Auxiliary-Assisted Palladium-Catalyzed Arylation and Alkylation of sp² and sp³ Carbon−Hydrogen Bonds

TLDR

The method uses a carboxylic acid amide substrate (2‑methylthioaniline or 8‑aminoquinoline), aryl or alkyl iodide, Pd(OAc)₂, and an inorganic base. The auxiliary‑directed Pd‑catalyzed β‑arylation and alkylation of sp³/sp² C–H bonds in carboxylic acid derivatives achieves selective monoarylation of primary sp³ C–H with 2‑methylthioaniline, secondary sp³ with 8‑aminoquinoline, and alkylation best with 8‑aminoquinoline, tolerates various functional groups, and has been supported by isolation of a palladacycle intermediate.

Abstract

We have developed a method for auxiliary-directed, palladium-catalyzed β-arylation and alkylation of sp3 and sp2 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 sp3 C−H bonds can be achieved. If arylation of secondary sp3 C−H bonds is desired, 8-aminoquinoline auxiliary may be used. For alkylation of sp3 and sp2 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.