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3,5-Dimethylpyrazole was employed as a monodentate directing group for palladium-catalyzed ortho-sp 2 C-H arylation with aryl iodides. The reaction shows good functional group tolerance and outstanding selectivity for mono- ortho-arylation. Ozonolysis of ortho-arylated arylpyrazoles gave acylated biphenylamines that were further arylated to afford unsymmetrically substituted 2,6-diarylacetanilides.

We have developed a method for palladium-catalyzed, pyrazole-directed sp 3 C-H bond arylation by aryl iodides. The reaction employs a Pd(OAc) 2 catalyst at 5-10 mol % loading and silver(I) oxide as a halide-removal agent, and it proceeds in acetic acid or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of the pyrazole moiety affords pharmaceutically important β-phenethylamines., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The scope of palladium-catalyzed, auxiliary-assisted direct arylation and alkylation of sp(2) and sp(3) C-H bonds of amine and carboxylic acid derivatives has been investigated. The method employs a palladium acetate catalyst, substrate, aryl, alkyl, benzyl, or allyl halide, and inorganic base in tert-amyl alcohol or water solvent at 100-140 °C. Aryl and alkyl iodides as well as benzyl and allyl bromides are competent reagents in this transformation. The picolinic acid auxiliary is used for amine γ-functionalization, and the 8-aminoquinoline auxiliary is used for carboxylic acid β-functionalization. Some optimization of base, additives, and solvent is required for achieving best results.

The palladium-catalyzed direct arylation of indoles, pyrroles, and furans by aryl chlorides has been demonstrated. The method employs a palladium acetate catalyst, 2-(dicyclohexylphosphino)-biphenyl ligand, and an inorganic base. Electron-rich and electron-poor aryl chlorides as well as chloropyridine coupling partners can be used, and arylated heterocycles are obtained in moderate to good yields. Optimization of base, ligand, and solvent is required for achieving best results.

We have developed a method for auxiliary-directed, palladium-catalyzed beta-arylation and alkylation of sp(3) and sp(2) C-H bonds in carboxylic acid derivatives. The method employs a carboxylic acid 2-methylthioaniline- or 8-aminoquinoline amide substrate, aryl or alkyl iodide coupling partner, palladium acetate catalyst, and an inorganic base. By employing 2-methylthioaniline auxiliary, selective monoarylation of primary sp(3) C-H bonds can be achieved. If arylation of secondary sp(3) C-H bonds is desired, 8-aminoquinoline auxiliary may be used. For alkylation of sp(3) and sp(2) C-H bonds, 8-aminoquinoline auxiliary affords the best results. Some functional group tolerance is observed and amino- and hydroxy-acid derivatives can be functionalized. Preliminary mechanistic studies have been performed. A palladacycle intermediate has been isolated, characterized by X-ray crystallography, and its reactions have been studied.

The transition-metal-catalyzed functionalization of C-H bonds is a powerful method for generating carbon-carbon bonds. Although significant advances to this field have been reported during the past decade, many challenges remain. First, most of the methods are substrate-specific and thus cannot be generalized. Second, conversions of unactivated (i.e., not benzylic or alpha to heteroatom) sp(3) C-H bonds to C-C bonds are rare, with most examples limited to t-butyl groups, a conversion that is inherently simple because there are no beta-hydrogens that can be eliminated. Finally, the palladium, rhodium, and ruthenium catalysts routinely used for the conversion of C-H bonds to C-C bonds are expensive. Catalytically active metals that are cheaper and less exotic (e.g., copper, iron, and manganese) are rarely used. This Account describes our attempts to provide solutions to these three problems. We have developed a general method for directing-group-containing arene arylation by aryl iodides. Using palladium acetate as the catalyst, we arylated anilides, benzamides, benzoic acids, benzylamines, and 2-substituted pyridine derivatives under nearly identical conditions. We have also developed a method for the palladium-catalyzed auxiliary-assisted arylation of unactivated sp(3) C-H bonds. This procedure allows for the beta-arylation of carboxylic acid derivatives and the gamma-arylation of amine derivatives. Furthermore, copper catalysis can be used to mediate the arylation of acidic arene C-H bonds (i.e., those with pK(a) values <35 in DMSO). Using a copper iodide catalyst in combination with a base and a phenanthroline ligand, we successfully arylated electron-rich and electron-deficient heterocycles and electron-poor arenes possessing at least two electron-withdrawing groups. The reaction exhibits unusual regioselectivity: arylation occurs at the most hindered position. This copper-catalyzed method supplements the well-known C-H activation/borylation methodology, in which functionalization usually occurs at the least hindered position. We also describe preliminary investigations to determine the mechanisms of these transformations. We anticipate that other transition metals, including iron, nickel, cobalt, and silver, will also be able to facilitate deprotonation/arylation reaction sequences.

A new palladium-catalyzed arylation process based on C-H activation has been developed. The utilization of pyridine-containing directing groups allows the beta-arylation of carboxylic acid derivatives and gamma-arylation of amine derivatives. Both primary and secondary sp3 C-H bonds, as well as sp2 C-H bonds, are reactive.

Four extensively fluorinated tetraphenylethylenes (TPE) and one extensively fluorinated triphenylethylene have been synthesized using combinations of copper‐catalyzed C−H functionalization reactions and Stille coupling reactions. Surprisingly, in contrast to the parent TPE, these compounds show little to no aggregation‐induced emission (AIE). Instead, photocyclization into fluorinated phenanthrene products occurs. Effects of solvent and oxygen on the yield and selectivity of this photocyclization have been examined. [ABSTRACT FROM AUTHOR]

We have developed a method for palladium-catalyzed, pyrazole-directed sp3 C−H bond arylation by aryl iodides. The reaction employs a Pd(OAc)2 catalyst at 5-10 mol % loading and silver(I) oxide as a halide-removal agent, and it proceeds in acetic acid or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of the pyrazole moiety affords pharmaceutically important β-phenethylamines. [ABSTRACT FROM AUTHOR]

Aminoquinoline-directed, palladium-catalyzed sp3 C–H bond arylation in phosphonamidates and phosphinic amides is reported. The reaction employs Pd(OAc)2 as a catalyst at 10 mol% loading and cesium phosphate or potassium carbonate as a base in 1,2-dichlorobenzene as a solvent. The directing group can be removed under basic conditions to afford phosphonic acid esters. The chemistry described here is the first example of unactivated sp3 C–H bond arylation by using a phosphorus-containing directing group. [ABSTRACT FROM AUTHOR]

The palladium-catalyzed direct arylation of anilides possessing several N-acyl substituents has been demonstrated. Removal of the acyl group by base hydrolysis allows a short and efficient synthesis of 2-aryl or 2,6-diarylanilines. The method is functional group tolerant and allows the presence of chloride and bromide substituents on both the anilide and aryl iodide coupling components. The arylation products can be converted to phenanthridines by the reaction with trifluoroacetic anhydride. [ABSTRACT FROM AUTHOR]

Two new palladium-catalyzed methods for the direct ortho-arylation of free benzoic acids have been developed. The first method employs stoichiometric silver acetate for iodide removal, aryl iodide as the coupling partner, and acetic acid solvent. This method is applicable to the arylation of electron-rich to moderately electron-poor benzoic acids and tolerates chloride and bromide substituents on both coupling partners. The second method involves the use of aryl chloride, cesium carbonate base, n-butyl-di-1-adamantyiphosphine ligand, and DMF solvent and is suitable for both electron-rich and electron-poor benzoic acids. Mechanistic studies of the second method point to the heterolytic C-H bond cleavage as the rate- determining step. [ABSTRACT FROM AUTHOR]