Palladium- and Copper-Catalyzed Arylation of Carbon−Hydrogen Bonds

Abstract

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.

“Greening Up” Cross-Coupling Chemistry

“…In comparison with other cross-coupling transformations, transition metal-catalyzed aryl C-H bond activation reactions provide an especially direct and atom economical approach to functionalizing aromatic rings [18,19]. In order to control regioselectivity and enhance reactivity of otherwise strong C-H bonds in arenes, various orthodirecting groups have been employed, with anilide-derivatives among the most convenient and broadly applicable substrates.…”

Palladium(0)-Catalyzed Benzylic C(<i>sp</i>³)–H Functionalization for the Concise Synthesis of Heterocycles and Its Applications

“…[9][10][11][12][13][14][15][16][17][18][19][20] Under Pd catalysis, there are two main approaches for activating unreactive C(sp 2 )-H and C(sp 3 )-H bonds, including: i) an intramolecular approach; and ii) a directing group approach. A variety of different directing groups and reaction conditions involving Pd catalysts have been developed for extending the substrate scope of C-H functionalization reactions.…”

Regioselective Catalytic Alkylation of N-Heterocycles in Continuous Flow

“…Direct C-C bond formation is rather uncommon in organic chemistry and typically requires multistep transformations [1]. In the 20th century, new catalyst systems opened the way for routine functionalization of relatively inert molecules.…”