Oxidative C−H/C−H Cross‐Coupling Reactions between N‐Acylanilines and Benzamides Enabled by a Cp*‐Free RhCl3/TFA Catalytic System

By making use of a dual‐chelation‐assisted strategy, a completely regiocontrolled oxidative C?H/C?H cross‐coupling reaction between an N‐acylaniline and a benzamide has been accomplished for the first time. This process constitutes a step‐economic and highly efficient pathway to 2‐amino‐2′‐carboxybiaryl scaffolds from readily available substrates. A Cp*‐free RhCl₃/TFA catalytic system was developed to replace the [Cp*RhCl₂]₂/AgSbF₆ system generally used in oxidative C?H/C?H cross‐coupling reactions between two (hetero)arenes (Cp*=pentamethylcyclopentadienyl, TFA=trifluoroacetic acid). The RhCl₃/TFA system avoids the use of the expensive Cp* ligand and AgSbF₆. As an illustrative example, the procedure developed herein greatly streamlines the total synthesis of the naturally occurring benzo[c]phenanthridine alkaloid oxynitidine, which was accomplished in excellent overall yield.     

meta‐Selective C−H Arylation of Fluoroarenes and Simple Arenes

Fluorine is known to promote ortho‐C?H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho‐palladation intermediate and is then relayed to the meta position, leading to meta‐selective C?H arylation of fluoroarenes. Deuterium experiment suggests that this meta‐arylation is initiated by ortho C?H activation and the catalytic cycle is terminated by C‐2 protonation. A dual‐ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.     

An Enantioselective Bidentate Auxiliary Directed Palladium‐Catalyzed Benzylic C−H Arylation of Amines Using a BINOL Phosphate Ligand

A new enantioselective palladium(II)‐catalyzed benzylic C?H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ‐C?H arylations of alkyl amines, and proceeds with up to 97 % ee. The 2,2′‐dihydroxy‐1,1′‐binaphthyl (BINOL) phosphoric acid ligand, Cs₂CO₃, and solvent‐free conditions are essential for high enantioselectivity. Mechanistic studies suggest that multiple BINOL ligands are involved in the stereodetermining C?H palladation step.     

Ligand‐Promoted meta‐C−H Functionalization of Benzylamines

Meta‐C−H functionalization of benzylamines has been developed using a Pd^II/transient mediator strategy. Using 2‐pyridone ligands and 2‐carbomethoxynorbornene (NBE‐CO₂Me) as the mediator, arylation, amination, and chlorination of benzylamines are realized. This protocol features a broad substrate scope and is compatible with heterocylic coupling partners. Moreover, the loading of the Pd can be lowered to 2.5 mol % by using the optimal ligand.     

Ligand‐Enabled Auxiliary‐Free meta‐C−H Arylation of Phenylacetic Acids

The meta ‐C−H arylation of free phenylacetic acid was realized using 2‐carbomethoxynorbornene (NBE‐CO₂Me) as a transient mediator. Both the modified norbornene and the mono‐protected 3‐amino‐2‐hydroxypyridine type ligand are crucial for this auxiliary‐free meta ‐C−H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta ‐arylated products in high yields.     

Electrooxidative Ruthenium‐Catalyzed C−H/O−H Annulation by Weak O‐Coordination

Electrocatalysis has been identified as a powerful strategy for organometallic catalysis, and yet electrocatalytic C?H activation is restricted to strongly N‐coordinating directing groups. The first example of electrocatalytic C?H activation by weak O‐coordination is presented, in which a versatile ruthenium(II) carboxylate catalyst enables electrooxidative C?H/O?H functionalization for alkyne annulations in the absence of metal oxidants; thereby exploiting sustainable electricity as the sole oxidant. Mechanistic insights provide strong support for a facile organometallic C?H ruthenation and an effective electrochemical reoxidation of the key ruthenium(0) intermediate.     

Cobalt‐Catalyzed Oxidative C−H/C−H Cross‐Coupling between Two Heteroarenes

The first example of cobalt‐catalyzed oxidative C?H/C?H cross‐coupling between two heteroarenes is reported, which exhibits a broad substrate scope and a high tolerance level for sensitive functional groups. When the amount of Co(OAc)₂?4 H₂O is reduced from 6.0 to 0.5 mol %, an excellent yield is still obtained at an elevated temperature with a prolonged reaction time. The method can be extended to the reaction between an arene and a heteroarene. It is worth noting that the Ag₂CO₃ oxidant is renewable. Preliminary mechanistic studies by radical trapping experiments, hydrogen/deuterium exchange experiments, kinetic isotope effect, electron paramagnetic resonance (EPR), and high resolution mass spectrometry (HRMS) suggest that a single electron transfer (SET) pathway is operative, which is distinctly different from the dual C?H bond activation pathway that the well‐described oxidative C?H/C?H cross‐coupling reactions between two heteroarenes typically undergo.     

