Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Protocol
  • Published:

Synthesis of complex benzenoids via the intermediate generation of o-benzynes through the hexadehydro-Diels-Alder reaction

Nature Protocols volume 8, pages 501–508 (2013)Cite this article

Subjects

Abstract

The hexadehydro-Diels-Alder (HDDA) cascade enables the synthesis of complex benzenoid products with various substitution patterns through aryne intermediates. The first stage of this cascade involves the generation of a highly reactive ortho-benzyne intermediate by a net [4+2] cycloisomerization of a triyne substrate. The benzyne can be rapidly 'trapped' either intramolecularly or intermolecularly with myriad nucleophilic or π-bond-donating reactants. As a representative example of a general procedure for synthesizing highly substituted benzenoids, this protocol describes the synthesis of a typical triyne substrate and its use as the reactant in an HDDA cascade to form a phthalide. The synthetic procedure detailed herein (four chemical reactions) takes 16–20 h of active effort over a period of several days for the preparation of the triyne precursor and ∼2 h of active effort over a 3-d period for the generation and trapping of the benzyne and isolation of the phthalide product.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The hexadehydro-Diels-Alder (HDDA) cascade.
Figure 2: Examples of HDDA cascade processes, including both intermolecular and intramolecular trapping reactions.
Figure 3: Intermediates involved (benzyne 5 and zwitterion 6) in the HDDA cascade conversion of triyne 4 to phthalide 7.
Figure 4: Synthesis route to obtain substrate 4 and its HDDA cascade to produce the tricyclic phthalide derivative 7.

Similar content being viewed by others

References

  1. Himeshima, Y., Sonoda, T. & Kobayashi, H. Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditions. Chem. Lett. 12, 1211–1214 (1983).

    Article  Google Scholar 

  2. Miyawaki, K., Suzuki, R., Kawano, T. & Ueda, I. Cycloaromatization of a non-conjugated polyenyne system: synthesis of 5H-benzo[d]fluoreno[3,2-b]pyrans via diradicals generated from 1-(2-(4-(2-alkoxyethylphenyl)butan-1,3-diynyl))phenylpetan-2,4-diyn-1-ols and trapping evidence for the 1,2-didehydrobenzene diradical. Tetrahedron Lett. 38, 3943–3946 (1997).

    Article  CAS  Google Scholar 

  3. Bradley, A.Z. & Johnson, R.P. Thermolysis of 1,3,8-nonatriyne: evidence for intramolecular [2+4] cycloaromatization to a benzyne intermediate. J. Am. Chem. Soc. 119, 9917–9918 (1997).

    Article  CAS  Google Scholar 

  4. Tsui, J.A. & Sterenberg, B.T. A metal-templated 4 + 2 cycloaddition reaction of an alkyne and a diyne to form a 1,2-aryne. Organometallics 28, 4906–4908 (2009).

    Article  CAS  Google Scholar 

  5. Kimura, H., Torikai, K., Miyawaki, K. & Ueda, I. Scope of the thermal cyclization of nonconjugated ene-yne-nitrile system: a facile synthesis of cyanofluorenol derivatives. Chem. Lett. 37, 662–663 (2008).

    Article  CAS  Google Scholar 

  6. Hoye, T.R., Baire, B., Niu, D., Willoughby, P.H. & Woods, B.P. The hexadehydro-Diels-Alder reaction. Nature 490, 208–212 (2012).

    Article  CAS  Google Scholar 

  7. Jork, H., Funk, W., Fischer, W. & Wimmer, H. Thin-layer Chromatography Reagents and Detection Methods; Vol. 1a: Physical and Chemical Detection Methods: Fundamentals, Reagents I. (VCH, 1990).

  8. Still, W.C., Kahn, M. & Mitra, A. Rapid chromatographic technique for preparative separations with moderate resolution. J. Org. Chem. 43, 2923–2925 (1978).

    Article  CAS  Google Scholar 

  9. Brandsma, L. Halogenation of acetylenes. in Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 191–202 (Elsevier, 2004).

  10. Wenk, H.H., Winkler, M. & Sander, W. One century of aryne chemistry. Angew. Chem. Int. Edn. 42, 502–528 (2003).

    Article  CAS  Google Scholar 

  11. Nicolaou, K.C., Snyder, S.A., Montagnon, T. & Vassilikogiannakis, G. The Diels-Alder reaction in total synthesis. Angew. Chem. Int. Edn. 41, 1668–1698 (2002).

