In the late 1960s, the laboratory of chemist Jean-Marie Conia investigated small carbocyclic molecules, specifically as products of ene-type reactions with carbonyls. These efforts culminated in a 1975 review paper titled “The Thermal Cyclisation of Unsaturated Carbonyl Compounds.”
In its original manifestation, the Conia-ene reaction comprised the intramolecular cyclization of ε,ζ-unsaturated ketones or aldehydes to functionalized cyclopentanes upon intense heating. The proposed mechanism invoked a six-membered, ene reaction-like transition state in which the enol tautomer reacts concertedly with the pendant alkene.
The same conditions were found to give six- and nine-membered rings with the appropriate substrates, although with lower yields and diastereoselectivity. In the case of γ,δ- and δ,ε-unsaturated ketones, equilibrium favored the linear product over the cyclopropane or cyclobutane. Alkynyl ketones were also found to cyclize under thermal conditions, giving a mixture of the conjugated and skipped cyclic enones.
Two key drawbacks prevented wider implementation of the initial Conia-ene reaction. First, molecules with additional functional groups were often incompatible with the high temperatures required for conversion. Second, regio- and diastereoselectivity depended entirely on the substrate, offering little to no control over the orientation of the product.