Enhanced Reactivity for the Wagner-Jauregg Reaction Under Aqueous Conditions

The Wagner-Jauregg reaction produces up to four new carbon-carbon bonds and eight new stereocenters, but limitations, such as high requisite temperatures, a restricted substrate scope, and significant undesired polymer formation, have resulted in this reaction receiving minimal attention. While generally considered a subtype of the Diels-Alder reaction, in which a styrenyl diene is employed in a tandem double-Diels-Alder reaction, a second, structurally distinct, stereochemically complex product can also be produced by the Wagner-Jauregg reaction, resulting from a Diels-Alder-ene cascade. Very few attempts to improve reaction conditions, expand substrate scope, or optimize product selectivity have been published. Through reaction optimization, supplemented by density functional theory calculations, we have explored the role of diene, dienophile, and solvent in controlling both the yields and product selectivity. This has led to the discovery of lower-temperature, aqueous reaction conditions that can produce the Diels-Alder-ene product, even with electron-poor dienes, with high selectivity and good yield. This work expands the understanding of the steric and electronic factors influencing product selectivity in [4 + 2]-cycloadditions and upgrades the reaction from a historical curiosity to a practical synthetic tool.