Supporting Information of Cu(I)-Catalyzed Three-Component Reaction of Diazo Compound with Terminal Alkyne and Nitrosobenzene for the Synthesis of Trifluoromethyl Dihydroisoxazoles Xinxin Lv, Zhenghui Kang, Dong Xing *, *, and Wenhao Hu, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China E-mail: dxing@sat.ecnu.edu.cn; huwh9@mail.sysu.edu.cn Table of contents 1. General Information & Materials S2 2. Experimental Procedures S2-S8 3. X-ray Diffraction Parameters and Data of 4n S9 4. Characterization Data of the Products S10-S16 5. Notes and References S16 6. 1 H, 13 C and 19 F NMR Spectra of the Products S17-S44 S1
1. General Information & Materials All 1 H NMR (400 MHz) and 13 C NMR (100 MHz) and 19 F NMR (376 MHz) spectra were recorded on Brucker spectrometers in CDCl3. Tetramethylsilane (TMS) served as an internal standard (δ = 0) for 1 H NMR, and CDCl3 was used as internal standard (δ = 77.0) for 13 C NMR. Chemical shifts are reported in parts per million as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). High-resolution mass spectrometry (HRMS) was performed on IonSpec FT-ICR or Waters Micromass Q-TOF micro Synapt High Definition Mass Spectrometer. Single crystal X-ray diffraction data were recorded on Bruker-AXS SMART APEX II single crystal X-ray diffractometer. HPLC analysis was performed on Dalian Elite (UV230+ UV/Vis Detector and P230P High Pressure Pump). Chiralpak IA was purchased from Daicel Chemical Industries, LTD. Yields for all compounds were combined yields for all isomers unless otherwise indicated. Chemical shifts of 19 F NMR are reported as parts per million in δ scale using benzotrifluoride (-63.72 ppm) as internal standard. Nitrosoarenes, 1 Diazo compounds 2 were prepared according to the literature methods. All solvents and reagents were purchased from Sinopharm Chemical Reagent Co., Ltd, and directly used without any purification. All reactions were carried out under nitrogen atmosphere. 2. Experimental Procedures General procedure for the Cu(I)-catalyzed three-component reaction of diazo compounds with terminal alkynes and nitrosobenzenes Under a nitrogen atmosphere, to the solution of CuI (0.04 mmol), phenylacetylene (0.60 mmol) and nitrosobenzene (0.40 mmol) in acetonitrile (2 ml) was added the solution S2
of diazo compound (0.60 mmol) in acetonitrile (2 ml) via a syringe pump over 2 h at room temperature. After completion of the addition, the resultant solution was stirred overnight. The solvent was removed and the crude residue was purified by flash chromatography on silica gel (eluent: EtOAc/light petroleum ether =1/100~1/50) to afford pure products. Experimental procedure for a 2 mmol-scale reaction of 3a Under a nitrogen atmosphere, to the solution of CuI (0.2 mmol, 0.1 eq), phenylacetylene (3.0 mmol, 1.5 eq) and nitrosobenzene (2.0 mmol, 1.0 eq) in acetonitrile (5 ml) was added the solution of diazo compound (3.0 mmol) in acetonitrile (5 ml) via a syringe pump over 5 h at room temperature. After completion of the addition, the resultant solution was stirred 16 h. The solvent was removed and the crude residue was purified by flash chromatography on silica gel (eluent: EtOAc/light petroleum ether =1/100~1/80) to afford pure product (4a: 649 mg). Experimental procedure for the control experiment of phenylacetylene 1a and nitrone 5: Under a nitrogen atmosphere, to the solution of nitrosobenzene 3a (0.60 mmol, 1.0 equiv) in MeCN (2.0 ml) was added the solution of diazo compound 2a (0.60 mmol, 1.5 equiv) in MeCN (2.0 ml) for 2h via a syringe pump at room temperature. After S3
