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The hexadehydro-Diels–Alder reaction

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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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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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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