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      Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl)trimethylsilane

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            Abstract

            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.

            Main article text

            Heterocycles have an extensive history and are present in a wide variety of drugs, most vitamins, many natural products, biomolecules, and biologically active compounds [14]. Man-made fluorinated organic compounds have become a remarkable success in the pharmaceutical industry, despite their relatively young history [520]. In this context, fluorinated heterocycles have gained attention as new drug candidates over the past few decades in medicine and agro-chemistry [2128]. Fluorinated and trifluoromethylated compounds have been well targeted in this research area [520, 2128], and difluoromethylated compounds are next [16, 2128]. 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 [3134]. Thus, the difluoromethylation of biologically active molecules is an effective strategy for the design new candidates of pharmaceuticals and agrochemicals [16].

            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 [3638]. 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) [3941], and a fluorinated building block strategy based on the use of inexpensive reagents under organocatalysis with an eye on industrial purposes [3638]. 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).

            Figure 1.
            BRAVECTOTM, trifluoromethyl-diaryisoxazolines 1 and their difluoromethyl analogs 2.

            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 styryl-4-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 diaryl-isoxazolines 2 and their styryl analogs 4 were synthesized by this method. The nitro group in products 2 (X = NO2) 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 [4447]; hence, our method is the first example of the synthesis of 3,5-diaryl-5-(difluoromethyl)-2-isoxazolines by a direct difluoromethylation reaction (Figure 2).

            Figure 2.
            Two strategies for difluoromethylated isoxazolines 2 and newly obtained difluoromethylated isoxazolines 2 and 4.

            In our previous studies, direct trifluoromethylation into the 5-position of isoxazoles was achieved by using the Ruppert–Prakash reagent, Me3SiCF3 [3941]. Therefore, difluoromethylation with Me3SiCF2H instead of Me3SiCF3 under the same conditions is an ideal extension of this strategy. However, the use of Me3SiCF2H instead of Me3SiCF3 is not just a simple extension of direct trifluoromethylation, due to the rather inactive character of Me3SiCF2H [48, 49]. According to molecular orbital calculations of (difluoromethyl)- and (trifluoromethyl)fluorotrimethylsilicates reported by Fuchikami et al. [48], the bond order of the Si-CF2H bond (0.436) is significantly higher than that of the Si-CF3 bond (0.220); eventually, the cleavage of the Si-CF2H bond is more difficult than that of the Si-CF3 bond. Since Fuchikami's report, difluoromethylsilanes were believed to be not very useful for nucleophilic difluoromethylation until a recent report emerged from Hu et al. in 2011. They developed a Lewis base that could activate the nucleophilic difluoromethylation of various aldehydes, ketones, and imines with Me3SiCF2H at room temperature or even at low temperature [49]. Encouraged by their work, combined with the advances of our previous work, we initialized the optimization of the reaction conditions for the difluoromethylation of 4-nitro-3,5-diphenylisoxazole (3a), using Me3SiCF2H.

            We first attempted difluoromethylation under the previous best conditions for trifluoromethylation of 3a [39, 40] or 4-triflyl-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).

            Table 1.
            Optimization of reaction conditions.
            EntryBaseAdditivebSolventYield (%)a
            1NaOAc[CH3(CH2)15N(CH3)3]Br (30 mol%)DMF24
            2KOAcDMSONRb
            3tBuOKDMFNRb
            4KOAcDMFNRb
            5KOHDMFNRb
            6KOAc18-crown-6 (1.5 equiv)DMF22
            7KF18-crown-6 (1.5 equiv)DMF33
            8Me4NFDMF53
            9cMe4NFDMF52
            10Et4NF·H2ODMFtraceb
            11nBu4NF·H2ODMFtraceb
            12Me4NF[CH3(CH2)15N(CH3)3]Br (30 mol%)DMF52
            13Me4NFTHFtraceb
            14Me4NFNMPNRb
            15Me4NFDMSOtraceb
            16Me4NFDMA11
            17Me4NFDMINRb
            a

            The yield of isolated product.

            b

            Determined by 19F NMR analysis of the crude reaction mixture.

            c

            Reaction ran for 48 h.

            Assigning the best condition as the standard, we examined the scope of substrates 3 for our difluoromethlyation reaction in order to establish the generality of the process. A series of 3,5-diary-4-nitro-isoxazole 3 with different substituents at aromatic rings, including electron-donating and electron-withdrawing groups, were converted into corresponding difluoromethylated adducts smoothly in moderate yields with good to excellent diastereoselectivities (d.r. = 85:15–97:3, Table 2, 2a2e). It should be noted that isoxazoles having a different electron-withdrawing group at the 4-position, SO2CF3 and SO2Ph, i.e., 3,5-diphenyl-4-(trifluoromethanesulfonyl)isoxazole 3f and 3,5-diphenyl-4-(phenylsulfonyl)isoxazole 3g, were also suitable substrates for this transformation, affording difluoromethylated adducts 2f and 2g in moderate yields but rather low diastereoselectivities.

            Table 2.
            Stereoselective difluoromethylation of 3,5-diarylisoxazole 3 by nucleophilic difluoromethylation.a
            a

            Yield of the isolated products.

