Al Vicente Riano D. Lisboa

Catalytic functionalization of unactivated π‐bonds is a cornerstone of modern organic synthesis, offering efficient pathways to complex molecules. The emergence of the bidentate directing auxiliary strategy has fundamentally reshaped and significantly broadened the scope of transition‐metal‐catalyzed π‐bond functionalization. A key feature of this strategy is the formation of chelated intermediates where the bidentate directing auxiliary, tethered to the alkene or alkyne substrate, coordinates strongly to the transition metal catalyst. This chelation provides numerous advantages, including enhanced reaction kinetics, superior chemoselectivity, and improved catalyst efficiency, thereby enabling previously challenging reaction types on unactivated π‐bonds. This review highlights the recent significant progress in π‐bond functionalization enabled by bidentate directing auxiliaries, focusing on transformations catalyzed by palladium, nickel, copper, and other transition metals. We systematically discuss major reaction types, including hydrofunctionalization, difunctionalization, and C–H activation across various substrates, while emphasizing the underlying design principles that govern reactivity and selectivity in these systems.

Catalytic functionalization of unactivated π‐bonds is a cornerstone of modern organic synthesis, offering efficient pathways to complex molecules. The emergence of the bidentate directing auxiliary strategy has fundamentally reshaped and significantly broadened the scope of transition‐metal‐catalyzed π‐bond functionalization. A key feature of this strategy is the formation of chelated intermediates where the bidentate directing auxiliary, tethered to the alkene or alkyne substrate, coordinates strongly to the transition metal catalyst. This chelation provides numerous advantages, including enhanced reaction kinetics, superior chemoselectivity, and improved catalyst efficiency, thereby enabling previously challenging reaction types on unactivated π‐bonds. This review highlights the recent significant progress in π‐bond functionalization enabled by bidentate directing auxiliaries, focusing on transformations catalyzed by palladium, nickel, copper, and other transition metals. We systematically discuss major reaction types, including hydrofunctionalization, difunctionalization, and C–H activation across various substrates, while emphasizing the underlying design principles that govern reactivity and selectivity in these systems.

In this work, we demonstrate that directing group flexibility plays a decisive role in overcoming reactivity barriers in Pd^II-catalyzed alkene functionalization. Kinetic, organometallic, and DFT studies reveal that employing the rigid 8-aminoquinoline (AQ) auxiliary in α,α-disubstituted substrates leads to high activation barriers for a rate-determining protonation transition state arising from geometric distortion. Guided by these insights, we show that judicious tuning of the directing group can minimize energetic penalties with the use of a flexible 2-pyridylmethylamine (PM) auxiliary. This mechanistically informed approach led to a 115-fold rate increase for the model α,α-dimethyl substrate and broadens the scope to sterically encumbered alkenes, including α-spiro(hetero)cyclic systems, with tolerance for diverse N-H and C-H nucleophiles. Furthermore, we demonstrate that the mechanistic framework developed for hydroamination extends to other difunctionalization reactions such as carboamination and cyclopropanation. This work expands access to structurally complex and lipophilic scaffolds from readily available alkenes.

In this work, we demonstrate that directing group flexibility plays a decisive role in overcoming reactivity barriers in PdII-catalyzed alkene functionalization. Kinetic, organometallic, and DFT studies reveal that employing the rigid 8-aminoquinoline (AQ) auxiliary in α,α-disubstituted substrates leads to high activation barriers for a turnover-limiting product dissociation step arising from geometric distortion. Guided by these insights, we show that judicious tuning of the directing group can minimize energetic penalties with the use of a flexible 2-pyridylmethylamine (PM) auxiliary. This mechanistically informed approach led to a 115-fold rate increase for the model α,α-dimethyl substrate and broadens the scope to sterically encumbered alkenes, including α-spiro(hetero)cyclic systems, with tolerance for diverse N–H and C–H nucleophiles. Furthermore, we demonstrate that the mechanistic framework developed for hydroamination extends to other difunctionalization reactions such as carboamination and cyclopropanation. This work expands access to structurally complex and lipophilic scaffolds from readily available alkenes.

Here we present the ambiphilic reactivity of alkyl sulfonyl fluorides in the stereoselective synthesis of diverse cyclopropanes from olefins, under palladium(II) catalysis. The sulfonyl fluoride functionality serves as both an acidifying group and an internal oxidant within the ambiphile, enabling successive carbopalladation and oxidative addition steps in the catalytic cycle, respectively. The transformation grants access to cis -substituted cyclopropanes and exhibits broad compatibility with various alkyl sulfonyl fluorides, including those bearing –CN, –CO ₂ R, isoxazolyl, pyrazolyl and aryl groups. With internal alkene substrates, 1,2,3-trisubstituted cyclopropanes that are otherwise challenging to synthesize are formed in good-to-moderate yields and predictable diastereoselectivity. Detailed mechanistic insights from reaction progress kinetic analysis and density functional theory calculations reveal that the S _N 2-type C–SO ₂ F oxidative addition is the turnover-limiting and diastereoselectivity-determining step.

This Letter describes the photocatalytic C(sp²)-H amination of electron-rich arenes with azoles via an electron donor-acceptor (EDA) pathway. The acceptor in this system is proposed to be a pyridin-1-ium salt generated in situ from the combination of pyridine and either LiOTf or HOTf. The reactions proceed with irradiation using 370 nm LEDs, and the pyridine/acid acceptor can serve as a catalyst under aerobic conditions. This represents a rare example of a catalytic acceptor in EDA photochemistry.

The ambiphilic reactivity of alkyl sulfonyl fluorides in the stereoselective synthesis of diverse cyclopropanes from ole-fins under palladium(II) catalysis is presented. The sulfonyl fluoride functionality serves as both an acidifying group and an internal oxidant within the ambiphile, enabling the successive carbopalladation and oxidative addition steps in the catalytic cycle, respectively. The transformation grants access to cis-substituted cyclopropanes and exhibits broad compatibility with various alkyl sulfonyl fluorides, including those bearing –CN, –CO2R, isoxazolyl, pyrazolyl, and aryl groups. With internal alkene substrates, 1,2-3-trisubstituted cyclopropanes that are otherwise challenging to synthesize are formed in good to moderate yield and predictable diastereoselectivity. Detailed mechanistic insights from reaction progress kinetic analysis (RPKA) and density functional theory (DFT) calculations reveal that the SN2-type C–SO2F oxidative addition is the turnover-limiting and diastereoselectivity-determining step.

An in situ generated pyridinium trifluoromethoxide salt (PyOCF₃) is a highly effective deoxyfluorination reagent for the synthesis of acid fluorides. PyOCF₃ is formed at room temperature from the reaction of 2,4-dinitro(trifluoromethoxy)benzene with 4-dimethylaminopyridine. PyOCF₃ undergoes slow release of fluorophosgene and fluoride, which serve as the electrophile and nucleophile, respectively, for deoxyfluorination. A wide substrate scope and high functional group tolerance are demonstrated. Furthermore, the acid fluorides can be purified by filtration and telescoped to various known reactions.