Controlling Pd(iv) reductive elimination pathways enables Pd(ii)-catalysed enantioselective C(sp3)−H fluorination

Abstract

The development of a Pd(II)-catalyzed enantioselective fluorination of C(sp3)–H bonds would offer a new approach to making chiral organofluorines. However, such a strategy is particularly challenging because of the difficulty in differentiating prochiral C(sp3)–H bonds through Pd(II)-insertion, as well as the sluggish reductive elimination involving Pd–F bonds. Here, we report the development of a Pd(II)-catalyzed enantioselective C(sp3)–H fluorination using a chiral transient directing group strategy. In this work, a bulky, amino amide transient directing group was developed to control the stereochemistry of C–H insertion step and selectively promote C(sp3)–F reductive elimination pathway from Pd(IV)–F intermediate. Stereochemical analysis revealed that while the desired C(sp3)–F formation proceeds via an inner-sphere pathway with retention of configuration, the undesired C(sp3)–O formation occurs through an SN2-type mechanism. The elucidation of the dual mechanism allows us to rationalize the profound ligand effect on controlling reductive elimination selectivity from high-valent Pd species.

Enantio‐ and Diastereoswitchable C−H Arylation of Methylene Groups in Cycloalkanes

“…Ligands L5 and L9 may facilitate the reductive elimination from different Pd IV conformers, resulting in the release of different diastereomers. This would be in agreement with reports on stereodivergent reaction outcomes based on reductive elimination from Pd IV species …”

Transient Ligand‐Enabled Transition Metal‐Catalyzed C−H Functionalization

“…Very recently, Yu and co‐workers disclosed a Pd II ‐catalyzed enantioselective C(sp 3 )−H fluorination using a catalytic amount of chiral ligand L22 . In their work, a bulky amino amide ligand played a vital role in achieving high enantioselectivity and in promoting C−F reductive elimination (Scheme c) . Following those studies, the benzylic C(sp 3 )−H arylation of 2‐methylbenzaldehyde was also achieved by Ma, Lei, and Hu, who used acetohydrazide ( L23 ) as the transient ligand (Scheme d) .…”

Synthesis of Axially Chiral Biaryl‐2‐amines by PdII‐Catalyzed Free‐Amine‐Directed Atroposelective C−H Olefination

“…Although aniline-type amines have been used as efficient DGs in transition-metal-catalyzed CÀH functionalization of biaryl compounds, [12] the development of their asymmetric versions is more challenging and remains limited. [13] Recently, Inspired by the elegant work of Yu and co-workers on a chiral transient-directing-group strategy, [14] our group achieved several examples of Pd II -catalyzed atroposelective CÀH functionalization of biaryl aldehydes with commercially available tert-leucine (Tle) as a catalytic transient chiral auxiliary (TCA). [10] Attempts to adopt this strategy to biaryl-2-amines by searching for suitable chiral aldehydes as TCAs failed.…”