Reverse Regioselectivity of Aminopalladation: Palladium-Catalyzed Oxidative Tandem Cyclization for the Construction of Aza-oxabicyclo[4.2.1]nonane

Palladium-catalyzed oxidative tandem cyclization enabled by nucleopalladation has been demonstrated to be an effective strategy for the construction of polycyclic structures. However, due to the tendency to form a thermodynamically favorable smaller metallacycle, the regioselectivity of nucleopalladation is relatively fixed, which limits the application of this methodology. Herein, we report an unprecedented Pd-catalyzed oxidative tandem cyclization reaction of <i>N</i>-allylaniline and 3-butenoic acid for the synthesis of aza-oxabicyclo[4.2.1]nonane. This methodology is fulfilled through sequential Markovnikov aminopalladation/intramolecular alkene insertion/Pd oxidation/C-O bond reductive elimination. Substrate scope testing demonstrated that the reaction is compatible with various sensitive functional groups. Mechanistic experiments indicated that Markovnikov and anti-Markovnikov selectivity follow a competitive process. The employment of the pyridine-oxazoline (pyox) ligand and ethylene glycol is crucial for the Markovnikov selectivity.