Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid

Meyer, Claudio F.; Hell, Sandrine M.; Misale, Antonio; Trabanco, Andrés A.; Gouverneur, Véronique

doi:10.1002/anie.201903801

Cited by 127 publications

(63 citation statements)

References 49 publications

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“…In addition, CF 2 H group can be considered as the isostere of a thiol, a hydroxyl, and an amide, which brings out its potential value in drug development with novel scaffold 20,21 . However, unlike well-developed synthesis of fluorinated and trifluoromethylated compounds, the construction of difluoromethylated substances [22][23][24][25][26][27] , especially for difluoromethylated heterocycles, which widely exist in bioactive molecules (Fig. 1a), has been less explored.…”

mentioning

confidence: 99%

Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis

Zhang

Xiang

Chen³

et al. 2020

Nat Commun

132

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The discovery of modern medicine relies on the sustainable development of synthetic methodologies to meet the needs associated with drug molecular design. Heterocycles containing difluoromethyl groups are an emerging but scarcely investigated class of organofluoro molecules with potential applications in pharmaceutical, agricultural and material science. Herein, we developed an organophotocatalytic direct difluoromethylation of heterocycles using O 2 as a green oxidant. The C-H oxidative difluoromethylation obviates the need for pre-functionalization of the substrates, metals and additives. The operationally straightforward method enriches the efficient synthesis of many difluoromethylated heterocycles in moderate to excellent yields. The direct difluoromethylation of pharmaceutical moleculars demonstrates the practicability of this methodology to late-stage drug development. Moreover, 2′-deoxy-5-difluoromethyluridine (F 2 TDR) exhibits promising activity against some cancer cell lines, indicating that the difluoromethylation methodology might provide assistance for drug discovery.

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mentioning

confidence: 99%

Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis

Zhang

Xiang

Chen³

et al. 2020

Nat Commun

132

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“…In order to address the problem of installing CF 2 H group, we then started to search other CF 2 H precursors. Very recently, Prof. Gouverneur reported the efficient hydrodifluoromethylation reaction of alkenes using difluoroacetic acid as CF 2 H source and phenyliodine(III) diacetate as oxidant under blue LEDs . Inspired by this significant progress, we then envisioned whether difluoroacetic acid could be used as CF 2 H precursor in this 1,2‐aryl migration reaction.…”

Section: Resultsmentioning

confidence: 99%

Fluoroalkylation of Allylic Alcohols with Concomitant (Hetero)aryl Migration: Access to Fluoroalkylated Ketones and Evaluation of Antifungal Action against Magnaporthe grisea

et al. 2020

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Fluoroalkyl(hetero)arylation of allylic alcohols with perfluoroalkyl iodide or difluoroacetic acid as fluoroalkyl source was developed herein, delivering functionalized ketones containing an α‐quaternary center. Formation of the fluoroalkyl radical was followed by its intermolecular addition to alkenes and the migration of a (hetero)aryl group with the concomitant generation of a ketone group to finish the domino sequence. Mechanistic studies indicated that the aryl migration proceeded through neophyl rearrangement in a radical pathway. Moreover, preliminary antifungal evaluation against Magnaporthe grisea is also described for the first time.

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“…When R 1 is hydrogen, a new carbocation (60) forms via successive alkyl and double hydride shifts and reacts with a fluoride ion to give 55 a. If R 1 is a methyl group, 58 undergoes an alkyl migration to form a more stable tertiary carbocation (61), which is then trapped by fluoride to provide 56 a.…”

Section: Amino- Oxy-or Carbofluorination Of Alkenesmentioning

confidence: 99%

“…Gouverneur and coworkers reported a regioselective visible-light-initiated hydrodifluoromethylation of alkenes (184) in tetrahydrofuran (THF) by using difluoroacetic acid as a difluoromethyl radical source and PhI(OAc) 2 as an oxidant (Scheme 36). [61] This transition-metal-free approach did not require photocatalysts and operationally complex, over-engineered processes, and allowed the multigram one-pot synthesis of pharmaceutically relevant building blocks for application in medicinal chemistry, which were shorter and safer synthetic routes compared to those relying on classical deoxyfluorination processes. [61] The control experiments and the radical trap and deuterium labeling studies suggested the presence of * CF 2 H radicals and a radical-based mechanism (Scheme 36).…”

Section: Difluoromethylation Triggered By Hypervalent Iodine(iii) Reamentioning

confidence: 99%

Fluorination and Fluoroalkylation Reactions Mediated by Hypervalent Iodine Reagents

Han

Zhang

2020

Adv Synth Catal

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This review summarizes the progress in the fluorination and fluoroalkylation of electron-rich systems with diverse fluorine (F) and fluoroalkyl (R fn) reagents employing hypervalent iodine compounds as initiators in the last few decades. Because of the strong electrophilicity, high oxidizing properties, low toxicity, air and moisture stability, ready availability, ease of handling, and mild reaction conditions, the hypervalent iodine reagents have been widely utilized in modern organic chemistry. In particular, the use of hypervalent iodine reagents to initiate the CÀ F and CÀ R fn (R fn =CF 2 H, CF 3 , perfluoroalkyl, OCH 2 CF 3 , SCF 3 , SeCF 3 and etc) bond formation has been increasingly developed. In these reactions, hypervalent iodine compounds behave as powerful oxidants or electrophiles and activate the fluorination/fluoroalkylation reagents, the transitionmetal catalysts, or the substrates to in situ form electrophilic or radical intermediates, which subsequently participate in fluorination, difluoromethylation, trifluoromethylation, perfluoroalkylation, trifluoroethoxylation, fluoroalkylthiolation, trifluoromethylselenolation and others under mild conditions. Although great achievements have been made in this area, they are just the initial phase and still require a wide scope for improvement. It is anticipated that this review will draw much attention from the organic chemistry community and inspire more contributions in the development of new hyper-valent-iodine-mediated fluorination and fluoroalkylation reactions.

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Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid

Cited by 127 publications

References 49 publications

Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis

Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis

Fluoroalkylation of Allylic Alcohols with Concomitant (Hetero)aryl Migration: Access to Fluoroalkylated Ketones and Evaluation of Antifungal Action against Magnaporthe grisea

Fluorination and Fluoroalkylation Reactions Mediated by Hypervalent Iodine Reagents

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