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.