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 regioand 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 regioand excellent diastereoselectivities. Since the trifluoromethylated analogs 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. Heterocycles have an extensive history and are present in a wide variety of drugs, most vitamins, many natural products, biomolecules, and biologically active compounds [1–4]. Manmade fluorinated organic compounds have become a remarkable success in the pharmaceutical industry, despite their relatively young history [5–20]. In this context, fluorinated heterocycles have gained attention as new drug candidates over the past few decades in medicine and agro-chemistry [21–28]. Fluorinated and trifluoromethylated compounds have been well targeted in this research area [5–20, 21–28], and difluoromethylated compounds are next [16, 21–28]. The difluoromethyl (CF2H) group is known to be isosteric and isopolar to a hydroxy (OH) and thiol (SH) unit. The CF2H group can also act as a more lipophilic hydrogen donor than OH and NH groups through hydrogen bonding [31–34]. Thus, the difluoromethylation of biologically active molecules is an effective strategy for the design new candidates of pharmaceuticals and agrochemicals [16]. BRAVECTOTM (fluralaner) is a highly potent insect and acarid RDL and GluCl inhibitor that was just recently approved in chewable tablets for dogs against fleas and ticks [35]. A systematically large number of research disclosed that 3,5-diaryl-5-(trifluoromethyl)-2-isoxazoline unit 1 is a key skeleton for its biological activity [36–38]. Since 2010, our group has also made contributions to this fascinating structure by the direct late-stage trifluoromethylation of aromatic isoxazoles with Ruppert–Prakash reagent (trifluoromethyl) trimethylsilane (Me3SiCF3) [39–40, 41], and a fluorinated building block strategy based on the use of inexpensive reagents under organocatalysis with an eye on industrial purposes [36–38]. We are now interested in the synthesis of difluoromethyl analogs of this key structure, i.e., 3,5-diaryl-5-(difluoromethyl)-2-isoxazolines 2. More than 27,000 isoxazolines 1 with a quaternary carbon bearing a CF3 group at the 5-position have been synthesized and patented [42]; however, common structures bearing a CF2H group 2 are rare [43] (19 compounds, 4 patents Figure 1). In this paper, we disclose the first direct difluoromethylation at the 5-position of diary-isoxazoles 3 by nucleophilic addition using (difluoromethyl) trimethylsilane (Me3SiCF2H) in the presence of tetramethylammonium fluoride at room temperature. A series of diary-isoxazoles 3 having a nitro (X = NO2), triflyl (X = SO2CF3), or phenylsulfonyl (X = SO2Ph) group at the 4-postion are nicely CF2H-functionalized under the same mild conditions with good to high diastereoselectivity. Nucleophilic difluoromethylation of 1,6-conjugated styryl4-nitro isoxazoles was also achieved with Me3SiCF2H under the same reaction conditions to provide CF2H-adducts 4, with high regioand excellent diastereoselectivities. A wide variety of CF2H analogs of agrochemically attractive diarylisoxazolines 2 and their styryl analogs 4 were synthesized by this method. The nitro group in products 2 (X = NO2) SOR-CHEM