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

Abstract

The development of a Pd(II)-catalysed 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)-catalysed 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 the C-H insertion step and selectively promote the C(sp³)-F reductive elimination pathway from the 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 S_N2-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.

Figure 1. Enantioselective C(sp³)–H Fluorination

a, The possibility of multiple reductive elimination pathways from Pd(IV) species generated with [F⁺] as oxidant presents a challenging selectivity issue. b, This work: Pd(II)-catalyzed enantioselective C(sp³)–H fluorination using chiral transient directing group strategy. c, Profound ligand effect was observed on reductive elimination selectivity (C(sp³)–O vs. C(sp³)–F). Stereochemical analysis of products suggests that such ligand effect origins from the dual mechanism of Pd(IV) reductive elimination step.

Figure 2. Experimental evidence for the dual mechanism of Pd(IV) reductive elimination

a, Stereochemical analysis of acetoxylation & fluorination reveals opposite configuration. b, Deuterium incorporation experiments show that C(sp³)–H insertion process is irreversible under our catalytic conditions. c, Bicyclic palladacycle 8 was synthesized and characterized via X-ray crystallography. Identical stereochemical outcome was observed with the catalytic conditions when 8 was reacted with [F⁺].

Figure 3. Controlling reductive elimination pathways from putative Pd(IV) intermediates

Trends of reductive elimination selectivity observed with anionic and neutral transient directing groups.

Figure 4. Access to diverse chiral organofluorines

a, NaN₃ (4.0 equiv.), HMPA (0.2 M), r.t., 36 h. b, piperidine (3.0 equiv.), K₂CO₃ (3.0 equiv.), DMF (0.2 M), 100 °C, 12 h. c, PhOH (3 equiv.), K₂CO₃ (3.0 equiv.), DMF (0.2 M), 100 °C, 2 h. d, NaSMe (3.0 equiv.), DMF (0.2 M), 60 °C, 4 h. e, Ethyl thioglycolate (3.0 equiv.), K₂CO₃ (3.0 equiv.), DMF (0.2 M), 60 °C, 3 h. f, NaN₃ (3.0 equiv.), DMF (0.2 M), 100 °C, 12 h. g, guanidine carbonate (2.5 equiv.), DMA (0.2 M), 150 °C, 1 h. h, 3-amino-1,2,4-triazole (2.0 equiv.), Cs₂CO₃ (3.0 equiv.), DMF (0.2 M), 100 °C, 2 h.