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

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

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42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)501-508
Number of pages8
JournalNature Protocols
Volume8
Issue number3
DOIs
StatePublished - Feb 2013

Bibliographical note

Funding Information:
acknowleDGMents 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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