Copper-Catalyzed Functionalization of Benzylic C–H Bonds with N-Fluorobenzenesulfonimide: Switch from C–N to C–F Bond Formation Promoted by a Redox Buffer and Brønsted Base

Abstract

A copper catalyst in combination with N-fluorobenzenesulfonimide (NFSI) has been reported to functionalize benzylic C–H bonds to the corresponding benzylic sulfonimides via C–N coupling. Here, we reported a closely related Cu-catalyzed method with NFSI that instead leads to C–F coupling. This switch in selectivity arises from changes to the reaction conditions (Cu/ligand ratio, temperature, addition of base) and further benefits from inclusion of MeB­(OH)2 in the reaction. MeB­(OH)2 is shown to serve as a “redox buffer” in the reaction, responsible for rescuing inactive Cu­(II) for continued promotion of fluorination reactivity.

Copper catalyzed late-stage C(sp3)-H functionalization of nitrogen heterocycles

“…The bis(phenyl)sulfonamide radical then abstracts a hydrogen atom from C(sp 3 )-H adjacent to nitrogen of compound 1 to generate the corresponding radical A. In Path I, a radical chain propagation process is proposed, which is supported by recent work on alkyl radical fluorination 51,52 , especially the work on fluorine transfer to alkyl radical from N-F reagents 51 reaction to generate the fluorination intermediate B 53,54 with regeneration of L/Cu(I) complex. Finally, the fluorinated intermediate B undergoes a nucleophilic substitution promoted by NH(SO 2 Ph) 2 via the iminium intermediate C to afford the final CDC product 2 with elimination of HF 54 .…”

Benzylic C–H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

“…Cu-catalyzed radical-relay reactions that use N-uorobenzenesulfonimide (NFSI) as the oxidant have expanded rapidly in recent years 19,[29][30][31][32][33][34][35][36][37][38][39] and offered a possible strategy to achieve C-H isocyanation as these methods oen support oxidative coupling with the C-H substrate as the limiting reagent. Several mechanistic features of these reactions merit consideration.…”

“…[35][36][37] A second mechanistic feature involves radical functionalization, which can proceed by several different pathways. Cu I can initiate radical-chain uorination of C-H bonds 36,37,[40][41][42][43] with NFSI, but Cu/NFSI methods more commonly promote oxidative coupling of C-H bonds with nucleophilic reaction partners (Nu ¼ CN, N 3 , OR, Ar, among others). The mechanism of coupling can vary and depends on the coupling partner (Fig.…”

Alkali Metal Fluorides in Fluorinated Alcohols: Fundamental Properties and Applications to Electrochemical Fluorination

“…It is noteworthy that 2 was obtained in quantitative yield even in the presence of HFIP since it was reported that an additive amount of HFIP can activate the benzylic fluorine group via hydrogen bonding. − We attributed this to the hydrogen bonding interaction between the fluoride ion of CsF with HFIP, which decreased the interaction of HFIP with the benzylic fluoride.…”