Cobalt‐Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes

A cobalt‐catalyzed chelation‐assisted tandem C?H activation/C?C cleavage/C?H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C?C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C?N bonds. Here the inexpensive catalyst system exhibits good functional‐group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m‐CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C?H cobaltation, β‐carbon elimination, and intramolecular C?H cobaltation sequence.     

Rhodium‐Catalyzed Annelation of Benzoic Acids with α,β‐Unsaturated Ketones with Cleavage of C−H,CO−OH,and C−C Bonds

In the presence of a [Cp*RhCl₂]₂ catalyst, the Lewis acid In(OTf)₃, and the mild base Na₂CO₃, aromatic carboxylates and α,β‐unsaturated ketones undergo a unique hydroarylation/Claisen/retro‐Claisen process to give the corresponding indanones. In this carboxylate‐directed ortho‐C?H annelation, the C?COR bond of the ketone and the CO?OH group of the aromatic carboxylate are cleaved, and the hydroxy group is transferred from the aromatic to the aliphatic acyl residue. This reactivity is synthetically useful, particularly when starting from cyclic ketones, which are converted into indanones bearing aliphatic carboxylate side chains, thus greatly increasing the molecular complexity of aromatic carboxylates in a single step.     

Copper‐Catalyzed Oxidative C−H Bond Functionalization of N‐Allylbenzamide for Regioselective C−N and C−O Bond Formation

Copper‐catalyzed oxidative couplings of N‐allylbenzamides for C?N and C?O bond formations have been developed through C?H bond functionalization. To demonstrate the utility of this approach, it was applied to the synthesis of β‐aminoimides and imides. To the best of our knowledge, these are the first examples in which different classes of N‐containing compounds have been directly prepared from the readily available N‐allylbenzamides using an inexpensive catalyst/oxidant/base (CuSO₄/TBHP/Cs₂CO₃) system.     

Rational Development of Remote C−H Functionalization of Biphenyl: Experimental and Computational Studies

A simple and efficient nitrile‐directed meta‐C?H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U‐shaped template to achieve a molecular U‐turn and assemble the large‐sized cyclophane transition state for the remote C?H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta‐C?H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta‐selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand‐containing Pd–Ag heterodimeric transition state (TS) favors the desired remote meta‐selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non‐directed meta‐C?H activation. Substituted 2‐pyridone ligands were found to be key in assisting the cleavage of the meta‐C?H bond in the concerted metalation–deprotonation (CMD) process.     

Copper‐Mediated Decarboxylative Coupling of Benzamides with ortho‐Nitrobenzoic Acids by Directed C−H Cleavage

A copper‐mediated decarboxylative coupling of benzamides with ortho ‐nitrobenzoic acids by 8‐aminoquinoline‐directed C−H cleavage has been developed. This reaction proceeds smoothly with only a copper salt to produce the corresponding biaryl compounds in good yields. The products can be easily transformed into various nitrogen‐containing heterocyclic compounds. Moreover, the combination of copper and a suitable base promotes a decarboxylative C−H arylation and cyclization sequence to deliver phenanthridinone derivatives in one pot.     

Carboxy Group as a Remote and Selective Chelating Group for C−H Activation of Arenes

The first example of carboxy group assisted, remote‐selective C(sp²)?H activation with a Pd^II catalyst has been developed and proceeds through a possible κ² coordination of the carboxy group, thus suppressing the ortho‐C?H activation through κ¹ coordination. Besides meta‐C?H olefination, direct meta‐arylation of hydrocinnamic acid derivatives with low‐cost aryl iodides has been achieved for the first time. These findings may motivate the exploration of novel reactivities of the carboxy assisted C?H activation reactions with intriguing selectivities.     

Facile P−C/C−H Bond‐Cleavage Reactivity of Nickel Bis(diphosphine) Complexes

Unusual cleavage of P?C and C?H bonds of the P₂N₂ ligand, in heteroleptic [Ni(P₂N₂)(diphosphine)]²⁺ complexes under mild conditions, results in the formation of an iminium formyl nickelate featuring a C,P,P‐tridentate coordination mode. The structures of both the heteroleptic [Ni(P₂N₂)(diphosphine)]²⁺ complexes and the resulting iminium formyl nickelate have been characterized by NMR spectroscopy and single‐crystal X‐ray diffraction analysis. Density functional theory (DFT) calculations were employed to investigate the mechanism of the P?C/C?H bond cleavage, which involves C?H bond cleavage, hydride rotation, Ni?C/P?H bond formation, and P?C bond cleavage.     

