Cyano Diels-Alder and Cyano Ene Reactions. Applications in a Formal [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines
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Danheiser Revised Text JACS 2010 132 13203.pdf
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Author(s)
Sakai, Takeo
Danheiser, Rick Lane
Date Issued
September 2010
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Sakai, Takeo, and Rick L. Danheiser. “Cyano Diels−Alder and Cyano Ene Reactions. Applications in a Formal [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines.” Journal of the American Chemical Society 132.38 (2010): 13203-13205.
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Author's final manuscript
Abstract
Two metal-free, formal [2 + 2 + 2] cycloaddition strategies for the construction of polycyclic pyridine derivatives are described that proceed via pericyclic cascade mechanisms featuring the participation of unactivated cyano groups as enophile and dienophile cycloaddition partners.
The nitrile functional group rarely participates as an enophile or dienophile in Alder ene and Diels−Alder cycloadditions.(1, 2) Herein we describe two formal [2 + 2 + 2] strategies for the synthesis of substituted pyridines that proceed via pericyclic cascade processes involving the unusual reaction of unactivated nitriles as 2-π cycloaddition components. As outlined in Scheme 1, the first strategy begins with a propargylic ene reaction(3) which is followed by an intramolecular Diels−Alder reaction in which an unactivated cyano group functions as the dienophile. When the initial propargylic ene step is blocked (e.g., by substitution at the appropriate propargylic carbon), then a second cascade sequence is operative which leads to the same pyridine products. This alternate pathway begins with an intramolecular propargylic ene reaction in which an unactivated cyano group serves as the enophilic π-bond. To our knowledge, the participation of an unactivated cyano group in a thermal ene reaction is unprecedented.(4, 5) The resulting allenylimine then functions as a 1-azadiene in an intramolecular hetero Diels−Alder reaction(6) leading (after tautomerization) to the isolated pyridine product. Overall, these transformations provide strategies for achieving metal-free, formal [2 + 2 + 2] cycloadditions(7) that complement the well established transition-metal-catalyzed methodology(8) for the synthesis of this important heterocyclic ring system.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/ja106901u
