A general route for the synthesis of β,β-difluorocarboxylic acids

Cohen, Or; Rozen, Shlomo

doi:10.1016/j.tet.2008.03.018

Cited by 13 publications

(5 citation statements)

References 26 publications

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“…The use of bulky and electron-rich Buchwald ligands SPhos and XPhos [21] significantly promoted the a-arylation of 1 and the hydrated by-products were inhibited simultaneously, but starting material 1 was not completely consumed yet (entries 8- 9). The use of DavePhos and JohnPhos resulted in lower yield of 2a (entries [10][11]. Monodentate ligands and bidentate ligands showed similar catalytic efficiencies as SPhos and XPhos in the a-arylation reactions (entries [12][13][14][15][16], although they could promote the reductive elimination of fluoroalkyl palladium(II) intermediates [22].…”

Section: Resultsmentioning

confidence: 99%

Palladium catalyzed direct α-arylation of α,α-difluoroketones with aryl bromides

Guo

Wang

Qing

2012

Journal of Fluorine Chemistry

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Section: Resultsmentioning

confidence: 99%

Palladium catalyzed direct α-arylation of α,α-difluoroketones with aryl bromides

Guo

Wang

Qing

2012

Journal of Fluorine Chemistry

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“…Analyzing possible pathways to obtain compound 9 , we suspected facile HF elimination under basic conditions as the main possible side process, which was found for a number of β,β-difluorocarbonyl compounds. , This assumption was confirmed by a failure to synthesize compound 9 from accessible 3,3-difluoroglutaric acid ( 13 ) (Scheme ). We observed decomposition of monoester 14 under typical conditions of Curtius rearrangement presumably as a result of HF elimination.…”

Section: Resultsmentioning

confidence: 95%

Radical Reactions of Alkyl 2-Bromo-2,2-difluoroacetates with Vinyl Ethers: “Omitted” Examples and Application for the Synthesis of 3,3-Difluoro-GABA

et al. 2015

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Addition reactions of perfluoroalkyl radicals to ordinary or polyfluorinated alkenes have been frequently used to synthesize perfluoroalkylated organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate, diethyl (bromodifluoromethyl)phosphonate, [(bromodifluoromethyl)sulfonyl]benzene, and ethyl 2-bromo-2-fluoroacetate were involved in Na2S2O4-mediated radical additions to vinyl ethers in the presence of alcohols to give difluoro or monofluoroacetyl-substituted acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)sulfonyl-substituted alkyl acetals. This methodology has also been applied as a key step in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing the series of isomeric difluoro GABAs. Comparison of the pKa values of 3-fluoro- and 3,3-difluoro-GABA with that of the fluorine free parent compound showed that introduction of each fluorine lead to acidification of both the amino and the carboxyl functions by approximately one unit.

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“…[192] Similar results (but somewhat lower diastereoselectivities) were obtained upon hydrogenation of functional- ChemMedChem ized p-fluorinated arenes using rhodium nanoparticles on molecularly modified silica as the catalyst. [220] Recently, Leung and co-workers described a highly efficient multigram synthesis of trans-4-fluorocyclohexylamine (249) starting from highly accessible 4,4-difluorocyclohexanecarboxylic acid (241) (Scheme 77). [194] The key steps of the synthetic scheme included HF elimination, diastereoselective double bond hydrogenation, and Hoffmann amide rearrangement.…”

Section: Synthesis Of γ-And δ-Fluorinated Cycloalkyl Building Blocksmentioning

confidence: 99%

“…[248] Also, fluorination of 1,3-dithiane X with BrF 3 was reported to give ester 311 in 70 % yield (Scheme 91). [249] The synthetic intermediates shown in Schemes 84-91 were used to obtain a number of building blocks using common organic chemistry transformations (Figure 5), including:…”

Section: Other Gem-difluorocycloalkyl Building Blocksmentioning

confidence: 99%

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Fluorinated Cycloalkyl Building Blocks for Drug Discovery

et al. 2022

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The review covers various aspects of fluorinated cycloalkyl (C3−C7) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine‐containing substrates, as well as some newer reactions like fluorination of non‐activated and remotely activated C−H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.

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A general route for the synthesis of β,β-difluorocarboxylic acids

Cited by 13 publications

References 26 publications

Palladium catalyzed direct α-arylation of α,α-difluoroketones with aryl bromides

Palladium catalyzed direct α-arylation of α,α-difluoroketones with aryl bromides

Radical Reactions of Alkyl 2-Bromo-2,2-difluoroacetates with Vinyl Ethers: “Omitted” Examples and Application for the Synthesis of 3,3-Difluoro-GABA

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

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