Catalytic Behavior of Mono‐N‐Protected Amino‐Acid Ligands in Ligand‐Accelerated C−H Activation by Palladium(II)

Mono‐N‐protected amino acids (MPAAs) are increasingly common ligands in Pd‐catalyzed C?H functionalization reactions. Previous studies have shown how these ligands accelerate catalytic turnover by facilitating the C?H activation step. Here, it is shown that MPAA ligands exhibit a second property commonly associated with ligand‐accelerated catalysis: the ability to support catalytic turnover at substoichiometric ligand‐to‐metal ratios. This catalytic role of the MPAA ligand is characterized in stoichiometric C?H activation and catalytic C?H functionalization reactions. Palladacycle formation with substrates bearing carboxylate and pyridine directing groups exhibit a 50–100‐fold increase in rate when only 0.05 equivalents of MPAA are present relative to Pd^II. These and other mechanistic data indicate that facile exchange between MPAAs and anionic ligands coordinated to Pd^II enables a single MPAA to support C?H activation at multiple Pd^II centers.     

Palladium‐Catalyzed Enantioselective C−H Olefination of Diaryl Sulfoxides through Parallel Kinetic Resolution and Desymmetrization

The first example of Pd^II‐catalyzed enantioselective C?H olefination with non‐chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized with high enantioselectivity (up to 99 %) through both desymmetrization and parallel kinetic resolution (PKR). This is the first report of Pd^II‐catalyzed enantioselective C(sp²)?H functionalization through PKR, and it represents a novel strategy to construct sulfur chiral centers.     

PdII‐Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II‐catalyzed enantioselective C(sp³)?H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C?H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II‐catalyzed enantioselective β‐C(sp³)?H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C?H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.     

N‐Heterocyclic Carbene Ligand‐Enabled C(sp3)−H Arylation of Piperidine and Tetrahydropyran Derivatives

Pd^II‐catalyzed C(sp³)?H arylation of saturated heterocycles with a wide range of aryl iodides is enabled by an N‐heterocyclic carbene (NHC) ligand. A C(sp³)?H insertion step by the Pd^II/NHC complex in the absence of ArI is demonstrated experimentally for the first time. Experimental data suggests that the previously established NHC‐mediated Pd⁰/Pd^II catalytic manifold does not operate in this reaction. This transformation provides a new approach for diversifying pharmaceutically relevant piperidine and tetrahydropyran ring systems.     

Palladium‐Catalyzed Regioselective Diarylation of o‐Carboranes By Direct Cage B−H Activation

Palladium‐catalyzed intermolecular coupling of o‐carborane with aromatics by direct cage B?H bond activation has been achieved, leading to the synthesis of a series of cage B(4,5)‐diarylated‐o‐carboranes in high yields with excellent regioselectivity. Traceless directing group ‐COOH plays a crucial role for site‐ and di‐selectivity of such intermolecular coupling reaction. A Pd^II–Pd^IV–Pd^II catalytic cycle is proposed to be responsible for the stepwise arylation.     

Synthesis of Diversely Functionalized Oxindoles Enabled by Migratory Insertion of Isocyanide to a Transient σ‐Alkylpalladium(II) Complex

Palladium‐catalyzed intramolecular carbopalladation of N‐aryl acrylamides followed by migratory insertion of an isocyanide‐coordinated C(sp³)?Pd intermediate afforded an alkylimidoyl?Pd^II complex, which can be intercepted by a nucleophile, including heteroarenes. In addition to amides, the alkylimidoyl?Pd^II complex was successfully converted into esters, ketones, and bis‐heterocyclic compounds. An unprecedented palladium‐catalyzed enantioselective domino process involving isocyanide was also documented.     

Ligand‐Promoted ortho‐CH Amination with Pd Catalysts

2,4,6‐Trimethoxypyridine is identified as an efficient ligand for promoting a Pd‐catalyzed ortho‐C? H amination of both benzamides and triflyl‐protected benzylamines. This finding provides guidance for the development of ligands that can improve or enable Pd^II‐catalyzed C? H activation reactions directed by weakly coordinating functional groups.     

