Palladium‐Catalyzed meta‐C‐H Alkoxylation and Amidation via the Polarity Reversal of Nucleophilic Reagents

Norbornene‐mediated remote meta‐selective C‐H functionalizations of arenes have been limited to relatively weakly electronegative and “soft” species, such as aryl, alkyl, and alkylamino moieties. Herein, we describe the first example of the use of a nucleophilic reagent, such as an alcohol or amide, to replace the electrophilic reagent during the palladium‐catalyzed meta‐C‐H alkoxylation or amidation reaction of an arene. The reaction conditions are mild and highly site‐selective, thereby facilitating the direct introduction of natural products or drug molecules containing hydroxyl or amido groups at the meta‐positions of arenes. In addition, the directing group is rapidly convertible into the corresponding aldehyde, which further enhances the applicability of the reaction. Control experiments and density functional theory (DFT) calculations revealed that alcohol and amide polarity reversal induced by hypervalent iodine reagents and the subsequent formation of a Pd(IV) intermediate via the oxidative addition of the aryl‐norbornyl‐palladacycle intermediate are crucial for promoting the entire catalytic reaction cycle.