Mapping Ambiphile Reactivity Trends in the Anti‐(Hetero)annulation of Non‐Conjugated Alkenes via PdII/PdIV Catalysis

In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti‐selective carbo‐ or heteroannulation with non‐conjugated alkenyl amides under PdII/PdIV catalysis. Detailed optimization of the reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n=3–5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through PdII/amine co‐catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct PdII/PdIV mechanism involving Wacker‐type directed nucleopalladation. This difference results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments. A method to access 5‐, 6‐ and 7‐membered carbo‐ and heterocycles from non‐conjugated alkenyl amides and ambiphilic organohalides is described. Under PdII/PdIV catalysis, this [n+2] annulation proceeds in an anti‐selective fashion and tolerates a wide array of ambiphiles, which are systematically benchmarked with respect to nucleophile identity, electrophile identity, and product ring‐size. Otherwise unreactive ambiphilic ortho‐haloacetophenones can be activated using an amine co‐catalyst.