    Article  CAS  Google Scholar 

  12. Stoermer, R. & Kahlert, B. Ueber das 1- und 2-Bromcumaron. Ber. Dtsch. Chem. Ges. 35, 1633–1640 (1902).

    Article  CAS  Google Scholar 

  13. Roberts, J.D., Simmons, H.E., Carlsmith, L.A. & Vaughan, C.W. Rearrangement in the reaction of chlorobenzene-1-C14 with potassium amide. J. Am. Chem. Soc. 75, 3290–3291 (1953).

    Article  CAS  Google Scholar 

  14. Huisgen, R. & Rist, H. Über Umlagerungen bei nucleophilen Substitutionen in der aromatischen Reihe und ihre Deutung. Naturwissenschaften 41, 358–359 (1954).

    Article  CAS  Google Scholar 

  15. Wittig, G. & Pohmer, L. Intermediäre Bildung von Dehydrobenzol (Cyclohexadienin). Angew. Chem. 67, 348 (1955).

    Article  CAS  Google Scholar 

  16. Hoffmann, R.W. Dehydrobenzone and Cycloalkynes. Organic Chemistry, a Series of Monographs, Vol. 11 (Academic Press, 1967).

  17. Kitamura, T. Synthetic methods for the generation and preparative application of benzyne. Aust. J. Chem. 63, 987–1001 (2010).

    Article  CAS  Google Scholar 

  18. Yoshida, H., Ohshita, J. & Kunai, A. Aryne, ortho-quinone methide, and ortho-quinodimethane: synthesis of multisubstituted arenes using the aromatic reactive intermediates. Bull. Chem. Soc. Jpn. 83, 199–219 (2010).

    Article  CAS  Google Scholar 

  19. Worlikar, S.A. & Larock, R.C. Pd-catalyzed reactions involving arynes. Curr. Org. Chem. 15, 3214–3232 (2011).

    Article  CAS  Google Scholar 

  20. Gampe, C.M. & Carreira, E.M. Arynes and cyclohexyne in natural product synthesis. Angew. Chem. Int. Edn. 51, 3766–3778 (2012).

    Article  CAS  Google Scholar 

  21. Tadross, P.M. & Stoltz, B.M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112, 3550–3577 (2012).

    Article  CAS  Google Scholar 

  22. Bhunia, A., Yetra, S.R. & Biju, A.T. Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes. Chem. Soc. Rev. 41, 3140–3152 (2012).

    Article  CAS  Google Scholar 

  23. Okuma, K. Reaction of arynes with carbon-heteroatom double bonds. Heterocycles 85, 515–544 (2012).

    Article  CAS  Google Scholar 

  24. Yoshida, H. & Takaki, K. Multicomponent coupling reaction of arynes for construction of heterocyclic skeletons. Heterocycles 85, 1333–1349 (2012).

    Article  CAS  Google Scholar 

  25. Kovalev, I.S. et al. Aryne intermediates in the synthesis of polynuclear heterocyclic systems. Chem. Heterocycl. Compds. 48, 536–547 (2012).

    Article  CAS  Google Scholar 

  26. Yoshida, H. & Takaki, K. Aryne insertion reactions into carbon-carbon -bonds. Synlett 23, 1725–1732 (2012).

    Article  CAS  Google Scholar 

  27. Michael, A. & Bucher, J.E. Über die Einwirkung von Eissigsäureanhydrid auf Phenylpropiolsäure. Chem. Zentrblt 731–733 (1898).

  28. Diels, O. & Alder, K. Syntheses in the hydroaromatic series. Justus Liebigs Ann. Chem. 460, 98–122 (1928).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

D.N. and P.H.W. thank the University of Minnesota Graduate School Doctoral Dissertation Fellowship and the National Science Foundation Graduate Research Fellowship program, respectively. Financial support from the US National Institutes of Health (GM65597 and CA76497) is acknowledged.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, USA

    Beeraiah Baire, Dawen Niu, Patrick H Willoughby, Brian P Woods & Thomas R Hoye

Authors
  1. Beeraiah Baire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dawen Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick H Willoughby
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian P Woods
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas R Hoye
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.B., D.N., P.H.W., B.P.W. and T.R.H. contributed equally to developing the experimental procedures and writing the manuscript.

Corresponding author

Correspondence to Thomas R Hoye.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baire, B., Niu, D., Willoughby, P. et al. Synthesis of complex benzenoids via the intermediate generation of o-benzynes through the hexadehydro-Diels-Alder reaction. Nat Protoc 8, 501–508 (2013). https://doi.org/10.1038/nprot.2013.017

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2013.017

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing