Site‐Selective C−S Bond Formation at C−Br over C−OTf and C−Cl Enabled by an Air‐Stable,Easily Recoverable,and Recyclable Palladium(I) Catalyst

This report widens the repertoire of emerging Pd^I catalysis to carbon–heteroatom, that is, C−S bond formation. While Pd⁰‐catalyzed protocols may suffer from the formation of poisonous sulfide‐bound off‐cycle intermediates and lack of selectivity, the mechanistically diverse Pd^I catalysis concept circumvents these challenges and allows for C−S bond formation (S–aryl and S–alkyl) of a wide range of aryl halides. Site‐selective thiolations of C−Br sites in the presence of C−Cl and C−OTf were achieved in a general and a priori predictable fashion. Computational, spectroscopic, X‐ray, and reactivity data support dinuclear Pd^I catalysis to be operative. Contrary to air‐sensitive Pd⁰, the active Pd^I species was easily recovered in the open atmosphere and subjected to multiple rounds of recycling.     

Modular and Selective Arylation of Aryl Germanes (C−GeEt3) over C−Bpin,C−SiR3 and Halogens Enabled by Light‐Activated Gold Catalysis

Selective C –C couplings are powerful strategies for the rapid and programmable construction of bi‐ or multiaryls. To this end, the next frontier of synthetic modularity will likely arise from harnessing the coupling space that is orthogonal to the powerful Pd‐catalyzed coupling regime. This report details the realization of this concept and presents the fully selective arylation of aryl germanes (which are inert under Pd⁰/Pd^II catalysis) in the presence of the valuable functionalities C?BPin, C?SiMe₃, C?I, C?Br, C?Cl, which in turn offer versatile opportunities for diversification. The protocol makes use of visible light activation combined with gold catalysis, which facilitates the selective coupling of C?Ge with aryl diazonium salts. Contrary to previous light‐/gold‐catalyzed couplings of Ar–N₂⁺, which were specialized in Ar–N₂⁺ scope, we present conditions to efficiently couple electron‐rich, electron‐poor, heterocyclic and sterically hindered aryl diazonium salts. Our computational data suggest that while electron‐poor Ar–N₂⁺ salts are readily activated by gold under blue‐light irradiation, there is a competing dissociative deactivation pathway for excited electron‐rich Ar–N₂⁺, which requires an alternative photo‐redox approach to enable productive couplings.     

C−I‐Selective Cross‐Coupling Enabled by a Cationic Palladium Trimer

While there is a growing interest in harnessing synergistic effects of more than one metal in catalysis, relatively little is known beyond bimetallic systems. This report describes the straightforward access to an air‐stable Pd trimer and presents unambiguous reactivity data of its privileged capability to differentiate C?I over C?Br bonds in C?C bond formations (arylation and alkylation) of polyhalogenated arenes, which typical Pd⁰ and Pd^I‐Pd^I catalysts fail to deliver. Experimental and computational reactivity data, including the first location of a transition state for bond activation by the trimer, are presented, supporting direct trimer reactivity to be feasible.     

Pd‐Catalyzed Decarboxylative Cross‐Coupling of 2‐Carboxyazine N‐Oxides with Various (Hetero)aryl Halides

Decarboxylative cross‐coupling reactions of substituted 2‐carboxyazine N‐oxides, with a variety of (hetero)aryl halides, by bimetallic Pd⁰/Cu^I and Pd⁰/Ag^I catalysis are reported. Two possible pathways, a conventional bimetallic‐catalyzed decarboxylative arylation, as well as a protodecarboxylative/direct C?H arylation sequence have been considered. These methods provide the first general decarboxylative arylation methodology for the 2‐carboxyazine series.     

Highly Efficient CSeCF3 Coupling of Aryl Iodides Enabled by an Air‐Stable Dinuclear PdI Catalyst

Building on our recent disclosure of catalysis at dinuclear Pd^I sites, we herein report the application of this concept to the realization of the first catalytic method to convert aryl iodides into the corresponding ArSeCF₃ compounds. Highly efficient C? SeCF₃ coupling of a range of aryl iodides was achieved, enabled by an air‐, moisture‐, and thermally stable dinuclear Pd^I catalyst. The novel SeCF₃‐bridged dinuclear Pd^I complex 3 was isolated, studied for its catalytic competence and shown to be recoverable. Experimental and computational data are presented in support of dinuclear Pd^I catalysis.     

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.     

Trifluoromethylthiolation of Aryl Iodides and Bromides Enabled by a Bench‐Stable and Easy‐To‐Recover Dinuclear Palladium(I) Catalyst

While palladium catalysis is ubiquitous in modern chemical research, the recovery of the active transition‐metal complex under routine laboratory applications is frequently challenging. Described herein is the concept of alternative cross‐coupling cycles with a more robust (air‐, moisture‐, and thermally‐stable) dinuclear Pd^I complex, thus avoiding the handling of sensitive Pd⁰ species or ligands. Highly efficient C? SCF₃ coupling of a range of aryl iodides and bromides was achieved, and the recovery of the Pd^I complex was accomplished via simple open‐atmosphere column chromatography. Kinetic and computational data support the feasibility of dinuclear Pd^I catalysis. A novel SCF₃‐bridged Pd^I dimer was isolated, characterized by X‐ray crystallography, and verified to be a competent catalytic intermediate.     

Enantioselective Cross‐Exchange between C−I and C−C σ Bonds

A palladium‐catalyzed enantioselective intramolecular σ‐bond cross‐exchange between C?I and C?C bonds is realized, providing chiral indanones bearing an alkyl iodide group and an all‐carbon quaternary stereocenter. Pd/TADDOL‐derived phosphoramidite is found to be an efficient catalytic system for both C?C bond cleavage and alkyl iodide reductive elimination. In addition to aryl iodides, aryl bromides can also be used for this transformation in the presence of KI. Density‐functional theory (DFT) calculation studies support the ring‐opening of cyclobutanones occuring through an oxidative addition/reductive elimination process involving Pd^IV species.     

Rhodium‐Catalyzed Intramolecular C−H Silylation by Silacyclobutanes

Silacyclobutane was discovered to be an efficient C?H bond silylation reagent. Under the catalysis of Rh^I/TMS‐segphos, silacyclobutane undergoes sequential C?Si/C?H bond activations, affording a series of π‐conjugated siloles in high yields and regioselectivities. The catalytic cycle was proposed to involve a rarely documented endocyclic β‐hydride elimination of five‐membered metallacycles, which after reductive elimination gave rise to a Si?Rh^I species that is capable of C?H activation.     

Directed C−H Activation and Tandem Cross‐Coupling Reactions Using Palladium Nanocatalysts with Controlled Oxidation

Controlled oxidation of palladium nanoparticles provided high‐valent Pd^IV oxo‐clusters which efficiently promote directed C−H halogenation reactions. In addition, palladium nanoparticles can undergo changes in oxidation states to provide both high‐valent Pd^IV and low‐valent Pd⁰ species within one system, and thus a tandem reaction of C−H halogenation and cross‐coupling (C−N, C−C, and C−S bond formation) was successfully established.     

Modular Functionalization of Arenes in a Triply Selective Sequence: Rapid C(sp2) and C(sp3) Coupling of C−Br,C−OTf,and C−Cl Bonds Enabled by a Single Palladium(I) Dimer

Full control over multiple competing coupling sites would enable straightforward access to densely functionalized compound libraries. Historically, the site selection in Pd⁰‐catalyzed functionalizations of poly(pseudo)halogenated arenes has been unpredictable, being dependent on the employed catalyst, the reaction conditions, and the substrate itself. Building on our previous report of C?Br‐selective functionalization in the presence of C?OTf and C?Cl bonds, we herein complete the sequence and demonstrate the first general arylations and alkylations of C?OTf bonds (in <10 min), followed by functionalization of the C?Cl site (in <25 min), at room temperature using the same air‐ and moisture‐stable Pd^I dimer. This allowed the realization of the first general and triply selective sequential C?C coupling (in 2D and 3D space) of C?Br followed by C?OTf and then C?Cl bonds.     

