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

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 [1–4]. Man-made 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].

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).

Figure 1.

BRAVECTO^TM, 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 [44–47]; 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 [39–41]. 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.

Entry	Base	Additiveb	Solvent	Yield (%)a
1	NaOAc	[CH3(CH2)15N(CH3)3]Br (30 mol%)	DMF	24
2	KOAc	–	DMSO	NRb
3	tBuOK	–	DMF	NRb
4	KOAc	–	DMF	NRb
5	KOH	–	DMF	NRb
6	KOAc	18-crown-6 (1.5 equiv)	DMF	22
7	KF	18-crown-6 (1.5 equiv)	DMF	33
8	Me4NF	–	DMF	53
9c	Me4NF	–	DMF	52
10	Et4NF·H2O	–	DMF	traceb
11	nBu4NF·H2O	–	DMF	traceb
12	Me4NF	[CH3(CH2)15N(CH3)3]Br (30 mol%)	DMF	52
13	Me4NF	–	THF	traceb
14	Me4NF	–	NMP	NRb
15	Me4NF	–	DMSO	traceb
16	Me4NF	–	DMA	11
17	Me4NF	–	DMI	NRb

^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, 2a–2e). 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 [50–66]. Generally, 4-nitro-5-styrylisoxazoles 5 have two electrophilic centres, both of which can be attacked by nucleophiles [50–66]. 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 (4a–4e). Moderate yields were obtained when R¹ was an electron-rich aromatic ring or a non-substrate benzene ring (4a–4c). 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.

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Competing Interests

The authors declare no competing interests.

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