The Conia-ene reaction refers to a class of intramolecular cyclization reactions between enols and alkenes or alkynes.

In the late 1960s, the laboratory of Jean-Marie Conia began studying small carbocyclic molecules, particularly those formed via ene-type reactions involving carbonyl compounds. Based on this research, a comprehensive paper titled “The Thermal Cyclisation of Unsaturated Carbonyl Compounds” was published in 1975. They found that compounds containing both a carbonyl group (with an α-hydrogen) and an alkenyl moiety could undergo intramolecular cyclization upon heating, yielding cyclic products. In recognition of Conia’s contributions to the discovery, development, and application of this reaction, it was named the Conia-ene reaction.

Mechanistically, the reaction is similar to the classical ene reaction. It is essentially a pericyclic C–C bond-forming reaction between an enol and an unsaturated π-system (alkene or alkyne).

• Reagents: Acids, metal catalysts

• Reactants: Enones, enols, alkyne–ketones

• Products: Cyclic compounds

• Reaction Type: Intramolecular cyclization

Experimental Tips:

• Traditional Conia-ene reactions require high temperatures, which limit their broader application. However, later developments—particularly in metal catalysis—have enabled the reaction to proceed under milder conditions, making it applicable in the total synthesis of natural products;

• To enable milder reaction conditions, one can use activated substrates, such as β-ketoesters or β-ketoamides, which contain electron-withdrawing groups at the β-position relative to the carbonyl;

• Alternatively, external Lewis acids or bases can be used to activate the substrate. For example, t-BuOK can promote keto–enol tautomerism, facilitating milder conditions for the reaction.

Reaction Mechanism

Original Literature:

• Jean-Marie Conia, Pierre Le Perchec. Synthesis, 1975, 1, 1–19.

Notable References:

• A Concise Total Synthesis of (+)-Waihoensene Guided by Quaternary Center Analysis, Angew. Chem. Int. Ed., 2020, 59, 13521–13525.

• Total Synthesis and Stereochemical Revision of the Chlorinated Sesquiterpene (±)-Gomerone C, Angew. Chem. Int. Ed., 2012, 51(6), 13066–13069.

• Entry to Heterocycles Based on Indium-Catalyzed Conia-Ene Reactions: Asymmetric Synthesis of (−)-Salinosporamide A†, Angew. Chem. Int. Ed., 2008, 47(33), 6244–6246.