Methylene Cycloalkene as a Reactive 1,3-Diene for Enantioselective Hydroamination

Herein, we report the first enantioselective functionalization of methylene cycloalkenes─an underexplored class of reactive 1,3-dienes. The process involves a palladium-catalyzed enantioselective hydroamination of methylene cycloalkenes using pyrazole derivatives, affording a variety of chiral tertiary amines. A machine-learning model based on universal descriptors from quasi-transition-state (UD-qTS) strategy, combined with a physicochemically grounded data-augmentation protocol, has been employed to accelerate the optimization process. Deuterium-labeling experiments and density functional theory (DFT) calculations revealed that the reaction proceeded through a ligand–to–ligand hydrogen transfer (LLHT) pathway, which is both the rate-determining and enantio-determination step. Subsequent inner-sphere nucleophilic attack by the pyrazole anion enables regioselective C3 (referring to 1,3-diene)–N1 (referring to pyrazole) bond formation. Furthermore, the resulting products can be transformed into acyclic alkenes, which are equivalent to the hydroamination products of acyclic 1,3-dienes.