Ligand-Enabled γ-C(sp³)–H Activation of Ketones

Abstract

We report the first example of Pd(II)-catalyzed γ-C(sp)-H activation of ketones directed by a practical 2,2-dimethyl aminooxyacetic acid auxiliary. 2-Pyridone ligands are identified to enable C(sp)-H activation for the first time. A rare six-membered palladacycle intermediate is isolated and characterized to elucidate the reaction mechanism. Both (hetero)arylation and vinylation of γ-C(sp)-H bonds are demonstrated. Sequential β- and γ-C(sp)-H (hetero)arylation of muscone showcases the utility of this method for late-stage diversification. A convenient Mn(II)-catalyzed auxiliary removal is also developed to further underscore the practicality of this transformation.

Reversing conventional site-selectivity in C(sp3)–H bond activation

“…Five-membered cyclopalladation of C(sp 3 )-H bonds has been known to be both kinetically and thermodynamically more favored over the six-membered or larger sized counterparts since its discovery in 1970s (Figure 1a) [13][14][15][16] . As a consequence, distal C(sp 3 )-H functionalization through a six-membered palladacycle is limited to the following rare examples: a) when five-membered cyclopalladation is not possible due to the lack of primary or secondary C-H bonds at the appropriate carbon [17][18][19][20][21] ; b) the five-membered palladacycle intermediate generated from a strong coordinating bidentate directing group is too stable to react with a special functionalization reagent, namely, 1,2-diphenyl alkynes 22 . In addition, this single observation is only limited to more reactive methyl C-H bonds.…”

Iterative Arylation of Amino Acids and Aliphatic Amines via δ‐C(sp3)−H Activation: Experimental and Computational Exploration

“…To commence with the functionalization process at the remote δ‐position of the ethyl ester of leucine ( 1 a ), the effects of pyridine‐ and pyridone‐based ligands were initially probed . 4‐Benzyloxy‐2(1 H )‐pyridone ( L14 ) was the only promising ligand from the series of ligands tested .…”

Diverse strategies for transition metal catalyzed distal C(sp3)–H functionalizations

“…61 Later in 2018, the same group detailed a directing group assisted approach for g-C(sp 3 )-H arylation and heteroarylation of aliphatic ketones. 62 An unique template 2,2-dimethyl aminooxyacetic acid was preinstalled in ketones. 5-Triuoromethyl-2-pyridone found tobe the most effective ligand for increasing yield of the arylated ketones.…”