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Oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C3) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. Substrates with tethers of varying lengths delivered five- and six-membered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition–conjugate addition cascade. Several experiments and theoretical calculations provide evidence for the proposed mechanistic pathway.

Systematic investigation of intramolecular silyloxypyrone-based [5 + 2] cycloadditions revealed three significant factors impacting conversion to cycloadduct: (1) the silyl transfer group has a substantial influence on the rate of reaction, and the robust t-butyldiphenylsilyl group was found to be more effective overall than the conventional t-butyldimethylsilyl group; (2) α,β-unsaturated esters were generally more reactive than terminal olefins and afforded appreciable quantity of cycloadduct even at room temperature; and (3) the proximity of the tether to the silyl transfer group revealed a critical alignment trend between the pyrone and the alkene. Taken together, these investigations provided insight regarding the steric and electronic parameters that impact the scope and limitation of these reactions.

Intramolecular oxidopyrylium-based [5 + 2] cycloadditions utilizing chiral auxiliaries were investigated. Both acetoxypyranones and silyloxypyrones were employed and sulfinimines, oxazolidinones, hydrazones, and chiral enamines were explored. Carbonyl-based auxiliaries gave low selectivity, but enamines afforded excellent diastereoselectivity. Overall, facial selectivity varied significantly providing insight regarding the scope and limitation of chiral auxiliary-based oxidopyrylium-alkene [5 + 2] cycloadditions.

We have developed an automated photochemical microfluidics platform that integrates a 1 kW high-pressure Hg vapor lamp and allows for analytical pulse flow or preparative continuous flow reactions. Herein, we will discuss the use of this platform toward the discovery of new chemotypes through multidimensional reaction screening. We will highlight the ability to discretely control wavelengths with optical filters, allowing for control of reaction outcomes.