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.     

Aryne-Enabled C−N Arylation of Anilines

Anilines are potentially high-value arylating agents, but are limited by the low reactivity of the strong C−N bond. We show that the reactive intermediate benzyne can be used to both activate anilines, and set-up an aryl transfer reaction in a single step. The reaction does not require any transition metal catalysts or stoichiometric organometallics, and establishes a metal-free route to valuable biaryl products by functionalizing the aniline C−N bond.     

meta-Selective C−H Functionalization of Pyridines

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization of C−H bonds in pyridines is a straightforward approach to access valuable substituted pyridines. Compared to the direct ortho- and para-functionalization, meta-selective pyridine C−H functionalization is far more challenging due to the inherent electronic properties of the pyridine entity. This review summarizes currently available methods for pyridine meta-C−H functionalization using a directing group, non-directed metalation, and temporary dearomatization strategies. Recent advances in ligand control and temporary dearomatization are highlighted. We analyze the advantages as well as limitations of current techniques and hope to inspire further developments in this important area.     

A High-Performance n-Type Thermoelectric Polymer from C−H/C−H Oxidative Direct Arylation Polycondensation

n-Type conjugated polymers (CPs) are crucial in the applications of organic electronics. Direct coupling of electron-deficient C−H monomer via selective C−H activation, namely C−H/C−H oxidative direct arylation polycondensation (Oxi-DArP), is an ideal approach toward such CPs. Herein, Oxi-DArP is firstly adopted to synthesize a high-performance n-type CP using a newly developed monomer, i.e., 3,6-di(thiazol-5-yl)-diketopyrrolopyrrole (Tz-5-DPP). Tz-5-DPP based homopolymer PTz - 5 - DPP with a molecular weight of 22 kDa has been synthesized via Oxi-DArP. After n-doping, PTz - 5 - DPP films exhibited electric conductivity values up to 8 S cm⁻¹ and power factors (PFs) up to 106 μW m⁻¹ K⁻². Notably, this PF value is the highest for n-type polymer thermoelectric materials to date. The Oxi-DArP synthesis and the excellent n-type performance of the polymer make this work an important step toward the straightforward and sustainable preparation of high-performance n-type polymer semiconductors.     

Enantio- and Diastereoswitchable C−H Arylation of Methylene Groups in Cycloalkanes

A complementary set of chiral N,N-ligands enables the Pd-catalyzed β-C−H arylation of unbiased internal methylene groups in good yield and with high levels of enantio- and diastereoinduction. Both the dia- and enantioselectivity can be reversed, thus allowing the selective arylation of any of the four β-C−H bonds in cycloalkanecarboxamides of various ring sizes. The method is applicable to a broad range of aryl iodides with electron-withdrawing and -donating substituents in the o-, m-, or p-position.     

Design of Chiral NHC-Carboxylates as Potential Ligands for Pd-Catalyzed Enantioselective C−H Activation

Despite numerous efforts, the synthesis of scalemic carbo- and heterocycles through Pd⁰-catalyzed C(sp³)−H activation employing chiral ancillary ligands or chiral bases is still limited. Inspired by the recently reported outstanding performance of IBiox-type NHC ligands and bifunctional ligands in similar transformations, a new class of bifunctional NHC-ligands bearing a pendant carboxylate group was designed. A library of 10 imidazolium-carboxylic acids was obtained in five to six steps from enantiopure l -tert-leucinol. In addition, four well-defined Pd(DMBPA)-NHC palladacycles were synthesized in good to excellent yields from the corresponding imidazolium precursors. These complexes were tested in a prototypical C(sp³)−H arylation reaction, and the most active one afforded the indoline product in low yield but significant enantioselectivity. These new bifunctional NHCs could find broader applications in catalytic enantioselective transformations occurring under milder conditions.     

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.     

Ligand-Controlled Direct γ-C−H Arylation of Aldehydes

The first example of Pd^II-catalyzed γ-C(sp³)−H functionalization of aliphatic and benzoheteroaryl aldehydes has been developed using a transient ligand and an external ligand, concurrently. A wide array of γ-arylated aldehydes were readily accessed without preinstalling internal directing groups. The catalytic mechanism was studied by performing deuterium-labelling experiments, which indicated that the γ-C(sp³)−H bond cleavage is the rate-limiting step during the reaction process. This reaction could be performed on a gram scale, and also demonstrated its potential application in the synthesis of new mechanofluorochromic materials with blue-shifted mechanochromic properties.     

