Ball-milling Synthesis of Tetrahydroquinolines via ‘One-pot’ Three-component Diels-Alder Reaction Catalyzed by Phosphotungstic Acid


We reported an economic and practical ball-milling method for the synthesis of tetrahydroquinoline derivatives via a ‘one-pot’ three-component Diels-Alder reaction of anilines, aldehydes and alkenes catalyzed by phosphotungstic acid at room temperature. For this reaction, a simple “one-pot” ball-milling operation was conducted, readily available starting materials were employed, ‘one-pot’ conditions were applied, and the most important was to use inexpensive and environmentally friendly catalyst phosphotungstic acid. Various tetrahydroquinolines, which might be potentially applicable in the pharmaceutical and biochemical areas, were conveniently synthesized in moderate to excellent yields.

This is a preview of subscription content, access via your institution.


  1. [1]

    Wallace O. B., Lauwers K. S., Jones S. A., Dodge A., Bioorg. Med. Chem. Lett., 2003, 13, 1907

    CAS  PubMed  Google Scholar 

  2. [2]

    Singer J. M., Barr B. M., Coughenour L. L., Walters M. A., Bioorg. Med. Chem. Lett., 2005, 15, 4560

    CAS  PubMed  Google Scholar 

  3. [3]

    Díaz J. L., Christmann U., Fernández A., Luengo M., Bordas M., Enrech R., Carro M., Pascual R., Burgueño J., Merlos M., Benet-Buchholz J., Cerón-Bertran J., Ramírez J., Reinoso R. F., Fernández de Henestrosa A. R., Vela J. M., Almansa C., J. Med. Chem., 2013, 56, 3656

    PubMed  Google Scholar 

  4. [4]

    Quan M. L., Wong P. C., Wang C., Woerner F., Smallheer J. M., Barbera F. A., Bozarth J. M., Brown R. L., Harpel M. R., Luettgen J. M., Morin P. E., Peterson T., Ramamurthy V., Rendina A. R., Rossi K. A., Watson C. A., Wei A., Zhang G., Seiffert D., Wexler R. R., J. Med. Chem., 2014, 57, 955

    CAS  PubMed  Google Scholar 

  5. [5]

    Wang W. B., Lu S. M., Yang P. Y., J. Am. Chem. Soc., 2003, 125, 10536

    CAS  PubMed  Google Scholar 

  6. [6]

    Lu S. M., Han X. W., Zhou Y. G., Adv. Synth. Cata1., 2004, 346, 909

    CAS  Google Scholar 

  7. [7]

    Reetz M. T., Li X. G., Chem. Commun., 2006, 20, 2159

    Google Scholar 

  8. [8]

    Zhou H. F., Li Z. W., Wang Z. J., Angew. Chem. In Ed., 2008, 47, 8464

    CAS  Google Scholar 

  9. [9]

    Sridharan V., Suryavanshi P. A., Menéndez J. C., Chem. Rev., 2011, 111, 7157

    CAS  PubMed  Google Scholar 

  10. [10]

    Povarov L. S., Russ. Chem. Rev., 1967, 36, 656

    Google Scholar 

  11. [11]

    Savitha G., Perumal P. T., Tetrahedron Lett., 2006, 47, 3589

    CAS  Google Scholar 

  12. [12]

    Kawabata T., Kato M., Mizugaki T., Ebitani K., Kaneda K., Chem. Eur. J., 2005, 11, 288

    Google Scholar 

  13. [13]

    Li H. Y., Horn J., Campbell A., House D., Nelson A., Marsden S. P., Chem. Commun., 2014, 50, 10222

    CAS  Google Scholar 

  14. [14]

    Tan Y. J., Zhang Z., Wang F. J., Wu H. H., Li Q. H., RSC Adv., 2014, 4, 35635

    CAS  Google Scholar 

  15. [15]

    Imrich H. G., Conrad J., Bubrin D., Beifuss U., J. Org. Chem., 2015, 80, 2319

    CAS  PubMed  Google Scholar 

  16. [16]

    Huang Y. H., Wang S. R., Wu D. P., Huang P. Q., Org. Lett., 2019, 21, 1681

    CAS  PubMed  Google Scholar 

  17. [17]

    Babu G., Perumal P. T., Tetrahedron Lett., 1998, 39, 3225

    CAS  Google Scholar 

  18. [18]

    Crousse B., Bégué J., Bonnet-Delpon D., J Org. Chem., 2000, 65

  19. [19]

    Sundararajan G., Prabagaran N., Varghese B., Org. Lett., 2001, 3, 1973

    CAS  PubMed  Google Scholar 

  20. [20]

    Lin X. F., Cui S. L., Wang Y. G., Tetrahedron Lett., 2006, 47, 4509

    CAS  Google Scholar 

  21. [21]

    Cheng D., Zhou J., Saiah E., Org. Lett., 2002, 4, 4411

    CAS  PubMed  Google Scholar 

  22. [22]

    Stevenson P. J., Nieuwenhuyzen M., Osborne D., Chem. Commun., 2002, 444

    Google Scholar 

  23. [23]