            We next investigated the difluoromethylation of 4-nitro-5-styrylisoxazoles 5. These compounds are flexible building blocks that bear a number of different functionalities [5066]. Generally, 4-nitro-5-styrylisoxazoles 5 have two electrophilic centres, both of which can be attacked by nucleophiles [5066]. Although the addition of carbon nucleophiles at the 4-position of 5 is rare, according to our previous work [39, 40], nucleophilic trifluoromethylation to conjugated alkenes with Me3SiCF3 fundamentally occurs exclusively by a 1,2-addition, and not a 1,4-addition. These results indicate that the addition of an aromatic isoxazole ring at the 5-position is specific to the trifluoromethylation reaction. In this work, we investigated the nucleophilic difluoromethylation of various 4-nitro-5-styrylisoxazoles 5 under the same reaction conditions to afford 1,2-addition difluoromethylated compounds as main products, while a very small amount of the 1,4-addition of difluoromethylated compound was observed (less than 10% of all difluoromethylated products) (Table 3). 3-Methyl-5-difluoromethyl-5-styrylisoxazoles were obtained with complete diastereoselectivity as single isomers (4a4e). Moderate yields were obtained when R1 was an electron-rich aromatic ring or a non-substrate benzene ring (4a4c). When R1 was an electron-poor aromatic ring, lower yields of corresponding products were obtained (4d and 4e). 3-Aryl-5-styrylisoxazoles were next investigated for the difluoromethylation and gave the corresponding products smoothly as single isomers (4f and 4g).

            Table 3.
            Regio- and diastereoselective difluoromethylation of 4-nitro-5-styrylisoxazoles by nucleophilic addition.a
            a

            Yield of the isolated products.

            In conclusion, the activation of aromatic isoxazoles with a strong electron-withdrawing group at the 4-position has resulted in the realization of the first diastereoselective difluoromethylation at the 5-position of isoxazoles 3 by nucleophilic addition using Me3SiCF2H. Regio- and diastereoselective difluoromethylation by nucleophilic addition was also achieved in the reaction with 1,6-conjugated styryl-4-nitroisoxazoles 4 under the same reaction conditions. Notably, a strong electron-withdrawing group at the 4-position is essential for this addition. No reaction was observed without the use of non-substituted 3,5-diphenyl isoxazole as substrate under the same reaction conditions. The nitro group of 2a was easily removed under radical reduction conditions to provide 6 in 96% yield (Figure 3). Therefore, this method provides a new series of highly functionalized 5-difluoromethyl-2-isoxazoline derivatives that may be attractive candidates for agrochemicals. The biological activities of selected 5-(difluoromethyl)-2-isoxazoline derivatives 2 and asymmetric variants of this method are now under consideration.

            Figure 3.
            Removal of the NO2 group of 2a to 6.

            EXPERIMENTAL SECTION

            All reagents were used as received from commercial sources, unless specified otherwise, or prepared as described in the literature. Reactions requiring anhydrous conditions were performed in oven-dried glassware under a positive pressure of nitrogen in glove box. Reaction mixtures were stirred magnetically. Solvents were transferred via syringe and were introduced into the reaction vessels though a rubber septum. All of the reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica gel (60-F254). The TLC plates were visualized with UV light and 7% phosphomolybdic acid or KMnO4 in water/heat. Column chromatography was carried out on a column packed with silica gel 60 N spherical neutral size 63–210 μm. The 1H-NMR (300 MHz) and 19F-NMR (282.3 MHz) spectra was recorded on a Varian Mercury 300. The 13C-NMR (150.9 MHz) was recorded on a Bruker Avance 600. Chemical shifts (δ) are reported in parts per million and coupling constants (J) are in hertz. Mass spectra were recorded on a SHIMADZU LCMS-2020. All the isoxazole substrates (3 and 5) were prepared according to the literature procedure [39, 40, 67].

            General procedure for the difuoromethylation of 4-nitroisoxazoles: in a flame dried test tube, 4-nitroisoxazole 3 or 5 (0.2 mmol) and Me4NF (0.3 mmol) added in glove box. DMF (2.0 mL) and Me3SiCF2H (0.4 mmol) was added in the mixture. After stirring at room temperature for 4.0 h, 1N HCl aq. was added to the reaction mixture and stirred for 30 minutes. After dilution with water, the whole reaction mixture was extracted with AcOEt, The combined organic phase was washed successively with water and saturated brine, and then dried over anhydrous Na2SO4. The solution was filtered and the solvent was removed under reduced pressure. The crude product was further purified by silica gel column chromatography or prepared TLC to give 2a–g and 4a–g.

            5-(difluoromethyl)-4-nitro-3,5-diphenyl-4,5-dihydroisoxazole (2a): Following the general procedure, 2a was isolated (33.7 mg, 53%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 5.95 (t, J = 54.9 Hz, 1H), 6.62 (s, 1H), 7.43–7.75 (m, 10H); 19F NMR (282 MHz, CDCl3) δ –128.52 (ddd, J = 505.6 Hz, 282.0 Hz, 53.6 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 152.86, 131.94, 130.36, 129.57, 129.12, 126.80, 126.53, 125.97, 113.82 (t, J = 254.6 Hz), 92.90, 92.05 (t, J = 21.4 Hz); MS (ESI, m/z) 317 [M-H] HRMS calc'd for [C16H12N2O3F2+Na]+: 341.0714, Found: 341.0712.

