODEIM)Universidad Industrial de Santander, Parque Tecnológico GuatiguaráPiedecuestaColombia

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