Chemo‐ and Site‐Selective Electro‐Oxidative Alkane Fluorination by C(sp<sup>3</sup>)−H Cleavage

Stangier, Maximilian; Scheremetjew, Alexej; Ackermann, Lutz

doi:10.1002/chem.202201654

Cited by 21 publications

(17 citation statements)

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“…Though several useful tools for benzylic C–H fluorination employing a photocatalytic system and a transition metal catalyst have been reported, a more operationally simple method that does not need a special reaction setup and additional sacrificing reagents is desirable. Herein, we report the first example of C–H nucleophilic fluorination using the Ag(I)/Selectfluor system that is applicable to all 1°, 2°, and 3° C–H substrates. Notably, the reaction is greatly promoted by ubiquitous amide ligands and proceeds via radical/polar crossover, in which the alkyl radical is oxidized by Ag(II) species.…”

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confidence: 99%

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

2023

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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

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

2023

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“…Looking at organic chemistry we notice a tremendous growth of interest in the development of novel electrochemical methodologies. Ackermann, [1][2][3][4] Baran, [5][6][7][8] Lin, 9,10 Mei, [11][12][13] Waldvogel [14][15][16] and many other eminent scientists have proverbially brought electrosynthesis/electrocatalysis to light by turning it into a perfectly working synthetic tool. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] This, in turn, has many implications for the development of materials chemistry.…”

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confidence: 99%

Electrifying synthesis of organosilicon compounds – from electrosynthesis to electrocatalysis

Kuciński

2023

Inorg. Chem. Front.

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“…Herein, these drawbacks were addressed, leading to a broadly applicable electrochemical fluorination protocol that uses an inexpensive source of nucleophilic fluoride. [236] Scheme 2-1 Electrochemical benzylic C−H fluorination.…”

Section: Objectivesmentioning

confidence: 99%

“…Moreover, the electrolyte possesses a reasonable redox window, allowing on the one hand a facile proton reduction at the platinum cathode, and on the other hand offering high anodic stability, as confirmed by cyclovoltammetric studies performed by Dr. Stangier. [236,243] However, despite these important properties for efficient electrolysis and the generally easy handling of the developed setup, the hazardous nature of halogenated solvents remains an issue and efforts to at least partly replace them with less problematic components [247] were made. Polar, weakly-coordinating solvents were tested as 2:1 mixtures with HFIP (Table 3.1-2).…”

Section: Optimizationmentioning

confidence: 99%

“…Hence, the necessity of sustainability in all areas of trade and industry became evident and a shift towards renewable energies and raw materials, as well as general hazard minimization has been globally encouraged by scientists and politicians. [2] A generally accepted sustainability guideline for chemical production was summarized by Anastas, [3] with the key tasks being:…”

Section: Introductionmentioning

confidence: 99%

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Electrochemical Benzylic C−H Fluorination and 4d-Metallaelectro-Catalyzed C−H and C−C Functionalizations

Scheremetjew¹

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but the trend is that the mildest conditions and lowest catalysts loadings can be achieved when expensive palladium catalysts are employed.Scheme 1-2 General mechanism for palladium-catalyzed cross-coupling reactions.These methods nowadays belong to the standard repertoire of organic synthesis and their importance can be hardly overrated, since the production of an enormous number of lifesaving drugs relies on cross-coupling chemistry. These monumental achievements were honored with the Nobel Prize, awarded in 2010 to Akira Suzuki, Ei-ichi Negishi and Richard F. Heck, [20] and the Wolf Prize 2019, awarded to Stephen L. Buchwald and John F. Hartwig. [21] Despite these advances, catalysis in general and coupling reactions in particular remain an attractive research area due to multiple challenges that are still associated with the atom-and step-economy of the envisioned transformations. C−H ActivationThe prefunctionalization of substrates tworards the nucleophile/electrophile pair, that is needed for traditional cross-coupling, causes chemical waste during each synthetic step (Scheme 1-3, a). Moreover, many organometallic reagents call for special handling precautions due to their toxicity and/or hydrolytic sensitivity. An arguably more direct approach is reductive cross-coupling of two electrophiles (Scheme 1-3, b). [22] However, in addition to the innate challenge of overcoming undesired homocoupling, the waste balance is similarly problematic. In this context, C−H activation emerged as a powerful approach to unlock expedient reactivities of ubiquitously occurring C−H bonds while circumventing

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Chemo‐ and Site‐Selective Electro‐Oxidative Alkane Fluorination by C(sp³)−H Cleavage

Cited by 21 publications

References 86 publications

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

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

Electrifying synthesis of organosilicon compounds – from electrosynthesis to electrocatalysis

Electrochemical Benzylic C−H Fluorination and 4d-Metallaelectro-Catalyzed C−H and C−C Functionalizations

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Chemo‐ and Site‐Selective Electro‐Oxidative Alkane Fluorination by C(sp3)−H Cleavage

Cited by 21 publications

References 86 publications

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

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

Electrifying synthesis of organosilicon compounds – from electrosynthesis to electrocatalysis

Electrochemical Benzylic C−H Fluorination and 4d-Metallaelectro-Catalyzed C−H and C−C Functionalizations

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Chemo‐ and Site‐Selective Electro‐Oxidative Alkane Fluorination by C(sp³)−H Cleavage