Keary Mark Engle

The palladium-catalyzed “ anti-Mi chael” α - h ydroalkenylation and -hydroalkynylation of electron-deficient alkenes is reported. The unconventional selectivity of this reaction is achieved through the utilization of trans-spanning bidentate phosphine ligands that stabilize the proposed trans-Pd ^II L _n ( _R )(H) (R = alkenyl or alkynyl) intermediate, which is generated through successive reactions of Pd ⁰ L ⁿ _w ith an organohalide (or -pseudohalide) and TMA•HCO ₂ . The α - h ydrofunctionalization methods tolerate a variety of electron-deficient alkenes including α , β - u nsaturated amides and esters, as well as vinyl pyridines. A range of different alkenyl/alkynyl bromides and enol triflates are demonstrated to be effective coupling partners in the reaction. The method can be performed on decagram scale by implementing DBU•HCO ₂ H as a soluble formate source. Stoichiometric studies with CyXantPhos as a model ligand support the proposed trans-geometry of intermediates along the catalytic cycle, and rapid injection nuclear magnetic resonance (RI-NMR) experiments allow detection of the key trans- Pd ^{IIL n} ( _R )(H) species. DFT calculations reveal that ligand/electrophile steric interplay is the key factor that determines the α - regioselectivity of the reaction.

(S,S)-(R,R)-PhTRAP is a wide-bite-angle chiral bisphosphine initially reported by Ito and co-workers; despite its unique coordination geometry, prior catalytic applications have been largely limited to enantioselective hydrogenation and hydrosilylation. We recently leveraged the unique trans-spanning nature of this ligand in the Pd-catalyzed enantioselective anti-Michael (α-selective) hydroarylation of unsaturated carbonyl compounds. Previously reported syntheses of this ligand employ hygroscopic phosphorus building blocks and sensitive low-valent metal reagents and require hazardous reduction conditions, leading to operational challenges and variable yields. Here we describe an alternative synthesis of PhTRAP employing mild conditions, affording (+)-PhTRAP on a gram scale in 41% yield over four steps from the readily accessible planar-chiral scaffold iodo-Ugi amine. We further apply this synthetic route to access two previously unreported aryl-modified analogs in enantioenriched form, (S,S)-(R,R)-(3,5-Xyl)TRAP and (S,S)-(R,R)-(3,5-C6F2H3)TRAP. We determined the solid-state structures of this series of bisphosphines by X-ray crystallography and discuss the conformational differences across this series.

Transition metal-catalyzed enantioselective C–H functionalization has emerged as a next-generation synthetic paradigm, offering numerous opportunities for the de novo construction and late-stage modification of complex molecular architectures. In parallel with well-established precious metal catalysts, increasing research efforts have shifted toward the use of earth-abundant 3d transition metals, driven by their distinctive intrinsic properties and reactivity profiles. This review summarizes the rapid progress in 3d metal-catalyzed enantioselective C–H functionalization up to March 2025, encompassing both inner-sphere and outer-sphere mechanisms. Emphasis is placed on the underlying challenges and core strategic solutions that have enabled these developments. To provide a comprehensive perspective, the advancements are categorized based on distinct metal/ligand catalytic systems and subcategorized according to the type of C–H functionalization reactions. Key aspects such as ligand design, reaction development, mechanistic insights, synthetic applications, and current limitations are discussed in detail where appropriate.

A Pd(II)-catalyzed [3 + 2] annulation of alkenyl amides and nitroalkanes is described. The method furnishes intricately functionalized isoxazoline N-oxide products in a single step from simple starting materials, enabling expedient access to this underexplored class of heterocycles. With internal and α-functionalized olefins, the reaction proceeds with high diastereoselectivity, providing controlled entry into isoxazoline N-oxides with multiple stereogenic centers.

We describe two bis(perfluoroaryl)nickel(II) complexes, Ni(C6F5)2(NCPh)2 and [NBu4]2[{Ni(C6F5)2(μ–OH)2}2], as bench-stable, broadly soluble, and readily coordinating Ni(II) sources for applications in organometallic synthesis and catalysis. Their catalytic competence is demonstrated across representative transformations, including Suzuki–Miyaura coupling, Buchwald–Hartwig amination, Miyaura borylation, and recently developed alkene difunctionalization reactions, with performance comparable to or exceeding that of conventional Ni sources. The presumed activation pathway via reductive elimination of decafluorobiphenyl offers a benign route, minimizing off-cycle species formation.

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.

While methods to transform α , β -unsaturated carbonyl compounds into compounds bearing β -chiral centers are abundant, enantioselective construction of α -chiral carbonyl compounds from the same starting material remains largely unexplored. Herein, we report a palladium-catalyzed reaction for constructing chiral α -arylated amides and esters through an α -hydroarylation reaction using acrylamides and acrylates as starting materials. Extensive ligand screening revealed the trans -bisphosphine ( S , S )-( R , R )-PhTRAP as a uniquely effective ligand. A wide range of aryl and azaheteroaryl iodides smoothly couple with acrylamides under substantially mild conditions, affording α -arylated amides in high to excellent yields with excellent enantioselectivity. Insights towards the catalytic cycle and the uniqueness of the trans -spanning PhTRAP ligand in controlling regio- and enantioselectivity while suppressing hydrodehalogenation are gained through density functional theory (DFT) studies.

Access to new tailored monomers is essential to explore unprecedented polymer structures and modulate their properties. In previous work, we disclosed an iteroselective diarylation of 1,5-cyclooctadiene as an attractive platform for preparing diverse cyclooctene monomers; however, it was limited to C­(sp2) coupling partners. Established difunctionalization methods with C­(sp3) fragments rely on carbon-based radical formation, which is incompatible with 1,5-cyclooctadiene. This work describes a two-electron redox manifold for the nickel-catalyzed alkylarylation of 1,5-cyclooctadiene and discloses B-alkyl-borabicyclo­[3.3.1]­nonane (alkyl-9-BBN) as an effective transmetalating reagent for maintaining a polar reaction mechanism. The method provides 5,6-alkylarylated cyclooctenes suitable for ring-opening metathesis polymerization to obtain new materials. The properties of these polymers are benchmarked and fine-tuned by variation of coupling partners in the nickel catalysis. Density functional theory calculations revealed that destabilization of the pretransmetalation complex promotes the reactivity of alkyl-9-BBN in transmetalation compared to alkylboronic esters.