Direct perfluoroalkylation of aromatic and heteroaromatic compounds with perfluoroalkanesulfonyl chlorides catalysed by a ruthenium(II) phosphine complex

Kamigata, Nobumasa; Ohtsuka, T.; Fukushima, T.; Yoshida, Masato; Shimizu, Toshio

doi:10.1039/p19940001339

Cited by 77 publications

(59 citation statements)

References 14 publications

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“…Comparable replacement reactions are known for a number of perfluoroalkylated heterocyclic compounds and anilines [8][9][10]. Even substitution of b-fluorine atoms can occur provided the starting material allows a sequence a,b-elimination/Michael addition as found for a-perfluoroalkylated acetic acid derivatives or ketones [11,12].…”

Section: Resultsmentioning

confidence: 98%

Organofluorine compounds and fluorinating agents

Schwäbisch

Hein

Miethchen

2004

Journal of Fluorine Chemistry

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Section: Resultsmentioning

confidence: 98%

Organofluorine compounds and fluorinating agents

Schwäbisch

Hein

Miethchen

2004

Journal of Fluorine Chemistry

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“…Trifluoromethanesulfonyl chloride has been used in the presence of ruthenium(II) phosphine complex to introduce the CF 3 group onto alkenes, aromatics, and silyl enol ethers [153][154][155]. The reaction mechanism involves a redox-transfer reaction between CF 3 SO 2 Cl and Ru(II) catalyst to afford the corresponding anion radical precursor of CF 3 radical by extrusion of sulfur dioxide.…”

Section: Trifluoromethylacetyl and Trifluoromethylsulfonyl Derivativesmentioning

confidence: 99%

Strategies for nucleophilic, electrophilic, and radical trifluoromethylations

Ma¹,

Cahard²

2007

Journal of Fluorine Chemistry

533

177

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“…2; −0.90 V versus SCE) 19 is thermodynamically challenging, we questioned whether the incorporation of an electron-deficient system such as SO 2 within CF 3 X might enable more facile reduction 20 . Our investigations led us to the use of trifluoromethanesulphonyl chloride (known as triflyl chloride, TfCl), which has been employed in a non-general sense to effect aryl trifluoromethylation of benzene and other simple arenes via atom transfer catalysis 21–23 . In particular, the relative cost and ease of handling of TfCl in comparison to other • CF 3 sources rendered this a highly attractive reagent.…”

mentioning

confidence: 99%

Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

Nagib

MacMillan

2011

Nature

1,186

616

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Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents1. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion2. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF3) group, into drug candidates3. The CF3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug4–6. Although common pharmacophores often bear CF3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.

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Direct perfluoroalkylation of aromatic and heteroaromatic compounds with perfluoroalkanesulfonyl chlorides catalysed by a ruthenium(II) phosphine complex

Cited by 77 publications

References 14 publications

Organofluorine compounds and fluorinating agents

Organofluorine compounds and fluorinating agents

Strategies for nucleophilic, electrophilic, and radical trifluoromethylations

Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

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