PdII‐Catalyzed Mild CH ortho Arylation and Intramolecular Amination Oriented by a Phosphinamide Group

A novel protocol for the Pd‐catalyzed ortho‐arylation of aryl phosphinamide with boronic acid is reported. By using phosphinamide as a new directing group, the reaction proceeds efficiently under mild conditions at 40 °C. Mechanistic studies reveal that the reaction proceeds via a Pd^II to Pd⁰ cycle. The phosphinamide group is also shown to be an effective orienting group for direct C?H amination.     

Palladium‐Catalyzed Arylation of Olefins by Triarylphosphines via CP Bond Cleavage

C? H Arylation of olefins by triarylphosphines via C? P bond cleavage has been achieved with either Pd⁰ or Pd^II catalysts. A variety of olefins and triarylphosphines are tolerated, and we inferred that both Pd⁰ and Pd^II could function directly without pre‐oxidation or pre‐reduction.     

Palladium‐Catalyzed Cross‐Coupling of Alkenyl Carboxylates

Carboxylate esters have many desirable features as electrophiles for catalytic cross‐coupling: they are easy to access, robust during multistep synthesis, and mass‐efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non‐aromatic electrophiles, remain difficult to functionalize through cross‐coupling. We demonstrate that Pd catalysis is effective for coupling electron‐deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C?O bond activation. A Pd^0/II catalytic cycle is viable when using a Pd⁰ precatalyst, with turnover‐limiting C?O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β‐carboxyl elimination is proposed for Pd^II precatalysts. This work provides a clear path toward engaging myriad oxygen‐based electrophiles in Pd‐catalyzed cross‐coupling.     

Palladium‐Catalyzed Intramolecular Carbene Insertion into C(sp3)−H Bonds

A palladium‐catalyzed carbene insertion into C(sp³)?H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd⁰ and Pd^II, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp³)?C(sp³) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp³)?H bond functionalization reaction involves an unprecedented concerted metalation–deprotonation step.     

Trapping σ‐Alkyl–Palladium(II) Intermediates with Arynes Encompassing Intramolecular C−H Activation: Spirobiaryls through Pd‐Catalyzed Cascade Reactions

A palladium‐catalyzed cascade reaction based on the trapping of transient alkyl–Pd^II intermediates with arynes encompassing a C?H activation step has been developed. This synthetic pathway gives rise to hetero‐spirocyclic scaffolds containing a biaryl motif, and opens up new synthetic strategies in the design of cascade reactions since it gathers several aspects of Pd chemistry, i.e., intra‐ and intermolecular carbopalladation of unsaturated species, C?H activation and C?C coupling processes.     

Ligand‐Enabled Arylation of γ‐C−H Bonds

Pd^II‐catalyzed arylation of γ‐C(sp³)?H bonds of aliphatic acid‐derived amides was developed by using quinoline‐based ligands. Various γ‐aryl‐α‐amino acids were prepared from natural amino acids using this method. The influence of ligand structure on reactivity was also systematically investigated.     

Palladium‐Catalyzed CH Activation and Intermolecular Annulation with Allenes

A new and efficient Pd^II‐catalyzed intermolecular annulation of N‐benzoylsulfonamide with allenes for the synthesis of 3,4‐dihydroisoquinolin‐1(2H)‐ones is reported. This C?H functionalization is compatible with ambient air and moisture, and it can be applied to terminal or internal allenes with di?erent synthetically attractive functional groups. Control experiments and a kinetic isotope effect study are conducted and a plausible mechanism is proposed.     

Synthesis of Axially Chiral Styrenes through Pd‐Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd^II‐catalyzed atroposelective C?H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in Co^III‐catalyzed enantioselective C(sp³)?H amidation of thioamide. Mechanistic studies suggest that C?H cleavage is the enantioselectivity‐determining step.     

