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

SOR-CHEM Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl) trimethylsilane Xin Wang1, Etsuko Tokunaga2, and Norio Shibata1,2* 1 Department of Frontier Materials, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, Japan Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, Japan *Corresponding author’s e-mail address: Dedication: To Professor Iwao Ojima for his 70th birthday. 2 Published online: 18 December 2014 (version 2) Cite as: Wang et al., ScienceOpen Research 2014 (DOI: 10.14293/S2199-1006.1.SOR-CHEM.AD1QVW.v2) Reviewing status: Please note that this article is under continuous review. For the current reviewing status and the latest referee’s comments please click here or scan the QR code at the end of this article. Primary discipline: Chemistry Keywords: Fluorine, Difluoromethylation, Addition, Isoxazoline, Agrochemical, Insecticide ABSTRACT BRAVECTO™ (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) [39–41], 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 regio- and 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) 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 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]. 1 SOR-CHEM X. Wang et al.: Direct nucleophilic difluoromethylation of aromatic isoxazoles We first attempted difluoromethylation under the previous best conditions for trifluoromethylation of 3a [39, 40] or 4triflyl-3,5-diphenylisoxazole (3f) [41], however, the results were not satisfactory (Table 1, entries 1 and 2). There was no reaction in the presence of other basic conditions (entries 3– 5). Yield improved to 22–33% when phase-transfer catalyst 18-crown-6 (1.5 equiv) was added with potassium acetate and potassium fluoride (entries 6 and 7). Interestingly, ammonium salt tetramethylammonium fluoride (Me4NF) could cleave the Si-CF2H bond more efficiently. The reaction was attempted using Me4NF instead of a base, which gave the desired product in 53% yield (entry 8). Extension of the reaction time did not improve product yield (52%, entry 9). Traces of the desired product were detected when other quaternary ammonium salts replaced Me4NF (entries 10, 11). No effect on product yield (52%) was observed with a catalytic amount of cetyltrimethylammonium bromide (entry 12). Solvent screening did not improve the reaction (entries 13– 17), and the best condition was determined to be entry 8, by treating 3a with Me3CF2H (2.0 equiv) in N,N-dimethylformide (DMF) in the presence of Me4NF at room temperature for 4 h, and desired product 2a was obtained in 53% yield (entry 8). The stereochemistry of 2a was tentatively assigned according to comparisons with previous results [39, 40, 41], and finally it was clearly determined by X-ray analysis (CCDC 1057178). Assigning the best condition as the standard, we examined the scope of substrates 3 for our difluoromethlyation reaction Figure 1. BRAVECTOTM, trifluoromethyl-diaryisoxazolines 1 and their difluoromethyl analogs 2. can be removed under radical reaction conditions to afford 2 (X = H). The patented examples of this skeleton are synthesized by a so-called building block strategy [44–47]; hence, our method is the first example of the synthesis of 3,5-diaryl5-(difluoromethyl)-2-isoxazolines by a direct difluoromethylation reaction (Figure 2). In our previous studies, d (...truncated)