Dinuclear Gold-Catalyzed para-Selective C−H Arylation of Undirected Arenes by Noncovalent Interactions

The regioselectivity of C−H functionalization is commonly achieved by directing groups, electronic factors, or steric hindrance, which facilitate the identification of reaction sites. However, such strategies are less effective for reactants such as simple monofluoroarenes due to their relatively low reactivity and the modest steric demands of the fluorine atom. Herein, we present an undirected gold-catalyzed para-C−H arylation of a wide array of monofluoroarenes using air-stable aryl silanes and germanes at room temperature. A high para-regioselectivity (up to 98 : 2) can be realized by utilizing a dinuclear dppm(AuOTs)₂ (dppm=bis(diphenylphosphino)methane) as the catalyst and hexafluorobenzene as the solvent. This provides a general and practical protocol for the concise construction of structurally diverse para-arylated monofluoroarenes through C−H activation manner. It features excellent functional group tolerance and a broad substrate scope (>80 examples). Besides, this strategy is also robust for other simple monosubstituted arenes and heteroarenes. Our mechanistic studies and theoretical calculations suggest that para-C−H selectivity arises from highly electrophilic and structurally flexible dinuclear Ar−Au(III)−Au(I) species, coupled with noncovalent interaction induced by hexafluorobenzene.     

RhIII-Catalyzed C−H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

Rh^III-catalyzed C−H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.     

C−H Bond Arylation of Pyrazoles at the β-Position: General Conditions and Computational Elucidation for a High Regioselectivity

Direct arylation of most five-membered ring heterocycles are generally easily accessible and strongly favored at the α-position using classical palladium-catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent β-position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the β-position of pyrazoles, while C−H α-position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N-substituted pyrazoles simply proceeds via β-C−H bond functionalization. The β-regioselectivity is promoted by a ligand-free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2-ethoxyethan-1-ol significantly enhances the acidity of the proton at β-position of the pyrazoles and thus favors this direct β-C−H bond arylation. This selective pyrazoles β-C−H bond arylation was successfully applied for the straightforward building of π-extended poly(hetero)aromatic structures via further Pd-catalyzed combined α-C−H intermolecular and intramolecular C−H bond arylation in an overall highly atom-economical process.     

Gold-Catalyzed C−H Functionalization Polycondensation for the Synthesis of Aromatic Polymers

Homogeneous gold (Au) complexes have demonstrated tremendous utility in modern organic chemistry; however, their application for the synthesis of polymers remains rare. Herein, we demonstrate the first catalytic application of Au complexes toward the polycondensation of alkyne-containing comonomers and heteroarene nucleophiles. Polymerization occurs through successive intermolecular hydroarylation reactions to produce high molecular weight aromatic copolymers with 1,1-disubstituted alkene backbone linkages. Clear correlations between the rate and degree of polymerization (DP) were established based on catalyst structure and counterion pairing, thus enabling polymerization reactions that proceeded with remarkable efficiency, high reactivity, and exceptional DPs. The reactivity is broad in scope, enabling the copolymerization of highly functionalized aromatic and aliphatic monomers. These results highlight the untapped utility of Au catalysis in providing access to new macromolecular constructs.     

A meta-Selective C−H Alumination of Mono-Substituted Benzene by Using An Alkyl-Substituted Al Anion through Hydride-Eliminating SNAr Reaction

Reaction of an Al-centered anion with toluene proceeded to form C−H cleaved product with a perfect meta-selectivity and a relatively small kinetic isotope effect (KIE, k_H/k_D=1.51). DFT calculations suggested a two-step reaction mechanism and electronically controlled meta-selectivity arising from the electron-donating methyl group. The reaction with other mono-substituted arenes was also investigated.     

Enantioselective Silylation of Aliphatic C−H Bonds for the Synthesis of Silicon-Stereogenic Dihydrobenzosiloles

A rhodium(I)-catalyzed enantioselective silylation of aliphatic C−H bonds for the synthesis of silicon-stereogenic dihydrobenzosiloles is demonstrated. This reaction involves a highly enantioselective intramolecular C(sp³)−H silylation of dihydrosilanes, followed by a stereospecific intermolecular alkene hydrosilylation leading to the asymmetrically tetrasubstituted silanes. A wide range of dihydrosilanes and alkenes displaying various functional groups are compatible with this process, giving access to a variety of highly functionalized silicon-stereogenic dihydrobenzosiloles in good to excellent yields and enantioselectivities.     