            5-(difluoromethyl)-5-(naphthalen-2-yl)-4-nitro-3-phenyl-4,5-dihydroisoxazole (2b): following the general procedure, 2b was isolated (36.1 mg, 49%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 6.02 (t, J = 55.5 Hz, 1H), 6.70 (s, 1H), 7.44–8.15 (m, 12H); 19F NMR (282 MHz, CDCl3) δ –128.10 (ddd, J = 515.5 Hz, 283.1 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 152.98, 133.78, 132.89, 131.97, 129.59, 129.07, 128.82, 127.82, 127.71, 127.08, 126.83, 125.98, 122.80, 113.99 (t, J = 239.6 Hz), 92.98, 92.255 (t, J = 21.0 Hz); MS (ESI, m/z) 367 [M-H] HRMS calc'd for [C20H14 N2O3F2+Na]+: 391.0870, Found: 391.0898.

            5-(4-chlorophenyl)-5-(difluoromethyl)-4-nitro-3-phenyl-4,5-dihydroisoxazole (2c): following the general procedure, 2c was isolated (33.1 mg, 47%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 5.92 (t, J = 54.9 Hz, 1H), 6.58 (s, 1H), 7.40–7.73 (m, 9H); 19F NMR (282 MHz, CDCl3) δ –128.36 (ddd, J = 498.9 Hz, 284.0 Hz, 53.6 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 152.88, 136.85, 132.09, 129.62, 129.44, 128.05, 126.81, 125.76, 113.53 (t, J = 254.9 Hz), 92.90, 91.64 (t, J = 20.8 Hz); MS (ESI, m/z) 351 [M-H] HRMS calc'd for [C16H11N2O3ClF2+Na]+: 375.0324, Found: 375.0330.

            5-(difluoromethyl)-4-nitro-3-phenyl-5-(m-tolyl)-4,5-dihydroisoxazole (2d): following the general procedure, 2d was isolated (33.9 mg, 51%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.38 (s, 3H), 5.93 (t, J = 55.5 Hz, 1H), 6.58 (s, 1H), 7.22–7.74 (m, 9H); 19F NMR (282 MHz, CDCl3) δ –128.53 (ddd, J = 508.4 Hz, 282.0 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 152.85, 138.99, 131.90, 131.11, 129.56, 128.96, 126.79, 126.02, 123.50, 113.89 (t, J = 255.2 Hz), 92.89, 92.09 (t, J = 21.3 Hz), 21.67; MS (ESI, m/z) 331 [M-H] HRMS calc'd for [C17H14N2O3F2+Na]+: 355.0870, Found: 355.0876.

            3-(4-bromophenyl)-5-(3-chlorophenyl)-5-(difluoromethyl)-4-nitro-4,5-dihydroisoxazole (2e): following the general procedure, 2e was isolated (43.2 mg, 50%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 5.94 (t, J = 54.3 Hz, 1H), 6.57 (s, 1H), 7.35–7.68 (m, 8H); 19F NMR (282 MHz, CDCl3) δ –128.53 (ddd, J = 597.6 Hz, 284.0 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 152.17, 135.41, 132.94, 130.80, 130.44, 128.14, 126.79, 124.62, 113.43 (t, J = 254.9 Hz), 92.61, 91.69 (t, J = 21.4 Hz); MS (ESI, m/z) 431 [M-H].

            5-(difluoromethyl)-3,5-diphenyl-4-((trifluoromethyl)sulfonyl)-4,5-dihydroisoxazole (2f): following the general procedure, 2f was isolated (32.4 mg, 40%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 5.53 (s, 0.44H), 5.63 (s, 0.56H), 5.87 (t, J = 55.8 Hz, 0.56H), 6.85 (t, J = 55.2 Hz, 0.44H), 7.38–7.76 (m, 10H); 19F NMR (282 MHz, CDCl3) δ –73.03, –73.55, –123.00 (ddd, J = 900.4 Hz, 295.0 Hz, 53.3 Hz, 2F), –127.18 (ddd, J = 384.9 Hz, 280.9 Hz, 55.3 Hz, 2F); MS (ESI, m/z) 404 [M-H] HRMS calc'd for [C17H12NO3F5+Na]+: 428.0356, Found: 428.0355. 13C NMR is too complicate to be analyzed.

            5-(difluoromethyl)-3,5-diphenyl-4-(phenylsulfonyl)-4,5-dihydroisoxazole (2g): following the general procedure, 2g was isolated (34.7 mg, 42%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 5.52 (t, J = 51.0 Hz, 0.78H), 5.70 (t, J = 55.2 Hz, 0.22H), 7.03–7.78 (m, 15H); 19F NMR (282 MHz, CDCl3) δ –121.86 (ddd, J = 1305.4 Hz, 298.9 Hz, 53.3 Hz, 2F), –128.29 (ddd, J = 480.0 Hz, 280.0 Hz, 55.3 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 155.96, 137.15, 134.28, 131.13, 129.62, 129.10, 128.85, 128.73, 128.20, 128.01, 127.99, 114.16 (t, J = 255.5 Hz), 90.64 (t, J = 20.4 Hz), 72.36; MS (ESI, m/z) 412 [M-H] HRMS calc'd for [C22H17NO3F2+Na]+: 436.0795, Found: 436.0799.

