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Review of 'Direct Nucleophilic Difluoromethylation of Aromatic Isoxazoles Activated by Electron-Withdrawing Groups Using (Difluoromethyl)trimethylsilane'

A new method for the direct nucleophilic difluoromethylation of heterocycles
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    Rated 4.5 of 5.
Level of importance:
    Rated 3 of 5.
Level of validity:
    Rated 5 of 5.
Level of completeness:
    Rated 4 of 5.
Level of comprehensibility:
    Rated 5 of 5.
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Direct Nucleophilic Difluoromethylation of Aromatic Isoxazoles Activated by Electron-Withdrawing Groups Using (Difluoromethyl)trimethylsilane

The activation of aromatic diaryl isoxazoles with strong electron-withdrawing groups, such as the nitro, triflyl and the phenylsulfonyl groups, at the 4-position has enabled the first regio- and diastereoselective difluoromethylation at the 5-position of isoxazoles by nucleophilic addition using (difluoromethyl)trimethylsilane, Me3SiCF2H, to provide difluoromethylated isoxazolines in good yields. Conjugated styryl-4-nitroisoxazoles were also nicely converted into the corresponding CF2H adducts with high regio- and excellent diastereoselectivities. Since the trifluoromethylated analogues of the corresponding diaryl-isoxazolines are effective ectoparasiticides, represented by fluralaner, should a series of difluoromethylated isoxazolines be obtained, they would be of great importance as promising drug candidates in this field.

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    Review text

    Direct difluoromethylation strategies are important for the pharmaceutical industry. This paper presents an elegant nucleophilic difluoromethylation strategy, that is complementary to the radical method recently developed by Baran et al (Nature 2012, 492, 95). The substrate scope of this new work is rather constrained at this early stage: the substrates have been chosen to be highly reactive towards nucleophiles, and a strongly electron-withdrawing group (eg NO2) is an absolute requirement, however an option is demonstrated for removing the NO2 group afterwards if desired. Yields in the nucleophilic difluoromethylation reactions are moderate, and diastereoselectivity ranges from poor to excellent. Experimentally, the set-up is reasonably straightforward although a glove-box is required. Compounds are characterised by H-NMR, C-NMR, F-NMR and low-res MS. Several biologically promising fluorinated heterocycles have been created in this work.


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