Palladium-Catalyzed Atroposelective Kinetic C−H Olefination and Allylation for the Synthesis of C−B Axial Chirality

The direct C−H functionalization of 1,2-benzazaborines, especially asymmetric version, remains a great challenge. Here we report a palladium-catalyzed enantioselective C−H olefination and allylation reactions of 1,2-benzazaborines. This asymmetric approach is a kinetic resolution (KR), providing various C−B axially chiral 2-aryl-1,2-benzazaborines and 3-substituted 2-aryl-1,2-benzazaborines in generally high yields with excellent enantioselectivities (selectivity (S) factor up to 354). The synthetic potential of this reaction is showcased by late-stage modification of complex molecules, scale-up reaction, and applications.     

Reusable Pd@PEG Catalyst for Aerobic Dehydrogenative C−H/C−H Arylations of 1,2,3-Triazoles

Dehydrogenative C−H arylations of 1,2,3-triazoles were accomplished with the aid of a reusable palladium catalyst in PEG. The widely applicable oxidative palladium catalysis enabled the synthesis of fully decorated 1,2,3-triazoles with a broad functional-group tolerance and ample substrate scope. The sustainability of the aerobic C−H arylation was reflected by the use of PEG as green reaction medium and demonstrated by recycling studies of the catalyst and the reaction medium.     

Non-Directed C−H Arylation of Anisole Derivatives via Pd/S,O-Ligand Catalysis

Non-directed C−H arylation is one of the most efficient methods to synthesize biaryl compounds without the need of the prefuctionalization of starting materials, or the installment and removal of directing groups on the substrate. A direct C−H arylation of simple arenes as limiting reactants remains a challenge. Here we disclose a non-directed C−H arylation of anisole derivatives as limiting reagents with aryl iodides under mild reaction conditions. The arylated products are obtained in synthetically useful yields and the arylation of bioactive molecules is also demonstrated. Key to the success of this methodology is the use of a one-step synthesized S,O-ligand.     

Photoinduced Heterogeneous C−H Arylation by a Reusable Hybrid Copper Catalyst

Heterogeneous copper catalysis enabled photoinduced C−H arylations under exceedingly mild conditions at room temperature. The versatile hybrid copper catalyst provided step-economical access to arylated heteroarenes, terpenes and alkaloid natural products with various aryl halides. The hybrid copper catalyst could be reused without significant loss of catalytic efficacy. Detailed studies in terms of TEM, HRTEM and XPS analysis of the hybrid copper catalyst, among others, supported its outstanding stability and reusability.     

Rationalizing the AlI-Promoted Oxidative Addition of C−C Versus C−H Bonds in Arenes

The factors controlling the oxidative addition of C−C and C−H bonds in arenes mediated by Al^I have been computationally explored by means of Density Functional Theory calculations. To this end, we compared the processes involving benzene, naphthalene and anthracene which are promoted by a recently prepared anionic Al^I-carbenoid. It is found that this species exhibits a strong tendency to oxidatively activate C−H bonds over C−C bonds, with the notable exception of benzene, where the C−C bond activation is feasible but only under kinetic control reaction conditions. State-of-the-art computational methods based on the combination of the Activation Strain Model of reactivity and the Energy Decomposition Analysis have been used to rationalize the competition between both bond activation reactions as well as to quantitatively analyze in detail the ultimate factors controlling these transformations.     

Cross-Dehydrogenative Coupling Polymerization via C−H Activation for the Synthesis of Conjugated Polymers

Owing to their versatile (opto)electronic properties, conjugated polymers have found application in several organic electronic devices. Cross-coupling reactions such as Stille, Suzuki, Kumada couplings, and direct arylation reactions have proved to be effective for their synthesis. More atom-efficient oxidative direct arylation polymerization has also been reported for making homopolymers. However, growing interest toward donor-acceptor polymers has led to the recent emergence of cross-dehydrogenative coupling (CDC) polymerization to synthesize alternating copolymers without any prefunctionalization of monomers. Metal-catalyzed cross-coupling of two simple arenes via double C−H activation, or of an arene with an alkene via oxidative Heck-type reaction have been used so far for CDC polymerization. In this article, we discuss the development of CDC polymerization protocols along with the relevant small molecule CDC reactions for an improved understanding of these reactions.