            5-(difluoromethyl)-3-methyl-4-nitro-5-styryl-4,5-dihydroisoxazole (4a): following the general procedure, 4a was isolated (25.4 mg, 45%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.16 (s, 3H), 5.85 (t, J = 55.8 Hz, 1H), 5.89 (s, 1H), 6.56 (dd, J = 292.8 Hz, 16.2 Hz, 2H), 7.34–7.36 (m, 5H); 19F NMR (282 MHz, CDCl3) δ –130.72 (ddd, J = 833.3 Hz, 285.1 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 149.89, 137.93, 134.75, 129.47, 128.92, 127.39, 114.58, 113.72 (t, J = 256.5 Hz), 94.48, 89.22 (t, J = 23.2 Hz), 12.05; MS (ESI, m/z) 281 [M-H] HRMS calc'd for [C13H12N2O3F2+Na]+: 305.0714, Found: 305.0710.

            5-(difluoromethyl)-3-methyl-5-(4-methylstyryl)-4-nitro-4,5-dihydroisoxazole (4b): Following the general procedure, 4b was isolated (27.8 mg, 47%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 2.08 (s, 3H), 2.27 (s, 3H), 5.80 (t, J = 55.8 Hz, 1H), 6.40 (s, 1H), 6.41 (dd, J = 298.2 Hz, 15.6 Hz, 2H), 7.05–7.18 (m, 4H); 19F NMR (282 MHz, CDCl3) δ –130.29 (ddd, J = 803.4 Hz, 285.1 Hz, 53.3 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 149.86, 139.63, 137.76, 132.00, 129.60, 127.31, 113.46 (t, J = 256.5 Hz), 113.39, 112.08, 94.46, 89.28 (t, J = 22.9 Hz), 21.46, 12.05; MS (ESI, m/z) 295 [M-H] HRMS calc'd for [C14H14N2O3F2+Na]+: 319.0870, Found: 319.0885.

            5-(difluoromethyl)-3-methyl-5-(2-(naphthalen-1-yl)vinyl)-4-nitro-4,5-dihydroisoxazole (4c): Following the general procedure, 4c was isolated (28.6 mg, 43%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.20 (s, 3H), 5.95 (t, J = 58.5 Hz, 1H), 6.12 (s, 1H), 7.44–8.02 (m, 9H); 19F NMR (282 MHz, CDCl3) δ –130.79 (ddd, J = 866.0 Hz, 285.9 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 149.94, 135.92, 133.60, 132.77, 131.20, 129.71, 128.70, 126.81, 126.30, 125.61, 124.79, 123.69, 117.87, 113.70 (t, J = 255.9 Hz), 94.64, 89.33 (t, J = 23.2 Hz), 12.08; MS (ESI, m/z) 331 [M-H]; HRMS calc'd for [C17H14N2O3F2+Na]+: 355.0870, Found: 355.0868.

            5-(4-chlorostyryl)-5-(difluoromethyl)-3-methyl-4-nitro-4,5-dihydroisoxazole (4d): following the general procedure, 4d was isolated (17.7 mg, 28%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.16 (s, 3H), 5.84 (t, J = 54.3 Hz, 1H), 5.89 (s, 1H), 6.53 (dd, J = 285.6 Hz, 15.9 Hz, 2H), 7.30–7.38 (m, 4H); 19F NMR (282 MHz, CDCl3) δ –130.67 (ddd, J = 843.2 Hz, 285.9 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 149.92, 136.68, 135.36, 133.21, 129.16, 128.60, 115.26, 113.56 (t, J = 252.9 Hz), 94.48, 89.10 (t, J = 23.2 Hz), 12.03; MS (ESI, m/z) 315 [M-H] HRMS calc'd for [C13H11N2O3ClF2+Na]+: 339.0324, Found: 339.0328.

            5-(4-bromostyryl)-5-(difluoromethyl)-3-methyl-4-nitro-4,5-dihydroisoxazole (4e): following the general procedure, 4e was isolated (21.7 mg, 30%) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 2.17 (s, 3H), 5.84 (t, J = 55.2 Hz, 1H), 5.89 (s, 1H), 6.53 (dd, J = 275.7 Hz, 16.2 Hz, 2H), 7.22–7.48 (m, 4H); 19F NMR (282 MHz, CDCl3) δ –130.69 (ddd, J = 855.9 Hz, 285.9 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 149.92, 136.76, 133.64, 132.12, 128.85, 123.61, 115.38, 113.54 (t, J = 254.0 Hz), 94.48, 89.11 (t, J = 23.1 Hz), 12.03; MS (ESI, m/z) 359 [M-H] HRMS calc'd for [C13H11N2O3BrF2+Na]+: 382.9819, Found: 382.9802.

            5-(difluoromethyl)-4-nitro-3-phenyl-5-styryl-4,5-dihydroisoxazole (4f): following the general procedure, 4f was isolated (35.1 mg, 51%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 5.92 (t, J = 56.1 Hz, 1H), 6.42 (s, 1H), 6.66 (dd, J = 290.1 Hz, 16.2 Hz, 2H), 7.33–7.71 (m, 4H); 19F NMR (282 MHz, CDCl3) δ –130.24 (ddd, J = 813.6 Hz, 285.1 Hz, 53.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 152.34, 138.44, 134.71, 131.84, 129.56, 129.53, 128.94, 127.42, 126.76, 126.23, 114.11, 113.70 (t, J = 253.1 Hz), 92.18, 90.47 (t, J = 21.9 Hz); MS (ESI, m/z) 343 [M-H] HRMS calc'd for [C18H14N2O3F2+Na]+: 367.0870, Found: 367.0873.

