Catalytic capture of fleeting enamines with palladium electrophiles

Many reactive intermediates remain chemically inaccessible because they exist only in low equilibrium populations. Although enamines are fundamental nucleophiles in stoichiometric and catalytic reactions, their catalytic use has been largely restricted to systems in which their formation is thermodynamically favoured. Thermodynamically disfavoured enamines exist only transiently and in minute concentrations. Thus, their utilisation requires intermediates with both the stability to capture these fleeting species and the reactivity to drive the subsequent low-barrier bond-forming pathways to completion, thereby preventing the overall reactivity from being governed by the thermodynamics of enamine formation. Here, we demonstrate that low-population enamines can participate efficiently in catalysis through the Lewis-acid-assisted generation of cationic arylpalladium(II) intermediates. This strategy allows a palladium-catalysed α-arylation of acyclic ketones that exhibits broad functional-group tolerance under near-neutral conditions, providing access to transformations that are challenging under conventional conditions. The results of our experimental and theoretical studies support the formation of electrophilically activated cationic palladium intermediates that are responsible for enamine capture and the subsequent formation of carbon–carbon bonds. More broadly, our findings establish a catalytic strategy that involves thermodynamically disfavoured yet chemically valuable intermediates that ordinarily remain latent in equilibrium.