Pulsed electrolysis: enhancing primary benzylic C(sp<sup>3</sup>)–H nucleophilic fluorination

Atkins, Alexander P.; Chaturvedi, Atul K.; Tate, Joseph A.; Lennox, Alastair J. J.

doi:10.1039/d3qo01865b

“…In 2024, Lennox and co-workers reported their investigation in exploring how alternative electrolysis waveforms might assist in the generation of reactive primary benzylic cations for nucleophilic fluorination ( Figure 43 ) [ 104 ]. The challenge involved avoiding over-oxidation of the monofluorination product and overcoming mass transportation issues.…”

Section: Reviewmentioning

confidence: 99%

Benzylic C(sp³)–H fluorination

Atkins,

Dean,

Lennox

2024

Beilstein J. Org. Chem.

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The selective fluorination of C(sp3)–H bonds is an attractive target, particularly for pharmaceutical and agrochemical applications. Consequently, over recent years much attention has been focused on C(sp3)–H fluorination, and several methods that are selective for benzylic C–H bonds have been reported. These protocols operate via several distinct mechanistic pathways and involve a variety of fluorine sources with distinct reactivity profiles. This review aims to give context to these transformations and strategies, highlighting the different tactics to achieve fluorination of benzylic C–H bonds.

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“…These advancements have led to improved selectivity in chemical processes [36][37][38] and/or the preservation of electrode surfaces to prevent passivation. [39,40] Using Pt plates as electrodes, we performed pulsed electrosynthesis by investigating the effect of frequency (Hz) on the reaction (Figure 2F). We found that 0.2 Hz was the ideal frequency for the model substrate with up to 2.5-fold increase in yield.…”

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confidence: 99%

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis

Boudjelel,

Zhong,

Ballerini

et al. 2024

Angewandte Chemie

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Aryl radicals play a pivotal role as reactive intermediates in chemical synthesis, commonly arising from aryl halides and aryl diazo compounds. Expanding the repertoire of sources for aryl radical generation to include abundant and stable organoboron reagents would significantly advance radical chemistry and broaden their reactivity profile. While traditional approaches utilize stoichiometric oxidants or photocatalysis to generate aryl radicals from these reagents, electrochemical conditions have been largely underexplored. Through rigorous mechanistic investigations, we identified fundamental challenges hindering aryl radical generation. In addition to the high oxidation potentials of aromatic organoboron compounds, electrode passivation through radical grafting, homocoupling of aryl radicals, and decomposition issues were identified. We demonstrate that pulsed electrosynthesis enables selective and efficient aryl radical generation by mitigating the fundamental challenges. Our discoveries facilitated the development of the first electrochemical conversion of aryl potassium trifluoroborate salts into aryl C–P bonds. This sustainable and straightforward oxidative electrochemical approach exhibited a broad substrate scope, accommodating various heterocycles and aryl chlorides, typical substrates in transition‐metal catalyzed cross‐coupling reactions. Furthermore, we extended this methodology to form aryl C–Se, C–Te, and C–S bonds, showcasing its versatility and potential in bond formation processes.

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Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis

Boudjelel,

Zhong,

Ballerini

et al. 2024

Angew Chem Int Ed

6

0

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Aryl radicals play a pivotal role as reactive intermediates in chemical synthesis, commonly arising from aryl halides and aryl diazo compounds. Expanding the repertoire of sources for aryl radical generation to include abundant and stable organoboron reagents would significantly advance radical chemistry and broaden their reactivity profile. While traditional approaches utilize stoichiometric oxidants or photocatalysis to generate aryl radicals from these reagents, electrochemical conditions have been largely underexplored. Through rigorous mechanistic investigations, we identified fundamental challenges hindering aryl radical generation. In addition to the high oxidation potentials of aromatic organoboron compounds, electrode passivation through radical grafting, homocoupling of aryl radicals, and decomposition issues were identified. We demonstrate that pulsed electrosynthesis enables selective and efficient aryl radical generation by mitigating the fundamental challenges. Our discoveries facilitated the development of the first electrochemical conversion of aryl potassium trifluoroborate salts into aryl C–P bonds. This sustainable and straightforward oxidative electrochemical approach exhibited a broad substrate scope, accommodating various heterocycles and aryl chlorides, typical substrates in transition‐metal catalyzed cross‐coupling reactions. Furthermore, we extended this methodology to form aryl C–Se, C–Te, and C–S bonds, showcasing its versatility and potential in bond formation processes.

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Pulsed electrolysis: enhancing primary benzylic C(sp³)–H nucleophilic fluorination

Abstract: Pulsed electrolysis waveforms benefit primary benzylic cation generation and fluorination.

Cited by 6 publications

References 68 publications

Benzylic C(sp³)–H fluorination

Benzylic C(sp³)–H fluorination

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis

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Pulsed electrolysis: enhancing primary benzylic C(sp3)–H nucleophilic fluorination

Abstract: Pulsed electrolysis waveforms benefit primary benzylic cation generation and fluorination.

Cited by 6 publications

References 68 publications

Benzylic C(sp3)–H fluorination

Benzylic C(sp3)–H fluorination

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis

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Pulsed electrolysis: enhancing primary benzylic C(sp³)–H nucleophilic fluorination

Benzylic C(sp³)–H fluorination

Benzylic C(sp³)–H fluorination