            5-(difluoromethyl)-5-(4-methylstyryl)-4-nitro-3-phenyl-4,5-dihydroisoxazole (4g): following the general procedure, 4g was isolated (33.7 mg, 47%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ5.92 (t, J = 56.1 Hz, 1H), 6.42 (s, 1H), 6.66 (dd, J = 290.1 Hz, 16.2 Hz, 2H), 7.33–7.71 (m, 4H); 19F NMR (282 MHz, CDCl3) δ –130.28 (ddd, J = 802.6 Hz, 285.1 Hz, 54.4 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 152.32, 139.72, 138.27, 131.97, 131.80, 129.61, 129.51, 127.35, 126.74, 126.28, 113.76 (t, J = 257.4 Hz), 112.92, 92.17, 90.54 (t, J = 21.3 Hz), 21.46; MS (ESI, m/z) 357 [M-H] HRMS calc'd for [C19H16N2O3F2+Na]+: 381.1027, Found: 381.1025.

            Procedure for denitration of 2a

            To a stirred solution of 2a (31.8 mg, 0.10 mmol) in benzene (2.0 mL) were successively added AIBN (8.2 mg, 0.050 mmol, 0.5 equiv) and nBu3SnH (40.4 μL, 0.150 mmol, 1.5 equiv), and the whole mixture was heated under reflex for 2 h. After cooling down to room temperature, the solution was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 95/5) to give 6 (26.2 mg, 96%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 3.82 (dd, J = 124.8 Hz, 16.8 Hz, 2H), 5.91 (t, J = 55.2 Hz, 1H), 7.36–7.70 (m, 10H); 19F NMR (282 MHz, CDCl3) δ –129.10 (ddd, J = 371.1 Hz, 281.2 Hz, 55.3 Hz, 2F); 13C NMR (150.9 MHz, CDCl3) δ 156.46, 137.52 (d, J = 2.8 Hz), 130.73, 129.04, 128.95, 128.83, 128.73, 126.94, 126.48, 114.63 (t, J = 251.6 Hz), 88.46 (t, J = 22.5 Hz), 41.77; MS (ESI, m/z) 274 [M+H]+ HRMS calc'd for [C16H14NOF2]+: 274.1043, Found: 274.1045.

            Acknowledgements

            This research was financially supported in part by the Platform for Drug Discovery, Informatics, and Structural Life Science from MEXT Japan, the Advanced Catalytic Transformation (ACT-C) from the Japan Science and Technology (JST) Agency, and Scientific Research (B) (25288045) and Exploratory Research (25670055) from JSPS, and Kobayashi International Scholarship Foundation. We also thank Professor Jinbo Hu for a gift of Me3SiCF2H. We thank Dr. Motoo Shiro for X-ray cryptographic analysis of 2a.

            References

            1. , , . The chemistry of heterocycles: structure, reactions, syntheses and applications. Hoboken (NY): Wiley; 2003.

            2. Katritzky AR. Comprehensive heterocyclic chemistry III. 1st ed. Amsterdam (the Netherlands): Elsevier; 2008.

            3. , , , . Handbook of heterocyclic chemistry. 3rd ed. Oxford (UK): Elsevier; 2010.

            4. , , . Heterocycles in life and society: an introduction to heterocyclic chemistry, biochemistry and applications. 2nd ed. Chichester (UK): Wiley; 2011.

            5. Chambers RD. Fluorine in organic chemistry. New York (NY): John Wiley & Sons; 1973.

            6. , . Fusso Kagoubustu (Compounds of fluorine). Tokyo (Japan): Kodansha; 1979.

            7. Kirk KL. Biochemistry of halogenated organic compounds. New York (NY): Plenum Press; 1991; Chapter 3, pp. 65–103 and Chapter 5, pp. 145–150.

            8. , , . Fusso No Kagaku (Chemistry of fluorine). Tokyo (Japan): Kodansha Scientific; 1993; Chapter 5, pp. 151–192.

            9. , . Biomedical aspects of fluorine chemistry. In: , , editors. Amsterdam (the Netherlands): Elsevier; 1993, pp. 1–32.

            10. , , . Organofluorine chemistry: principles and commercial applications. New York (NY): Plenum Press; 1994.

            11. , , Eds. Fluorine-containing amino acids, synthesis and properties. Chichester (UK): John Wiley & Sons; 1995.

            12. Hiyama, T, Eds. Organofluorine compounds. Chemistry and applications. New York (NY): Springer; 2000.

            13. McCarthy JR. Utility of fluorine in biologically active molecules, ACS fluorine division tutorial, 219th National ACS Meeting. San Francisco (CA), March 26; 2000.

            14. McCarthy JR. Fluorine in Drug Design: A Tutorial Review. 17th Winter Fluorine Conference, St. Pete Beach (FL); 2005.

            15. Thayer AM. Rapid screening and optimization of enzymatic activity, along with available, easy-to-use enzymes, are making biocatalysis a handy tool for chiral synthesis. Chem Eng News. 2006;84(33):15–25. [Cross Ref]

            16. , . Bioorganic and medicinal chemistry of fluorine. Hoboken (NJ): Wiley; 2007.