Binuclear Aromatic C−H Bond Activation at a Dirhenium Site

The electronically unsaturated dirhenium complex [Re₂(CO)₈(μ‐H)(μ‐Ph)] ( 1 ) has been found to exhibit aromatic C?H activation upon reaction with N,N‐diethylaniline, naphthalene, and even [D₆]benzene to yield the compounds [Re₂(CO)₈(μ‐H)(μ‐η¹‐NEt₂C₆H₄)] ( 2 ), [Re₂(CO)₈(μ‐H)(μ‐η²‐1,2‐C₁₀H₇)] ( 3 ), and [D₆]‐ 1 , respectively, in good yields. The mechanism has been elucidated by using DFT computational analyses, and involves a binuclear C?H bond‐activation process.     

Ligand‐Accelerated Direct C−H Arylation of BINOL: A Rapid One‐Step Synthesis of Racemic 3,3′‐Diaryl BINOLs

An ortho‐selective rhodium‐catalyzed direct C?H arylation of 1,1′‐bi‐2‐naphthol (BINOL), to deliver the widely used but not easily available 3,3′‐diaryl BINOL, has been developed. This highly efficient one‐step synthetic approach is the shortest route to date and is greatly facilitated by the newly developed ligand system comprising tBu₂PCl, Ph₂‐cod, and Cy₃P?HBF₄. In addition, the same procedure can facilitate the challenging syntheses of 3‐bulkyaryl BINOLs in good to excellent yields.     

Synthesis of Triarylpyridines in Thiopeptide Antibiotics by Using a C−H Arylation/Ring‐Transformation Strategy

We have described a C?H arylation/ring‐transformation strategy for the synthesis of triarylpyridines, which form the core structure of thiopeptide antibiotics. This synthetic method readily gave 2,3,6‐triarylpyridines in a regioselective manner by a two‐phase approach: C?H arylation (a nickel‐catalyzed decarbonylative Suzuki–Miyaura cross‐coupling and decarbonylative C?H coupling for the synthesis of 2,4‐diaryloxazoles) and ring transformation ([4+2] cycloaddition of 2,4‐diaryloxazoles with (hetero)arylacrylic acids). To showcase these methods, we have accomplished the formal synthesis of thiopeptide antibiotics GE2270 s and amythiamicins.     

PdII‐Catalyzed Regio‐ and Enantioselective Oxidative C−H/C−H Cross‐Coupling Reaction between Ferrocenes and Azoles

Asymmetric C?H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein we disclose an asymmetric C?H/C?H cross‐coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Palladium(II)/monoprotected amino acid (MPAA) catalytic system which exhibits excellent reactivity and regioselectivity for oxazoles and thiazoles. This method offers a powerful strategy for constructing planar chiral ferrocenes. Mechanistic studies suggest that the C?H bond cleavage of azoles is likely proceeding through a S_EAr process and may not be a turnover limiting step.     

Cobalt(III)‐Catalyzed Intramolecular Cross‐Dehydrogenative C−H/X−H Coupling: Efficient Synthesis of Indoles and Benzofurans

An efficient cobalt(III)‐catalyzed intramolecular cross‐dehydrogenative C?H/N?H coupling of ortho‐alkenylanilines has been developed utilizing O₂ as a terminal oxidant. The developed reaction tolerates various reactive functional groups and allows the synthesis of diverse indole derivatives in good to excellent yields. The method was successfully extended to the synthesis of benzofurans through the intramolecular cross‐dehydrogenative C?H/O?H coupling of ortho‐alkenylphenols.     

Site‐Selective Remote Radical C−H Functionalization of Unactivated C−H Bonds in Amides Using Sulfone Reagents

A general and practical strategy for remote site‐selective functionalization of unactivated aliphatic C?H bonds in various amides by radical chemistry is introduced. C?H bond functionalization is achieved by using the readily installed N‐allylsulfonyl moiety as an N‐radical precursor. The in situ generated N‐radical engages in intramolecular 1,5‐hydrogen atom transfer to generate a translocated C radical which is subsequently trapped with various sulfone reagents to afford the corresponding C?H functionalized amides. The generality of the approach is documented by the successful remote C?N₃, C?Cl, C?Br, C?SCF₃, C?SPh, and C?C bond formation. Unactivated tertiary and secondary C?H bonds, as well as activated primary C?H bonds, can be readily functionalized by this method.