Amide-Ligand-Promoted Silver-Catalyzed C–H Fluorination via Radical/Polar Crossover

Abstract

We describe an efficient method for benzylic C−H fluorination via sequential hydrogen-atom transfer (HAT) and oxidative radical-polar crossover utilizing the Ag(I)/Selectfluor system. Amide ligands, such as benzamide and sulfonamide, substantially facilitate the processes leading to a carbocation intermediate, which subsequently reacts with nucleophilic fluorinating reagent to form a C−F bond. This protocol is applicable to the fluorination of all 1°, 2°, and 3°C−H bonds as well as to late-stage C−H fluorination of bioactive molecules.T he introduction of a C−F bond into organic molecules alters their physical, chemical, and biological properties, and consequently, fluorine-containing compounds are of interest in many research fields. 1 However, few fluorinecontaining compounds are found in nature, 2 and therefore, artificial construction of the C−F bond is required. Tremendous effort has been devoted to the development of C−F bond-forming reactions 3 by many research groups including ours, 4 but there is still a need for methods to form C−F bonds under mild conditions, which would be suitable for late-stage modification.An oxidation system using Ag(I) and Selectfluor (1) is one of the most powerful tools for the construction of the C−F bond under very mild conditions. 5 In this system, Ag(I) is considered to be oxidized by 1 to produce high-valent silver species, such as Ag(II) or Ag(III), acting as a strong singleelectron oxidant. The oxidation of Ag(I) is operationally simple, occurring even at room temperature, and various radical fluorinations using the Ag(I)/Selectfluor system have been developed (Scheme 1A). For example, Li and co-workers reported efficient methods for decarboxylative fluorination 5a and deboronofluorination. 5c These reactions begin with singleelectron transfer (SET) between high-valent silver species and appropriate functional groups to afford an alkyl radical, followed by fluorine-atom transfer (FAT) from 1 to give the corresponding product. Although these methods can form the C−F bond in a site-specific fashion, preinstallation of certain functional groups in the starting material is required. Given that most biologically active compounds possess an abundance of C(sp 3 )−H bonds, direct and regioselective C(sp 3 )−H fluorination would be an attractive option for rapid fluoro derivatization. In this context, Baxter and co-workers developed benzylic C−H fluorination with the Ag(I)/ Selectfluor system, 5f,h in which the diazabicyclo radical cation 1′ generated from 1 is considered to serve as a hydrogen-atom transfer (HAT) reagent. Then, FAT from 1 to the resulting alkyl radical leads to the fluorinated product (Scheme 1B). However, this reaction is not applicable to 3°C−H

Recent Advances in C—F Bond Formation from Carbon‐Centered Radicals

“…Recently, the Hamashima group disclosed a strategy for benzylic C—H fluorination using silver‐catalysis with selectfluor as an oxidant and fluoride as fluorine source (Scheme 52). [ 122 ] The authors found that amide ligands, such as benzamide and sulfonamide, significantly improve the reaction efficiency and selectivity by facilitating the formation of carbocation intermediate. The reaction also occurs via a radical‐polar crossover process, and can be used for late‐stage fluorination of bioactive molecules.…”

Benzylic C(sp3)–H fluorination

“…In 2023, Hamashima and co-workers disclosed an analogous, non-photochemical, silver-catalysed HAT radical-polar crossover mechanism for nucleophilic benzylic fluorination ( Figure 34 ) [ 85 ]. The authors proposed a similar mechanistic pathway to the photochemical methods, citing the use of amide ligands as important for modulating the silver catalyst stability and oxidation potentials.…”

Benzylic C(sp3)−H Alkoxylation through Visible‐Light‐Driven Oxidative Radical‐Polar Crossover

“…Inspired by their work, we envisioned that the corresponding alkoxylation would also be possible, if a silyl ether could scavenge the fluoride ion and instead liberate an alkoxide nucleophile (Scheme 1). In conjunction with our recent silver‐catalyzed benzylic C−F bond‐forming reaction via radical‐polar crossover, [2x] we herein present an efficient and metal‐free approach for benzylic C(sp 3 )−H alkoxylation. This method enables the incorporation of ether functional groups at primary, secondary, and tertiary benzylic positions, and is suitable for late‐stage C(sp 3 )−H alkoxylation of bioactive compounds.…”