            17. Kirk KL. Fluorination in medicinal chemistry: methods, strategies, and recent developments. Org Process Res Dev. 2008;12(2):305–21. [Cross Ref]

            18. Ojima I. Fluorine in medicinal chemistry and chemical biology. Oxford (UK): Blackwell; 2009.

            19. Kirsch P. Modern fluoroorganic chemistry. Weinheim (Germany): Wiley-VCH; 2013.

            20. , , , , , , , . Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem Rev. 2014;114(4):2432–506. [Cross Ref]

            21. . Fluorine in bioorganic chemistry. New York (NY): Wiley; 1991.

            22. , , . Organofluorine compounds in medicinal chemistry and biomedical applications. Amsterdam, New York (NY): Elsevier; 1993.

            23. Petrov VA. Fluorinated heterocyclic compounds: synthesis chemistry, and applications. Hoboken (NJ): Wiley; 2009.

            24. Welch JT. Tetrahedron report number 221: advances in the preparation of biologically active organofluorine compounds. Tetrahedron. 1987;43(14):3123–97. [Cross Ref]

            25. Silvester MJ. Recent advances in fluoroheterocyclic chemistry. Adv Heterocycl Chem. 1994;59:1–38. [Cross Ref]

            26. , . Synthesis of monotrifluoromethyl-substituted saturated cycles. Tetrahedron. 2000;56(23):3635–71. [Cross Ref]

            27. Erian AW. Recent trends in the chemistry of fluorinated five and six-membered heterocycles. J Heterocycl Chem. 2001;38(4):793–808. [Cross Ref]

            28. , , , , . Synthesis. 2009;23:3905–29.

            29. , , , , . Stereoselective Synthesis of anti- α-(difluoromethyl)- β-amino alcohols by boronic acid based three-component condensation. Stereoselective preparation of (2S,3R)-difluorothreonine. J Org Chem. 2002;67(11):3718–23. [Cross Ref]

            30. , , , , , , , , , . A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease. Bioorg Med Chem Lett. 2002;12(4):701–4. [Cross Ref]

            31. , . Hydrogen bond donor properties of the difluoromethyl group. J Org Chem. 1995;60(6):1626–31. [Cross Ref]

            32. , . Facile synthesis of chiral α-difluoromethyl amines from N-(tert-butylsulfinyl) aldimines. Angew Chem. 2005;117(36):6032–6.

            33. , . Facile synthesis of chiral α-difluoromethyl amines from N-(tert-butylsulfinyl) aldimines. Angew Chem Int Ed. 2005;44(36):5882–6. [Cross Ref]

            34. , , , . New electrophilic difluoromethylating reagent. Org Lett. 2007;9(10):1863–6. [Cross Ref]

            35. , , . A randomized, blinded, controlled and multi-centered field study comparing the efficacy and safety of Bravecto™ (fluralaner) against Frontline™ (fipronil) in flea- and tick-infested dogs. Parasit Vectors. 2014;7(1):83. [Cross Ref]

            36. , , , , , , , , . Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. J Med Chem. 1999;42(15):2760–73. [Cross Ref]

            37. , , . The reaction of hydroxylamine with aryl trifluoromethyl- β-diketones: synthesis of 5-hydroxy-5-trifluoromethyl- Δ2-isoxazolines and their dehydration to 5-trifluoromethylisoxazoles. J Fluorine Chem. 2006;127(7):880–8. [Cross Ref]

            38. , , , , , , . ChemInform abstract: asymmetric 1,3-dipolar cycloadditions of nitrile oxides and nitrones with fluorosubstituted chiral vinyl sulfoxides. J Chem Res Synop. 1996; 27(52) 348–9. [Cross Ref]

            39. , , , , . Trifluoromethylation of aromatic isoxazoles: regio- and diastereoselective route to 5-Trifluoromethyl-2-isoxazolines. Angew Chem. 2011;123(34):7949–52. [Cross Ref]

            40. , , , , . Trifluoromethylation of aromatic isoxazoles: regio- and diastereoselective route to 5-trifluoromethyl-2-isoxazolines. Angew Chem Int Ed. 2011;50(34):7803–06. [Cross Ref]

            41. , , , , , . Diastereoselective additive trifluoromethylation/halogenation of isoxazole triflones: synthesis of all-carbon-functionalized trifluoromethyl Isoxazoline Triflones. Chemistry Open. 2014; 3(1):14–18. [Cross Ref]

            42. More than 27 000 compounds of isoxazolines have been registered in SciFinder database in November 2014, and most of them have been protected by over 170 patents.

            43. Only 19 compounds of isoxazolines have been registered in SciFinder database in November 2014, and they have been protected by over 4 patents.

            44. , , , , . US20070066617, WO2005085216, 2005.

            45. , , , , . US20070066617, 2007.

            46. , . WO2009022746, 2009.

            47. , , , . WO2013026931, 2013.

