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

A new strategy for the efficient direct nucleophilic difluoromethylation of aromatic isoxazoles
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    Rated 4.5 of 5.
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    Rated 5 of 5.
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    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

    The development of new fluorination methodologies is extremely important, especially for the synthesis of drugs and many biologically active compounds bearing fluorinated moiety. In this article the authors developed a new efficient approach for the regio- and diastereoselective nucleophilic difluoromethylation of aromatic isoxazoles using TMSCF2H as a fluorinated reagent. The presence of EWGs at 4-position of aromatic isoxazoles such as nitro, triflyl and phenylsulfonyl was found as a crucial point to get moderate yielding of the corresponding products. This work is a well extension of their previous development, nevertheless the new important challenging task of introducing CF2H group was successfully realized. Additionally the nitro group can be easily cleaved, which makes this approach even more attractive. Based on that I recommend to publish this article in ScienceOpen.


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