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The pentadehydro-Diels–Alder reaction

Nature volume 532, pages 484–488 (2016)Cite this article

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Abstract

In the classic Diels–Alder [4 + 2] cycloaddition reaction1, the overall degree of unsaturation (or oxidation state) of the 4π (diene) and 2π (dienophile) pairs of reactants dictates the oxidation state of the newly formed six-membered carbocycle. For example, in the classic Diels–Alder reaction, butadiene and ethylene combine to produce cyclohexene. More recent developments include variants in which the number of hydrogen atoms in the reactant pair and in the resulting product is reduced2 by, for example, four in the tetradehydro-Diels–Alder (TDDA) and by six in the hexadehydro-Diels–Alder (HDDA)3,4,5,6,7 reactions. Any oxidation state higher than tetradehydro (that is, lacking more than four hydrogens) leads to the production of a reactive intermediate that is more highly oxidized than benzene. This increases the power of the overall process substantially, because trapping of the reactive intermediate8,9 can be used to increase the structural complexity of the final product in a controllable and versatile manner. Here we report an unprecedented overall 4π + 2π cycloaddition reaction that generates a different, highly reactive intermediate known as an α,3-dehydrotoluene. This species is in the same oxidation state as a benzyne. Like benzynes, α,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the HDDA process. We call this new cycloisomerization process a pentadehydro-Diels–Alder (PDDA) reaction—a nomenclature chosen for chemical taxonomic reasons rather than mechanistic ones. In addition to alkynes, nitriles (RC≡N), although non-participants in aza-HDDA reactions, readily function as the 2π component in PDDA cyclizations to produce, via trapping of the α,3-(5-aza)dehydrotoluene intermediates, pyridine-containing products.

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Figure 1: Terminology associated with various cyclizations in the Diels–Alder family of 4π + 2π reactions.
Figure 2: PDDA cascades of tetraynes.
Figure 3: Cyclizations of nitrile-containing diynes—the aza-PDDA.
Figure 4: Mechanistic aspects of the PDDA reaction.

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Acknowledgements

Financial support from the National Institute of General Medical Sciences (GM65597) and the National Cancer Institute (CA76497) of the US Department of Health and Human Services is acknowledged. Portions of this work were performed using resources available through the University of Minnesota Supercomputing Institute (MSI). NMR spectra were recorded using instrumentation purchased with funds from the NIH Shared Instrumentation Grant programme (S10OD011952). We thank D. J. Marell for guidance in several aspects of the computations.

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  1. Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, 55455, Minnesota, USA

    Teng Wang, Rajasekhar Reddy Naredla, Severin K. Thompson & Thomas R. Hoye

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  1. Teng Wang
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  2. Rajasekhar Reddy Naredla
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Contributions

T.W. and R.R.N. carried out the experiments and contributed equally to the overall work; S.K.T. performed the computational studies. All authors interpreted the results and prepared the manuscript.

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Correspondence to Thomas R. Hoye.

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Wang, T., Naredla, R., Thompson, S. et al. The pentadehydro-Diels–Alder reaction. Nature 532, 484–488 (2016). https://doi.org/10.1038/nature17429

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