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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) [3940, 41], 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 useless 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].

            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].

            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].

            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].

            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].

            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]. 13C NMR is to complicated to analyze.

            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].

            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].

            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 2.35 (s, 3H), 5.92 (t, J = 55.8 Hz, 1H), 6.40 (s, 1H), 6.61 (dd, J = 295.2 Hz, 15.6 Hz, 2H), 7.14–7.70 (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].

            5-(difluoromethyl)-3-methyl-5-(2-(naphthalen-1-yl)vinyl)-4-nitro-4,5-dihydroisoxazole (4c): Following the general procedure, 4e 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) 315 [M-H]

            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].

            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].

            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].

            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].

            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]+.

            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.

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            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.

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            Contributors
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            ScienceOpen Research
            ScienceOpen
            2199-1006
            18 December 2014
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            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
            2276:XE
            10.14293/S2199-1006.1.SOR-CHEM.AD1QVW.v1
            381e3013-939e-4fd2-8af1-6ea99ba6d8a9
            © 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 .

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