biostudies-literatureNi HQNational Institutes of HealthNIGMS NIH HHSe202114346https://www.ebi.ac.uk/biostudies/studies/S-EPMC8923970biostudies-literatureUnknown61(13)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 Pd^II /Pd^IV 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 Pd^II /amine co-catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct Pd^II /Pd^IV 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.Angewandte Chemie (International ed. in English)Mapping Ambiphile Reactivity Trends in the Anti-(Hetero)annulation of Non-Conjugated Alkenes via Pd^II /Pd^IV Catalysis.PMC89239705R35GM125052-053R35GM125052-04S2R35 GM125052McAlpine IJBedekar PGNi HQSach NWang FEngle KMCooper PTran-Dube MYang SDonaldson JSfalseMapping Ambiphile Reactivity Trends in the Anti-(Hetero)annulation of Non-Conjugated Alkenes via Pd^II /Pd^IV 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 Pd^II /Pd^IV 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 Pd^II /amine co-catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct Pd^II /Pd^IV 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.2022-01-01T00:00:00Z2022 Mar2025-04-05T16:11:09.236Z2025-04-05T16:11:09.236ZS-EPMC89239703500739310.1002/anie.202114346