Highly Stereoselective Cobalt(III)‐Catalyzed Three‐Component C−H Bond Addition Cascade

A highly stereoselective three‐component C(sp²)?H bond addition across alkene and polarized π‐bonds is reported for which Co^III catalysis was shown to be much more effective than Rh^III. The reaction proceeds at ambient temperature with both aryl and alkyl enones employed as efficient coupling partners. Moreover, the reaction exhibits extremely broad scope with respect to the aldehyde input; electron rich and poor aromatic, alkenyl, and branched and unbranched alkyl aldehydes all couple in good yield and with high diastereoselectivity. Multiple directing groups participate in this transformation, including pyrazole, pyridine, and imine functional groups. Both aromatic and alkenyl C(sp²)?H bonds undergo the three‐component addition cascade, and the alkenyl addition product can readily be converted into diastereomerically pure five‐membered lactones. Additionally, the first asymmetric reactions with Co^III‐catalyzed C?H functionalization are demonstrated with three‐component C?H bond addition cascades employing N‐tert‐butanesulfinyl imines. These examples represent the first transition metal catalyzed C?H bond additions to N‐tert‐butanesulfinyl imines, which are versatile and extensively used intermediates for the asymmetric synthesis of amines.     

Intermolecular,Branch‐Selective,and Redox‐Neutral Cp*IrIII‐Catalyzed Allylic C−H Amidation

Herein, we report the redox‐neutral, intermolecular, and highly branch‐selective amidation of allylic C?H bonds enabled by Cp*Ir^III catalysis. A variety of readily available carboxylic acids were converted into the corresponding dioxazolones and efficiently coupled with terminal and internal olefins in high yields and selectivities. Mechanistic investigations support the formation of a nucleophilic Ir^III–allyl intermediate rather than the direct insertion of an Ir–nitrenoid species into the allylic C?H bond.     

Palladium–Borane Cooperation: Evidence for an Anionic Pathway and Its Application to Catalytic Hydro‐/Deutero‐dechlorination

Metal–Lewis acid cooperation provides new opportunities in catalysis. In this work, we report a new type of palladium–borane cooperation involving anionic Pd⁰ species. The air‐stable DPB palladium complex 1 (DPB=diphosphine‐borane) was prepared and reacted with KH to give the Pd⁰ borohydride 2 , the first monomeric anionic Pd⁰ species to be structurally characterized. The boron moiety acts as an acceptor towards Pd in 1 via Pd→B interaction, but as a donor in 2 thanks to B‐H‐Pd bridging. This enables the activation of C?Cl bonds and the system is amenable to catalysis, as demonstrated by the hydro‐/deutero‐dehalogenation of a variety of (hetero)aryl chlorides (20 examples, average yield 85 %).     

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 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.     

Palladium‐Catalyzed Cascade CH Trifluoroethylation of Aryl Iodides and Heck Reaction: Efficient Synthesis of ortho‐Trifluoroethylstyrenes

A palladium‐catalyzed selective C? H bond trifluoroethylation of aryl iodides has been explored. The reaction allows for the efficient synthesis of a variety of ortho‐trifluoroethyl‐substituted styrenes. Preliminary mechanistic studies indicate that the reaction might involve a key Pd^IV intermediate, which is generated through the rate‐determining oxidative addition of CF₃CH₂I to a palladacycle; the bulky nature of CF₃CH₂I influences the reactivity. Reductive elimination from the Pd^IV complex then leads to the formation of the aryl–CH₂CF₃ bond.     

Palladium‐Catalyzed C−H Iodination of Arenes by Means of Sulfinyl Directing Groups

C?H iodination of aromatic compounds has been accomplished with the aid of sulfinyl directing groups under palladium catalysis. The reaction proceeds selectively at the peri‐position of polycyclic aryl sulfoxides or at the ortho‐position of phenyl sulfoxides. The iodination products can be further converted via iterative catalytic cross‐coupling at the expense of the C?I and C?S bonds. Computational studies suggest that peri‐C?H palladation would proceed via a non‐directed pathway, wherein neither of the sulfur nor oxygen atom of the sulfinyl group coordinates to the palladium before and at the transition state.     

Electrocatalytic Oxidant‐Free Dehydrogenative C−H/S−H Cross‐Coupling

An environmentally friendly electrocatalytic protocol has been developed for dehydrogenative C−H/S−H cross‐coupling. This method enabled C−S bond formation under catalyst‐ and oxidant‐free conditions. Under undivided electrolysis conditions, various aryl/heteroaryl thiols and electron‐rich arenes afforded the C−S bond‐formation products in 24–99 % yield. A preliminary mechanistic study indicated that the generation of aryl radical cation intermediates is key to the success of this transformation.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C? H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C? H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³)? C(sp³) bonds are elusive. Reported here is an asymmetric C? H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³)? C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.