    Yamanaka M., Nishida A., Nakagana M., Org. Lett., 2000, 2, 159

    CAS  PubMed  Google Scholar 

  24. [24]

    Ishitani H., Kobayashi S., Tetrahedron Lett., 1996, 37, 7357

    CAS  Google Scholar 

  25. [25]

    Muhuhi J., Spaller M. R., J. Org. Chem., 2006, 71, 5517

    Google Scholar 

  26. [26]

    Nagarajan R., Chitra S., Perumal P. T., Tetrahedron, 2001, 57, 3419

    CAS  Google Scholar 

  27. [27]

    Srinivas K. V. N. S., Das B., Synlett., 2004, 10, 1715

    Google Scholar 

  28. [28]

    Nagaiah K., Sreenu D., Rao R. S., Vashishta G., Yadav J. S., Tetra-hedron Lett., 2006, 47, 4409

    CAS  Google Scholar 

  29. [29]

    Su M. S., Ji X. J., Zhao B. B., Tian M., Ma J. J., J. Chem. Soc. Paki-stan, 2015, 37, 1130

    CAS  Google Scholar 

  30. [30]

    Liu Q., Zhao G. H., Dai Y. F., Ma N., Dai W., Rsc. Adv., 2019, 9, 9106

    CAS  Google Scholar 

  31. [31]

    Wang G. W., Shen Y. B., Wu X. L., Eur. J. Org Chem., 2008, 29, 4999

    Google Scholar 

  32. [32]

    Zillillah, Mgu T. A., Li Z., Green. Chem., 2014, 16, 1202

    CAS  Google Scholar 

  33. [33]

    Bhattacharya S., Ayass W. W., Taffa D. H., Schneemann A., Semrau A. L., Wannapaiboon S., Altmann P. J., Pöthig A., Nisar T., Balster T., Burtch N. C., Wagner V., Fischer R. A., Wark M., Ulrich K., J. Am. Chem. Soc., 2019, 1418, 3385

    Google Scholar 

  34. [34]

    Huang X. Q., Li J. K., Shen G. D., Xin N. N., Lin Z. G., Chi Y. N., Dou J. M., Li D. C., Hu C. W., Dalton Trans., 2018, 47, 726

    CAS  PubMed  Google Scholar 

  35. [35]

    Huang X. Q., Zhang X. M., Zhang D., Yang S., Feng X., Li J. K., Lin Z. G., Cao J., Pan R., Chi Y. N., Wang B., Hu C. W., Chem. A Eur. J., 2014, 20, 2557

    CAS  Google Scholar 

  36. [36]

    Boldyreva E., Chem. Soc. Rev., 2013, 42, 7719

    CAS  PubMed  Google Scholar 

  37. [37]

    Takacs L., Chem. Soc. Rev., 2013, 42, 7649

    CAS  PubMed  Google Scholar 

  38. [38]

    Zhu S. E., Li F., Wang G. W., Chem. Soc. Rev., 2013, 42, 7535

    CAS  PubMed  Google Scholar 

  39. [39]

    Chen L. R., Lemma B. E., Rich J. S., Mack J., Green Chem., 2014, 16, 1101

    CAS  Google Scholar 

  40. [40]

    Meng X., Bi X. R., Yu C. Y., Chen G. X., Chen B. H., Jing Z. Q., Zhao P. Q., Green Chem., 2018, 20, 4638

    CAS  Google Scholar 

  41. [41]

    Düvel A., Dalton. Trans., 2019, 48, 859

    PubMed  Google Scholar 

  42. [42]

    Shen G. D., Zhao L. Y., Wang Y. C., Xia W. F., Yang M. S., Zhang T. X., RSC Adv., 2016, 6, 84748

    CAS  Google Scholar 

  43. [43]

    Shen G. D., Yang B. C., Huang X. Q., Hou Y. X., Gao H., Cui J. C., Cui C. S., Zhang T. X., J. Org. Chem., 2017, 82, 3798

    CAS  PubMed  Google Scholar 

  44. [44]

    Shen G. D., Zhao L. Y., Zhao X. L., Huangfu X. L., Li Z., Wang R., Zhang T. X., Synlett., 2017, 28, 1111

    CAS  Google Scholar 

  45. [45]

    Shen G. D., Zhao L. Y., BA O W. L., Chem. Res. Chinese Universities, 2016, 32(6), 947

    CAS  Google Scholar 

Download references

Author information



Corresponding authors

Correspondence to Guodong Shen or Xianqiang Huang.

Additional information

Supported by the Natural Science Foundation of Shandong Province, China(Nos.ZR2019QB022, ZR2019MB043).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, Z., Shen, G., Huang, X. et al. Ball-milling Synthesis of Tetrahydroquinolines via ‘One-pot’ Three-component Diels-Alder Reaction Catalyzed by Phosphotungstic Acid. Chem. Res. Chin. Univ. 36, 835–842 (2020).

Download citation


  • Ball-milling
  • Diels-Alder reaction
  • Phosphotungstic acid
  • Tetrahydroquinoline