Controlling Pd(IV) reductive elimination pathways enables Pd(II)-catalysed enantioselective C(sp3)-H fluorination

The development of a Pd(II)-catalysed enantioselective fluorination of C(sp(3))-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(sp(3))-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)-catalysed enantioselective C(sp(3))-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 the C-H insertion step and selectively promote the C(sp(3))-F reductive elimination pathway from the Pd(IV)-F intermediate. Stereochemical analysis revealed that while the desired C(sp(3))-F formation proceeds via an inner-sphere pathway with retention of configuration, the undesired C(sp(3))-O formation occurs through an S(N)2-type mechanism. Elucidation of the dual mechanism allows us to rationalize the profound ligand effect on controlling reductive elimination selectivity from high-valent Pd species.