            48. , . Difluoroalkylation of carbonyl compounds with (1,1-difluoroalkyl) silane derivatives. Synlett. 1995; 1995(7):717–8. [Cross Ref]

            49. , , , . Efficient and direct nucleophilic difluoromethylation of carbonyl compounds and imines with Me3SiCF2H at ambient or low temperature. Org Lett. 2011;13(19):5342–5. [Cross Ref]

            50. , , , . Photodimerization of 3-methyl-4-nitro-5-styrylisoxazole in the solid state. J Heterocycl Chem. 1977;14(5):951–51. [Cross Ref]

            51. , , . Photochemical reactions of 3-methyl-4-nilro-5-styrylisoxazole in solution, in the solid slate and adsorbed on silica gel. J Heterocycl Chem. 1979;16(2):253–6. [Cross Ref]

            52. , , , . Alkaline hydrolysis of 3-methyl-4-nitro-5-styrylisoxazole with Na18OH. J Heterocycl Chem. 1980;17(7):1643–4. [Cross Ref]

            53. , , , , , . The preparation of coumaric acids via styrylisoxazoles. Heterocycles. 1983;20:263–7. [Cross Ref]

            54. , , , , , , . Preparation of 18O-bilabelled carboxylic acids: cinnahic and phenylpropiolic acids via styrylisoxazoles. J Labelled Compd Radiopharm. 1986;23(5):487–493. [Cross Ref]

            55. , , , , , , . Preparation of chloro- α-truxillic acids via 3-methyl-4-nitro-5-styrylisoxazole photodimers. Heterocycles. 1986;24(10):2863–70. [Cross Ref]

            56. , . Multicomponent synthesis of 3-heteroarylpropionic acids. Org Lett. 2006;8(22):5157–9. [Cross Ref]

            57. , . Multicomponent synthesis of 3-indolepropionic acids. Org Lett. 2007;9(2):303–5. [Cross Ref]

            58. , , , . Modular synthesis of isoxazolopyridones and pyrazolopyridones. Tetrahedron. 2007;63(9):2047–52. [Cross Ref]

            59. , , , . Modular syntheses of isoxazoloazepinones and pyrazoloazepinones. Tetrahedron. 2007;63:2684–8. [Cross Ref]

            60. , , , , . Three multicomponent reactions of 3,5-dimethyl-4-nitroisoxazole. Tetrahedron. 2007;63(39):9741–5. [Cross Ref]

            61. , . Synthesis of homochiral dihydroxy-4-nitroisoxazolines via one-pot asymmetric dihydroxylation−reduction. Org Lett. 2008;10(9):1807–10. [Cross Ref]

            62. , , , . Practical route for N,O-heteroatom interchange in 3,5-disubstituted-4-nitroisoxazoles. Tetrahedron Lett. 2008;49(6):941–4. [Cross Ref]

            63. , . A multicomponent synthesis of cyclopropanes. Tetrahedron Lett. 2008;49(43):6224–6. [Cross Ref]

            64. , , , . Aziridination of 3-methyl-4-nitro-5-styrylisoxazoles. Tetrahedron Lett. 2008;49(52), 7406–9. [Cross Ref]

            65. , , , , . Catalytic asymmetric conjugate addition of nitroalkanes to 4-nitro-5-styrylisoxazoles. Angew Chem. 2009;121(49):9506–9. [Cross Ref]

            66. , , , , . Catalytic asymmetric conjugate addition of nitroalkanes to 4-nitro-5-styrylisoxazoles. Angew Chem Int Ed. 2009;48(49):9342–5. [Cross Ref]

            67. , , , . Synthesis of isoxazole triflones. Eur J Org Chem. 2012;2012(7):1295–8. [Cross Ref]

            Competing Interests

            The authors declare no competing interests.

            Publishing Notes

            © 2014 Xin Wang et al. This work has been published open access under Creative Commons Attribution License CC BY 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com.

            Author and article information

            Contributors
            (View ORCID Profile)
            Journal
            SOR-CHEM
            ScienceOpen Research
            ScienceOpen
            2199-1006
            18 December 2014
            : 0 (ID: aeab23b4-61ff-4936-a252-0cd98d9fddcf )
            : 0
            : 1-7
            Affiliations
            [1 ]Department of Frontier Materials, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, Japan
            [2 ]Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, Japan
            Author notes
            [* ]Corresponding author's e-mail address: nozshiba@ 123456nitech.ac.jp

            Dedication: To Professor Iwao Ojima for his 70th birthday.

            Article
            2683:XE
            10.14293/S2199-1006.1.SOR-CHEM.AD1QVW.v2
            aeab23b4-61ff-4936-a252-0cd98d9fddcf
            © 2014 Xin Wang et al.

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            History
            Page count
            Figures: 6, Tables: 3, References: 67, Pages: 7
            Categories
            Original article

            Comments

            wrote:

            As mentioned by the authors, the difluoromethyl (CF2H) group is generally regarded as isosterer to a hydroxy (OH) and thiol (SH). However, the power of the difluoromethyl group is not well-understood because of lacking the general method for the introduction of the difluoromethyl group. The authors studied the factors that might affect the reaction of TMSCF2H with substituted isoxazoline-a medicinally important structure unit. As a result, the best reaction conditions were identified and a variety of substituted difluoromethylated isoxazolines were generated. The control of the diastereoselectivity is intriguing but nicely controlled for the vinyl substituted isoxazoline derivatives. Nice work.

            The study of the bioactivity of these compounds would be expected in the following investigation.

            2015-05-24 02:48 UTC
            +1

            Dear Qilong,

            Thank you very much for your kind comments on paper, and I agree with your comments that the potential of CF2H is not simple and great. More systmmatic biological studies on CF2H-compounds should be required and we also work on this line using our compounds.