Is PdII‐Promoted σ‐Bond Metathesis Mechanism Operative for the PdPEPPSI Complex‐Catalyzed Amination of Chlorobenzene with Aniline? Experiment and Theory

Reduction of the Pd?PEPPSI precatalyst to a Pd⁰ species is generally thought to be essential to drive Buchwald–Hartwig amination reactions through the well‐ documented Pd⁰/Pd^II catalytic cycle and little attention has been paid to other possible mechanisms. Considered here is the Pd?PEPPSI‐catalyzed aryl amination of chlorobenzene with aniline. A neat reaction system was used in new experiments, from which the potentially reductive roles of the solvent and labile ligand of the PEPPSI complex in leading to Pd⁰ species are ruled out. Computational results demonstrate that anilido‐containing Pd^II intermediates involving σ‐bond metathesis in pathways leading to the diphenylamine product have relatively low barriers. Such pathways are more favorable energetically than the corresponding reductive elimination reactions resulting in Pd⁰ species and other putative routes, such as the Pd^II/Pd^IV mechanism, single electron transfer mechanism, and halide atom transfer mechanism. In some special cases, if reactants/additives are inadequate to reduce a Pd^II precatalyst, a Pd^II‐involved σ‐bond metathesis mechanism might be feasible to drive the Buchwald–Hartwig amination reactions.     

Divergent and Stereoselective Synthesis of β‐Silyl‐α‐Amino Acids through Palladium‐Catalyzed Intermolecular Silylation of Unactivated Primary and Secondary C−H Bonds

A general and practical Pd^II‐catalyzed intermolecular silylation of primary and secondary C?H bonds of α‐amino acids and simple aliphatic acids is reported. This method provides divergent and stereoselective access to a variety of optical pure β‐silyl‐α‐amino acids, which are useful for genetic technologies and proteomics. It can also be readily performed on a gram scale and the auxiliary can be easily removed with retention of configuration. The synthetic importance of this method is further demonstrated by the late‐stage functionalization of biological small molecules, such as (?)‐santonin and β‐cholic acid. Moreover, several key palladacycles were successfully isolated and characterized to elucidate the mechanism of this β?C(sp³)‐H silylation process.     

Pd(II)‐Catalyzed CH Activation of Styrylindoles: Short,Efficient, and Regioselective Synthesis of Functionalized Carbazoles

A novel Pd^II‐catalyzed approach for the direct synthesis of highly functionalized carbazoles from unprotected styrylindoles has been developed. The reaction features a variety of olefin substrates, which are readily switchable by subtle tuning of the reaction conditions. Investigations of the mechanism suggest that the C?H activation proceeds via enamine formation.     

Palladium‐Catalyzed Desymmetrization of Silacyclobutanes with Alkynes to Silicon‐Stereogenic Silanes: A Density Functional Theory Study

The palladium‐catalyzed desymmetrization of silacyclobutanes using electron‐deficient alkynes proceeds with high enantioselectivity in the presence of a chiral P ligand; this provides a facile approach for the synthesis of novel silicon‐stereogenic silanes. In this work, we used hybrid density functional theory (DFT) to elucidate the mechanism of the palladium‐catalyzed desymmetrization of silacyclobutanes with dimethyl acetylenedicarboxylate. Full catalytic cycle including two different initiation modes that were proposed to be a possible initial step to the formation of the 1‐pallada‐2‐silacyclopentane/alkyne intermediate—the oxidative addition of the palladium complex to the silacyclobutane Si?C bond (cycle MA) or coordination of the Pd⁰ complex with the alkyne C≡C bond (cycle MB)—have been studied. It was found that the ring‐expansion reaction began with cycle MB is energetically more favorable. The formation of a seven‐membered metallocyclic Pd^II intermediate was found to be the rate‐determining step, whereas the enantioselectivity‐determining step, oxidative addition of silacyclobutane to the three‐membered metallocyclic Pd^II intermediate, was found to be quite sensitive to the steric repulsion between the chiral ligand and silacyclobutane.     

Utilizing Carbonyl Coordination of Native Amides for Palladium‐Catalyzed C(sp3)−H Olefination

Pd^II‐catalyzed C(sp³)?H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp³)?H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α‐H‐containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp³)?H activation. The method enables direct C(sp³)?H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.