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Further Information

Related Reactions
Ene Reaction
Synthesis of cyclopentanes
Synthesis of cyclohexanes

Conia-Ene Reaction

The Conia-Ene reaction is an intramolecular, thermal or Lewis acid-catalysed reaction of unsaturated carbonyl compounds to yield cyclised products.

Mechanism of the Conia-Ene Reaction

In the Conia-Ene reaction, enolisation is followed by a concerted 1,5-hydrogen shift:

Thus, the Conia-Ene Reaction is an intramolecular variant of the generally intermolecular Ene Reaction.

Reactions that generate cyclopentane and cyclohexane derivatives in good yields normally proceed at 350C, but medium-sized rings need higher temperatures and the yield is considerably lower.

Each step of the Conia-Ene reaction is reversible, as shown by some retro-Conia Ene reactions of cyclobutanes where the main product is the open-chain isomer.

The stereochemistry of the cyclisation is affected by the spatial arrangement of the two reactive centres, and this mainly depends on the configuration at the enol centre and the various steric effects arising from the chain conformation in the ground state.

In cases where the cyclic product is still enolisable, subsequent enolisation results in epimerisation that can modify the product ratio and therefore no simple conclusion regarding the stereoselectivity can be reached.

The scope of substrates includes precursors of ketones such as acetals and enol ethers, which also regenerate the ketone at high temperature. However, unsaturated β-ketoesters and β-diketones are also suitable starting materials. Their stronger enolic character enables reactions to proceed at lower temperatures.

For acetylenic substrates, double bond migration often occurs to favour a higher degree of substitution. No such migration is observed when a terminal methyl group stabilises the exo-double bond, or if the reaction is conducted at lower temperatures - for example with a β-diketone as substrate.

For a review of thermal Conia-Ene reactions and a detailed mechanistic discussion, please refer to a review by Conia and Le Perchec (Synthesis 1975, 1. DOI)

Nevertheless, the need for high temperatures severely limits the synthetic utility of the Conia-Ene reaction. A catalytic version that proceeds at ambient temperature and under neutral conditions would dramatically increase the reaction’s usefulness. In 2004, Toste reported a phosphinegold(I)-catalysed version for the intramolecular addition of a β-ketoester to an unactivated alkyne. For this reaction, two mechanistic hypotheses have been developed.

J. J. Kennedy-Smith, S. T. Staben, F. D. Toste, J. Am. Chem. Soc., 2004, 126, 4526-4527.

For this system, the deuterium-labelling experiments depicted below supported a mechanism involving enol addition to an Au-alkyne complex (mechanism A above).

Some recent developments for catalysed reactions, including enantioselective reactions, can be found in the recent literature section.

Recent Literature

A New Iron(III)-Salen Catalyst for Enantioselective Conia-ene Carbocyclization
S. Shaw, J. D. White, J. Am. Chem. Soc., 2014, 136, 13174-13177.

Gold(I)-Catalyzed Conia-Ene Reaction of β-Ketoesters with Alkynes
J. J. Kennedy-Smith, S. T. Staben, F. D. Toste, J. Am. Chem. Soc., 2004, 126, 4526-4527.

Catalytic Enantioselective Conia-Ene Reaction
B. K. Corkey, F. D. Toste, J. Am. Chem. Soc., 2005, 127, 17168-17169.

Ni(II)-Catalyzed Conia-Ene Reaction of 1,3-Dicarbonyl Compounds with Alkynes
Q. Gao, B.-F. Zheng, J.-H. Li, D. Yang, Org. Lett., 2005, 7, 2185-2188.

Rhenium-Catalyzed Insertion of Terminal Acetylenes into a C-H Bond of Active Methylene Compounds
Y. Kuninobu, A. Kawata, K. Takai, Org. Lett., 2005, 7, 4823-4825.

Enantioselective Conia-Ene-Type Cyclizations of Alkynyl Ketones through Cooperative Action of B(C6F5)3, N-Alkylamine and a Zn-Based Catalyst
M. Cao, A. Yesilcimen, M. Wasa, J. Am. Chem. Soc., 2019, 141, 4199-4203.

Yb(OTf)3-Promoted ZnCl2-Catalyzed Conia-Ene Reaction of Linear β-Alkynic β-Dicarbonyls
Y. Liu, R.-J. Song, J.-H. Li, Synthesis, 2010, 3663-3669.