            Best wishes,

            Norio

            2015-05-24 02:59 UTC
            Dear Professor Dmitry Katayev, Thank you very much for your strong support on our article. The CF2H-analoges of Bravecto is of very attractive, however, due to a lack of general synthetic methods, the research has less been examined. Our method for the preparation of CF2H-analoges by the direct difluoromethylation has a wide substrate generality. We hope the research of CF2H-analoges of Bravecto will be more activated. Incidentally, your contribution to this review is of great helpful not only for our paper but also for ScienceOpen, since the ScienceOpen has a very unique reviewing system which could change the style of reviewing in future. Norio
            2015-03-31 11:02 UTC
            +1
            wrote:
            Comments The authors reported a new method for the preparation of 5-difluoromethyl-2-isoxazoline derivatives through direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using TMSCF2H. Although this is an extension of their previous work and the yields of difluoromethylated products are moderate, the manuscript still can be published in ScienceOpen because of the difficulty in nucleophilic difluormethylation of aromatic isoxazoles. In addition, the resulting new 5-difluoromethyl-2-isoxazoline derivatives may have potential applications in agrochemicals. If the authors could stereoselectively synthesize compounds 2 and 4, it will improve the quality of the manuscript. Level of importance: 3 Is the publication of relevance for the academic community and does it provide important insights? Yes Does the work represent a new approach or new findings in comparison with other publications in the field? Yes Level of validity:4 Is the hypothesis clearly formulated? Yes Is the argumentation stringent? Yes Are the data sound, well-controlled and statistically significant? Yes Is the interpretation balanced and supported by the data? Yes Are appropriate and state-of-the-art methods used? Yes Level of completeness: 4 Do the authors reference the appropriate scholarly context? Yes Do the authors provide or cite all information to follow their findings or argumentation? Yes Do they cite the all relevant publications in the field? Yes Level of comprehensibility: 4 Is the language correct and easy to understand for an academic in the field? Yes Are the figures well displayed and captions properly described? Yes Is the article systematically and logically organized? Yes
            2015-03-19 11:52 UTC
            +1
            wrote:
            Comments The authors reported a new method for the preparation of 5-difluoromethyl-2-isoxazoline derivatives through direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using TMSCF2H. Although this is an extension of their previous work and the yields of difluoromethylated products are moderate, the manuscript still can be published in ScienceOpen because of the difficulty in nucleophilic difluormethylation of aromatic isoxazoles. In addition, the resulting new 5-difluoromethyl-2-isoxazoline derivatives may have potential applications in agrochemicals. If the authors could stereoselectively synthesize compounds 2 and 4, it will improve the quality of the manuscript. Level of importance: 3 Is the publication of relevance for the academic community and does it provide important insights? Yes Does the work represent a new approach or new findings in comparison with other publications in the field? Yes Level of validity:4 Is the hypothesis clearly formulated? Yes Is the argumentation stringent? Yes Are the data sound, well-controlled and statistically significant? Yes Is the interpretation balanced and supported by the data? Yes Are appropriate and state-of-the-art methods used? Yes Level of completeness: 4 Do the authors reference the appropriate scholarly context? Yes Do the authors provide or cite all information to follow their findings or argumentation? Yes Do they cite the all relevant publications in the field? Yes Level of comprehensibility: 4 Is the language correct and easy to understand for an academic in the field? Yes Are the figures well displayed and captions properly described? Yes Is the article systematically and logically organized? Yes
            2015-03-19 11:52 UTC
            +1
            Dear Professor 新刚 张, Thank you very much for your strong support on our manuscript. The yields of this transformation are moderate around 50% and the trifluoromethylation variant proceeds more easily. This is due to the difference of bond order between CF3-Si and CF2H-Si. The diastereoselectivities for 2 and 4 are high up to 100%, and enantioselective diifluoromethylation is the next challenge. Biological application of the series of these compounds will be examined in near future. Thank you very much one again for your positive support on our article. Best wishes, Norio
            2015-03-19 11:45 UTC
            +1
            A useful synthetic method of organofluorine compounds is described. Difluoromethylation of organic compounds is one of the challenging topics in organic chemistry. Even now, there have been the limited examples of difluoromethylation due to the difficulty. The authors have succeeded in nucleophilic difluoromethylation of aromatic isoxazoles bearing electron-withdrawing groups. The findings in this paper are of basic interest and the products are useful in several fields of science. Therefore, I support publication in ScienceOpen. Some corrections in the manuscript would be needed. (a) Page 1, line 10; [39–40, 41] -> [39–41] (b) Page 2, left, line 20; were believed to be useless -> were believed to be not very useful (‘useless’ is too strong, because there has been little knowledge about the reactivity of HCF2SiMe3 in detail until Hu’s report.) (c) Page 7, authors’ names in ref-44 and 45; all the first names and family names are incorrect.
            2015-03-09 13:14 UTC
            +1
            One person recommends this
            Dear Professor Amii, Thank you very much for your comments on our paper. I am so happy to receive your positive comments. The paper will be revised soon according to your suggestions. The journal, ScienceOpen, has a new style of revising system, and it is very challenging. We hope this journal should be sucsess. Best wishes, Norio .
            2015-03-09 13:46 UTC
            Dear Professor Luke Hunter, Thank you very much for your positive comments on our manuscript. I had been waiting for a very long time to get the first comment, since submission. This reviewing system should be improved to get success of ScienceOpen. The present our manuscript will be revised soon, based on your comments. Thank you very much once again for your support on our paper. Best wishes, Norio
            2015-03-07 23:12 UTC
            +1

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