Cyano Diels−Alder and Cyano Ene Reactions. Applications in a Formal [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines

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.i , ii 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 reactioniii 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.iv , v The resulting allenylimine then functions as a 1-azadiene in an intramolecular hetero Diels-Alder reaction vi leading (after tautomerization) to the isolated pyridine product. Overall, these transformations provide strategies for achieving metal-free, formal [2 + 2 + 2] cycloadditionsvii that complement the well established transition-metal-catalyzed methodologyviii for the synthesis of this important heterocyclic ring system.ix Tables 1 and 2 present examples of transformations leading to pyridines that proceed via the first pathway outlined in Scheme 1. x In this pathway the first step involves a propargylic ene reaction in which the alkyne rather than cyano group functions as the enophile component. The observations summarized below suggest that this pathway is dominant even when both pathways are possible.In the case of substrate 2, substitution of two methyl groups at one propargylic carbon precludes cyano ene reaction as the first step in the cascade so that it is pathway A that must be operative. Comparison of the relative rates of reactions of substrates lacking gemdimethyl substitution suggest that these transformations also proceed via the propargylic ene/cyano Diels-Alder mechanism. For example, activation of the terminal alkyne with an danheisr@mit.edu . Supporting Information Available: Experimental procedures, characterization data, and 1 H and 13 C NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. alkynyl substituent leads to a significant increase in the rate of disappearance of starting material (entries 1 and 4). This observation is consistent with an initial propargylic ene step, and would not be expected if the first step in the ...

Dehydrogenative [2 + 2 + 2] Cycloaddition of Cyano-yne-allene Substrates: Convenient Access to 2,6-Naphthyridine Scaffolds

“…In the first, Danheiser et al described a formal, metal-free [2 + 2 + 2] cycloaddition to form pyridines that takes place by a propargylic ene reaction, furnishing a vinylallene that subsequently participates in a Diels−Alder reaction with a tethered cyano group. 11 In the other, Mukai et al describe a rhodium(I)-catalyzed intramolecular carbonylative [2 + 2 + 1] cycloaddition (aza-Pauson−Khand type reaction) of allenenitrile substrates. 12 It should be noted that the authors postulate a mechanism in which the nitrile does not directly participate in the reaction but rather isomerizes to a ketenimine, which enters the catalytic cycle.…”

Rhodium‐Catalyzed Cascade Reactions of Dienynes Leading to Substituted Dihydronaphthalenes and Naphthalenes

“…[18] The reactions of both arylacetylene-and alkylacetylene-derived dienynes 1 l-n furnished vinyl-substituted 1,4-dihydronaphthalenes 9 l-n in good yields (Table 3, entries 2-4). [20] In the case of dienynes that possess a tertiary propargyl ether moiety, the carbonyl migration reaction proceeds via intermediates B, C, A, and D to afford rhodium carbonyl hydride E. However, we could not observe the formation of dienal 4, and so the direct formation of intermediate E from intermediate C is more likely. A plausible mechanism for the present cascade reactions is outlined in Scheme 5.…”

A New Approach for the Synthesis of Highly Substituted Aromatic Rings: The Alkyne‐Mediated Approach

“…A triyne or ene/diyne precursor undergoes a thermal cyclisation when subjected to microwave radiation to afford a tricycle with a tetrasubstituted benzene core (Scheme ) . Sakai and Danheiser extended this work to include the use of nitriles, hence forming a pyridine derivative …”

“…[8] Sakai and Danheiser extended this work to include the use of nitriles, hence forming ap yridine derivative. [9] Parsons and co-workers have demonstrated that at hermal intramolecular cyclisation can be used to form the lactonamycin core and other interesting fused heterocyclic and carbocy-clic compounds without the use of metal catalysis. [10] Further,i t was found that in general, ene-diynes can cyclise to afford furans and dihydrofurans.…”