Difunctionalization of alkenes to incorporate two functional groups across a double bond has emerged as a powerful transformation to greatly increase molecular complexity in organic synthesis with improved efficiency. Historically, palladium-catalyzed difunctionalization of alkenes has suffered from difficulties with introducing a second functional group through reductive elimination of a Pd(II) intermediate and competing β-hydride elimination reactions. To overcome these challenges, one strategy involves utilizing a steric bulky ligand to promote the reductive elimination steps from the Pd(II) center and impeding the β-hydride elimination reactions, which are beyond the scope of this Account. Alternatively, strong oxidants have been utilized to generate high-valent palladium species, which are prone to undergo reductive elimination to form a second C–X bond. This new strategy has been extensively applied to explore the difunctionalization of alkenes with enriched functional group diversity over the past decade. In this Account, we discuss our exploration and application of a “high-valent palladium strategy” for the synthesis of fluorine-containing organic molecules that are typically inaccessible from other methods. These studies were focused on the difunctionalization of alkenes that was initiated by nucleopalladation to form the alkyl C–Pd(II) species in high exo/endo regioselectivity. In the presence of nucleophilic fluorine-containing reagents (e.g., AgF, TMSCF₃, and AgOCF₃) and strong oxidants (hypervalent iodine and electrophilic fluorinating reagents), the in situ generated fluorine-containing high-valent Pd(IV) intermediates undergo reductive elimination to provide the corresponding alkyl C–F, C–CF₃, and C–OCF₃ bonds. Using these methods, we synthesized a variety of heterocycles containing fluorine, trifluoromethyl, and trifluoromethoxyl moieties from alkene substrates under mild reaction conditions. Besides hypervalent iodine reagents and electrophilic fluorinating reagents, our group has demonstrated that hydrogen peroxide, which is an environmentally friendly oxidant, can oxidize alkyl C–Pd(II) species to form high-valent alkyl C–Pd intermediates, and based on this observation, several catalytic difunctionalizations of alkenes, such as aminochlorination, aminoacetoxylation, and aminohydroxylation reactions, have been successfully developed. In addition, water was the only waste derived from the oxidant. All of these studies provide attractive methods for the stereoselective introduction of C–N and C–O bonds across double bonds via high-valent palladium intermediates. To gain a deeper understanding of this “high-valent palladium strategy”, systematic mechanistic studies were performed to illustrate the stereochemistry of aminopalladation and reductive elimination. These results are summarized in the final section and serve as a guide for further exploration of novel alkene transformation as well as in other areas, such as Pd-catalyzed C–H bond functionalization reactions.

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