A Ligand‐Enabled Palladium‐Catalyzed Highly para‐Selective Difluoromethylation of Aromatic Ketones

Abstract

Ap ractical and highly para-selective CÀHd ifluoromethylation of aromatic ketones has been developed by employing tetrakis(triphenylphosphine)palladium(0) as the catalyst and triphenylphosphine as the ligand. In addition to general aromatic ketones,t his transformation was compatible with bioactive compounds and well-known drugs,s uch as oxybenzone,ketoprofen, zaltoprofen, and propafenone.Moreover,amechanistic study revealed that apalladium intermediate coordinated by ac arbonyl group promotes highly paraselective difluoromethylation.

Direct C(sp2)–H alkylation of unactivated arenes enabled by photoinduced Pd catalysis

“…3a , top pathway), or (2) β-hydride elimination from an Pd(II)–alkyl intermediate ( IV ) generated by the reaction between the radical σ-complex ( I ) and a Pd(I) species (Fig. 3a , bottom pathway)–based on the preceding literatures suggesting that both could be operative in photo-excited Pd catalysis 16 , 28 , 34 , 39 , 54 , 55 . While the formation of intermediate IV through spin recombination of Pd(I) species and I could be facile, it should be noted that the resulting Pd(II)–alkyl species could undergo triplet excitation under visible light irradiation to cleave the Pd–alkyl bond, forming a Pd(I)/alkyl radical hybrid 28 , 41 .…”

“…5e ), suggesting that Pd(PPh 3 ) 2 I 2 is not involved in the productive catalytic cycle. Such a Pd(II) dihalide intermediate could potentially be generated from a second SET between a photoexcited doublet Pd(I) species and an alkyl halide, as suggested by Zhao 54 and Zhou 19 . Moreover, the DFT-computed transition states of the second single-electron reduction showed a 7.0 kcal/mol lower barrier for propyl iodide compared to propyl bromide, indicating that the inactive Pd(PPh 3 ) 2 × 2 complex can be more rapidly formed with alkyl iodides than alkyl bromides (Supplementary Fig.…”

“…For further confirmation, a stoichiometric experiment between Pd(PPh 3 ) 4 and 2af or 2afʹ was performed inspired by the studies reported by Zhao and co-workers (Fig. 5f ) 54 . In their Pd-catalyzed difluoromethylation of aromatic ketones with bromodifluoroacetate ( 2ar ) using Pd(PPh 3 ) 4 as the precatalyst, the desired product was not observed when the reaction was performed with a 1:1 ratio of Pd(PPh 3 ) 4 and 2ar .…”

Promising reagents for difluoroalkylation

“…In 2018, an efficient para-selective C-H difluoromethylation of aromatic ketones catalyzed by tetrakis(triphenylphosphine)palladium(0) was developed by the Zhao group (Scheme 77). 159 Additionally, several well-known drugs such as oxybenzone, ketoprofen, zaltoprofen, and propafenone were also well tolerated in this system. The role of AgF was unclear, it being likely to assist the palladium complex in activating the aromatic ring.…”

Recent Advances in Transition-Metal-Catalyzed Selective C–H Alkoxycarbonyldifluoromethylation Reactions of Aromatic Substrates

“…A cyclometalated ruthenium complex not only provided ortho-selective C−Hfunctionalized products with an electrophilic reagent but also acted as a strong bulk-electronic-transient-metal functional group to realize meta-or para-selective C−H transformations. 40 The other transition metals such as palladium, [21][22][23] molybedenum, 41 and nickel 42 all can used as an effective weak lewis acid to coordinate with the functional group adjacent to aromatic ring, leading to the para-selective C-H functionalizations. Although the reason is unclear, we may propose that when the metal complex coordinate with the main functional group on aromatic compounds, the introduction of the metal complex promotes the activation of the aromatic ring, and the steric hindrance of the ligand on the metal complex changes the dimensional environment of, meta, and para positions, leading to the reaction selective happens at the less hindered position on the aromatic ring.…”