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.

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 last 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 β-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 β-arylation of carboxylic acid derivatives and the γ-arylation of amine derivatives. Furthermore, copper catalysis can be used to mediate the arylation of acidic arene C-H bonds (i.e. those with pKa 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 coppercatalyzed 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.

We have developed a method for auxiliary-directed, palladium-catalyzed β-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 hydroxyacid 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 scope of palladium-catalyzed, auxiliary-assisted direct arylation and alkylation of sp2 and sp3 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 t-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. Picolinic acid auxiliary is used for amine γ-functionalization and 8-aminoquinoline auxiliary is used for carboxylic acid β-functionalization. Some optimization of base, additives, and solvent is required for achieving best results.

A method for the palladium-catalyzed arylation of pyridines and pyrazoles has been developed. Both aliphatic and aromatic C-H bonds may be functionalized using this method. A bromo substituent is tolerated on the aryl iodide coupling component. [reaction: see text]