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

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.

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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.

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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.

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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.

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Correspondence to Thomas R Hoye.

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The authors declare no competing financial interests.

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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

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