Pd(II)-catalyzed site-selective β- and γ-C(sp3)−H arylation of primary aldehydes is developed by rational design of L, X-type transient directing groups (TDG). External 2-pyridone ligands are identified to be crucial for the observed reactivity. By minimizing the loading of acid additives, the ligand effect is enhanced to achieve high reactivities of the challenging primary aldehyde substrates. Site selectivity can be switched from the proximate to the relatively remote position by changing the bite angle of TDG to match the desired palladacycle size. Experimental and computational investigations support this rationale for designing TDG to potentially achieve remote site-selective C(sp3)−H functionalizations. This protocol can be further extended to γ-C(sp3)−H (hetero)arylation of aliphatic ketones. A variety of aliphatic ketones were (hetero)arylated at the γ-position via a 5,6-membered fused cyclopalladation intermediate to afford the remotely arylated products in up to 88% yield. The improved reactivity of this catalytic system has also made possible the cyclic γ-methylene C(sp3)−H arylation of ketones. Mechanistic investigation and comparison to the γ-C–H arylation of aldehydes revealed a structural insight for designing site-selective TDG.

PdII-catalyzed β- and γ-C(sp3)−H arylation of primary aldehydes and ketones enabled by transient directing groups

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