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The hexadehydro-Diels–Alder reaction

Nature volume 490, pages 208–212 (2012)Cite this article

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Abstract

Arynes (aromatic systems containing, formally, a carbon–carbon triple bond) are among the most versatile of all reactive intermediates in organic chemistry. They can be ‘trapped’ to give products that are used as pharmaceuticals, agrochemicals, dyes, polymers and other fine chemicals. Here we explore a strategy that unites the de novo generation of benzynes—through a hexadehydro-Diels–Alder reaction—with their in situ elaboration into structurally complex benzenoid products. In the hexadehydro-Diels–Alder reaction, a 1,3-diyne is engaged in a [4+2] cycloisomerization with a ‘diynophile’ to produce the highly reactive benzyne intermediate. The reaction conditions for this simple, thermal transformation are notable for being free of metals and reagents. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.

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Figure 1: Diels-Alder reactions of varying oxidation states.
Figure 2: Mechanistic rationale, substrate synthesis and mild conditions for our initial two HDDA reactions.
Figure 3: Examples of intermolecular trapping of HDDA-generated benzynes.
Figure 4: Computed free energy changes for a representative HDDA-initiated cascade.

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References

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

    Article  CAS  Google Scholar 

  2. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes (Organic Chemistry, A Series of Monographs, Vol. 11, Academic, 1967)

    Google Scholar 

  3. Pellissier, H. & Santelli, M. The use of arynes in organic synthesis. Tetrahedron 59, 701–730 (2003)

    Article  CAS  Google Scholar 

  4. Dyke, A. M., Hester, A. J. & Lloyd-Jones, G. C. Organometallic generation and capture of ortho-arynes. Synthesis 4093–4112 (2006)

  5. Sanz, R. Recent applications of aryne chemistry to organic synthesis. A review. Org. Prep. Proced. Int. 40, 215–291 (2008)

    Article  CAS  Google Scholar 

  6. Gilchrist, T. L. in Science of Synthesis Vol. 43 (ed. Hopf, H.) 151–215 (Georg Thieme, 2008)

    Google Scholar 

  7. Chen, Y. & Larock, R. C. in Modern Arylation Methods (ed. Ackermann, L.) 401–473 (Wiley-VCH, 2009)

    Book  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. 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 

  10. 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 

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

    Article  CAS  Google Scholar 

  12. Onishchenko, A. S. Diene Synthesis (Israel Program for Scientific Translations, 1964)

    Google Scholar 

  13. 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 

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

  15. Wessig, P. & Müller, G. The dehydro-Diels–Alder reaction. Chem. Rev. 108, 2051–2063 (2008)

    Article  CAS  Google Scholar 

  16. 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 

  17. 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-alkoxymethylphenyl)butan-1,3-diynyl}]phenylpentan-2,4-diyn-l-ols and trapping evidence for the 1,2-didehydrobenzene diradical. Tetrahedr. Lett. 38, 3943–3946 (1997)

    Article  CAS  Google Scholar 

  18. 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 

  19. 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 

  20. Uchiyama, M. et al. Generation of functionalized asymmetric benzynes with TMP-zincates. Effects of ligands on selectivity and reactivity of zincates. J. Am. Chem. Soc. 124, 8514–8515 (2002)

    Article  CAS  Google Scholar 

  21. Chang, W.-T. et al. Cross-coupling with organosilicon compounds. Org. React. 75, 213–746 (2011)

    CAS  Google Scholar 

  22. Stiles, M., Miller, R. G. & Burckhardt, U. Reactions of benzyne intermediates in non-basic media. J. Am. Chem. Soc. 85, 1792–1797 (1963)

    Article  CAS  Google Scholar 

  23. Liu, Z. & Larock, R. C. Facile O-arylation of phenols and carboxylic acids. Org. Lett. 6, 99–102 (2004)

    Article  CAS  Google Scholar 

  24. Cheong, P. H.-Y. et al. Indolyne and aryne distortions and nucleophilic regioselectivities. J. Am. Chem. Soc. 132, 1267–1269 (2010)

    Article  CAS  Google Scholar 

  25. Garr, A. N. et al. Experimental and theoretical investigations into the unusual regioselectivity of 4,5-, 5,6-, and 6,7-indole aryne cycloadditions. Org. Lett. 12, 96–99 (2010)

    Article  CAS  Google Scholar 

  26. Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008)

    Article  CAS  Google Scholar 

  27. Ajaz, A. et al. Concerted vs. stepwise mechanisms in dehydro-Diels−Alder reactions. J. Org. Chem. 76, 9320–9328 (2011)

    Article  CAS  Google Scholar 

  28. Johnson, R. P. & Daoust, K. J. Interconversions of cyclobutyne, cyclopentyne, cyclohexyne, and their corresponding cycloalkylidene carbenes. J. Am. Chem. Soc. 117, 362–367 (1995)

    Article  CAS  Google Scholar 

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Acknowledgements

P.H.W. thanks the National Science Foundation for a graduate research fellowship. Financial support from the National Institutes of Health (GM65597 and CA76497) is acknowledged. This work was carried out in part using hardware and software provided by the University of Minnesota Supercomputing Institute.

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Authors and Affiliations

  1. Department of Chemistry, University of Minnesota, Minneapolis, 55455, Minnesota, USA

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

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  1. Thomas R. Hoye
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  2. Beeraiah Baire
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  3. Dawen Niu
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  4. Patrick H. Willoughby
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  5. Brian P. Woods
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Contributions

B.B. performed the initial experiments. All authors designed the experiments, analysed the data and wrote the manuscript.

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Correspondence to Thomas R. Hoye.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data comprising: I) General Experimental Protocols; II) Supplementary Figure 1; III) Preparation procedures and characterization data for all key compounds; IV) Computational details for geometry of fluorenonyne 24; V) Computational details for aryne 27-comp generation and trapping; VI) Copies of 1H and 13C NMR spectra of each isolated compound; VI) Supplementary References – see Contents for more details. (PDF 3552 kb)

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Hoye, T., Baire, B., Niu, D. et al. The hexadehydro-Diels–Alder reaction. Nature 490, 208–212 (2012). https://doi.org/10.1038/nature11518

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