Skip to main content

Synthesis of a Key Intermediate towards the Preparation of Efavirenz Using n-Butyllithium


A key reaction in one of the routes to efavirenz, an essential drug used in the treatment of acquired immunodeficiency syndrome (AIDS), is the ortho-lithiation reaction of N-Boc-4-chloroaniline. For the first time, we demonstrate that the reaction may be conducted using n-BuLi and show that the reaction may be performed in a flow reactor with a significantly higher yield (70%) compared to batch (28%) when using n-BuLi for the ortho-metalation reaction at a temperature of −45 °C. In addition, it was shown that tetramethylethylenediamine (TMEDA) did not need to be added to the flow reaction, which simplified the purification procedure.

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


  1. Clayden, J. Organolithiums: Selectivity for Synthesis; Elsevier: Oxford, 2002.

    Google Scholar 

  2. Schlosser, M. Organometallics in Synthesis Third Manual; Wiley: Hoboken, 2013.

    Book  Google Scholar 

  3. Reich, H. J. J. Org. Chem. 2012, 77, 5471–5491.

    CAS  Article  Google Scholar 

  4. Reich, H. J. Chem. Rev 2013, 113, 7130–7178.

    CAS  Article  Google Scholar 

  5. Capriati, V.; Perna, F. M.; Salomone, A. Dalton Trans. 2014, 43, 14204–14210.

    CAS  Article  Google Scholar 

  6. Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833–6837.

    CAS  Article  Google Scholar 

  7. Siddaiah, V.; Mahaboob Basha, G.; Srinuvasa, R.; Yessayya, V. Green Chem. Lett. Rev. 2012, 5, 337–342.

    CAS  Article  Google Scholar 

  8. Desponds, M.; Lehmann, O.; Moret, R.; Rauchschwalbe, E. Tetrahedron 1993, 49, 10175–10203.

    Article  Google Scholar 

  9. Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 311–314.

    Google Scholar 

  10. Kessar, S. V.; Singh, P. Chem. Rev 1997, 97, 721–738.

    CAS  Article  Google Scholar 

  11. Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, L. Adv Heterocycl. Chem. 1991, 52, 187–304.

    CAS  Article  Google Scholar 

  12. Undheim, K.; Benneche, T. Act. Chem. Scand. 1993, 47, 102–121.

    CAS  Article  Google Scholar 

  13. Nagaki, A.; Ichinari, D.; Yoshida, J.-I. J. Am. Chem. Soc. 2014, 136, 12245–12248.

    CAS  Article  Google Scholar 

  14. Yoshida, J.-I. Chem. Rev 2010, 10, 332–341.

    CAS  Google Scholar 

  15. Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2007, 129, 3046–3047.

    CAS  Article  Google Scholar 

  16. Murray, P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthrie, D.; Ley, S. V. Org. Process Res. Dev 2013, 17, 1192–1208.

    CAS  Article  Google Scholar 

  17. Correia, C. A.; Gilmore, K.; McQuade, D. T.; Seeberger, P. H. Angew. Chem. Int. Ed. 2015, 54, 4945–4948.

    CAS  Article  Google Scholar 

  18. Kensen, K. J. AIChE Journal 2017, 63, 858–869.

    Article  Google Scholar 

  19. Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem., Int. Ed. 2015, 54, 6688–6729.

    CAS  Article  Google Scholar 

  20. Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798–4801.

    CAS  Article  Google Scholar 

  21. Radesca, L. A.; Lo, Y. S.; Moore, J. R.; Pierce, M. E. Synth. Comm. 1997, 27, 4383–4384.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Paul Watts.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chada, S., Mandala, D. & Watts, P. Synthesis of a Key Intermediate towards the Preparation of Efavirenz Using n-Butyllithium. J Flow Chem 7, 37–40 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Efavirenz
  • n-butyllithium
  • continuous flow
  • trifluoroacetylation