Synthesis of β-(Hetero)aryl Ketones via Ligand-Enabled Nondirected C–H Alkylation

Abstract

β-Aryl ketones are essential structural units in natural products and bioactive molecules, commonly synthesized through coupling reactions involving prefunctionalized arenes or via directing group (DG) strategies. However, these conventional methods are often inefficient, requiring multiple synthetic steps that escalate both the cost and the complexity of the process. The need for additional steps, such as directing group installation and subsequent removal, further compromises the atom economy and overall efficiency. Herein, we report a palladium(II)-catalyzed dual ligand-enabled nondirected C−H alkylation with arene and heteroarene as a limiting reagent for the synthesis of β-(hetero)aryl ketones with less chemical waste. The combined influence of 2methyl quinoxaline and N-acetyl phenylalanine ligands imparts significant surge in selectivity, facilitating the diversification of drugs and natural products through C−H alkylation. Integrated experimental and computational mechanistic studies demonstrate C−H activation as both the regio-and rate-determining step. Interestingly, while the Pd−Ag heterobimetallic species is not directly involved in the 1,2-migratory insertion step, it is proposed to play a vital role during the product release phase of the catalytic cycle.