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Abstract
β-Aryl ketones are present in various natural products and bioactive molecules. Till now, -aryl
ketone has been synthesized through the directing group (DG) approach or Mizoroki-Heck
coupling. Herein, we reported a palladium(II) catalyzed dual ligand-enabled non-directed C−H
alkylation with arene and heteroarene as a limiting reagent for the synthesis of -(hetero)aryl
ketones. The combined influence of 2-methyl quinoxaline and N-acetyl phenylalanine ligands
imparts complementary selectivity, facilitating the diversification of drugs and natural products
through C−H alkylation. Integrated experimental and computational mechanistic studies
demonstrate the 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.
Supplementary materials
Title
of β-(Hetero)aryl Ketones via Ligand-Enabled Nondirected C−H Alkylation
Description
In summary, we have developed a novel catalyst system that employs the first non-directed C−H alkylation in a regioselective fashion. The catalyst system utilizes a 2-methyl quinoxaline and N-acetyl phenylalanine-based MPAA ligand to achieve moderate to high yield in various (hetero)arenes. The regioselectivity of the product was
governed by our catalyst system rather than the electronic properties of the substrates. This transformation also allows us to form alkylation bridge that can be used to conjugate drugs with natural products, providing new avenues for drug diversification with modulated bioactivity. DFT calculations emphasized that the significance of the
MPAA ligand in facilitating the regio- and TOF-determining C−H activation process through the CMD mechanism, featuring the characteristic [5,6]-palladacyclic transition state. Importantly, our findings suggested the involvement of the Pd−Ag heterobimetallic species in the product release phase, underscoring its significance in the overall catalytic process.
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