completion of the addition, the resultant solution was stirred for an additional 2 h. The solvent was removed and the crude residue was purified by flash chromatography on silica gel (eluent: EtOAc/light petroleum ether =1/20~1/10) to afford nitrone 5. Under a nitrogen atmosphere, to the solution of CuI (0.02 mmol, 0.1 equiv), phenylacetylene 1a (0.30 mmol, 1.5 equiv) in MeCN (1 ml) was added a solution of 5 (0.20 mmol, 1.0 equiv) in MeCN (1 ml). After completion of the addition, the resultant solution was stirred overnight. Crude 1 H NMR indicated that 5 was unreacted and no 4a formation was observed. Experimental procedure for the control experiment of trifluoromethyl allene 6 and nitrosobenzene 3a: Under a nitrogen atmosphere, to the solution of phenylacetylene 1a (0.60 mmol) in MeCN (2.0 ml) was added the solution of diazo compound 2a (0.60 mmol) in MeCN (2.0 ml) for 2 h via a syringe pump at room temperature. After completion of the addition, the resultant solution was stirred for an additional 2 h. The solvent was removed and the crude residue was purified by flash chromatography on silica gel (eluent: petroleum ether) to afford trifluoromethyl allene 6. Under a nitrogen atmosphere, to the solution of CuI (0.02 mmol, 0.1 equiv), nitrosobenzene 3a (0.20 mmol, 1.5 equiv) in MeCN (1 ml) was added a solution of trifluoromethyl allene 6 (0.30 mmol, 1.0 equiv) in MeCN (1 ml). After completion of the addition, the resultant solution was stirred overnight. Crude 1 H NMR indicated that 6 was unreacted and no 4a formation was observed. Experimental procedure for the control experiment of the trifluoromethyl S4
phenylacetylene 7 and nitrosobenzene 3a: Trifluoromethyl phenylacetylene 7 was prepared according to literature methods. 3 Under a nitrogen atmosphere, to the solution of CuI (0.02 mmol, 0.1 equiv) and nitrosobenzene 3a (0.20 mmol, 1.0 equiv) in MeCN (1 ml) was added the solution of trifluoromethyl phenylacetylene 7 (0.30 mmol, 1.5 equiv) in MeCN (1 ml) for 1 h via a syringe pump at room temperature. After completion of the addition, the resultant solution was stirred overnight. Crude 1 H NMR indicated that 7 was unreacted and no 4a formation was observed. Experimental procedure for the reactions starting from copper acetylide 8: Entry 1: Under a nitrogen atmosphere, to the solution of copper acetylide 8 (0.30 mmol, 1.5 equiv) and nitrosobenzene 3a (0.20 mmol, 1.0 equiv) in acetonitrile (1 ml) was added the solution of diazo compound 2a (0.30 mmol, 1.5 equiv) in acetonitrile (1 ml) for 1 h via a syringe pump at room temperature. After completion of the addition, the resultant solution was stirred overnight and subjected to 1 H NMR for analysis. Entry 2: Under a nitrogen atmosphere, to the solution of CuI (0.02 mmol, 0.1 equiv), copper acetylide 8 (0.30 mmol, 1.5 equiv) and nitrosobenzene 3a (0.20 mmol, 1.0 equiv) in acetonitrile (1 ml) was added the solution of diazo compound 2a (0.30 mmol, 1.5 equiv) in acetonitrile (1 ml) for 1 h via a syringe pump at room temperature. After completion of the addition, the resultant solution was stirred overnight. The solvent was removed S5
and the crude residue was purified by flash chromatography on silica gel (eluent: EtOAc/light petroleum ether =1/100~1/50) to afford pure product 4a. Entry 3: Under a nitrogen atmosphere, to the solution of NaI (0.02 mmol, 0.1 equiv), copper acetylide 8 (0.30 mmol, 1.5 equiv) and nitrosobenzene 3a (0.20 mmol, 1.0 equiv) in acetonitrile (1 ml) was added the solution of diazo compound 2a (0.30 mmol, 1.5 equiv) in acetonitrile (1 ml) for 1 h via a syringe pump at room temperature. After completion of the addition, the resultant solution was stirred overnight. The solvent was removed and the crude residue was purified by flash chromatography on silica gel (eluent: EtOAc/light petroleum ether =1/100~1/50) to afford pure product 4a. Experimental procedure for the deuterium-labeling studies of 1f, 2a, 3a and D2O Under a nitrogen atmosphere, to the solution of CuI (0.04 mmol, 0.1 equiv), phenylacetylene 1f (0.60 mmol, 1.5 equiv), nitrosobenzene 3a (0.40 mmol, 1.0 equiv) and D2O (4 mmol, 10.0 equiv) in SuperDry MeCN 4 (2.0 ml) was added the solution of diazo compound 3a (0.60 mmol, 1.5 equiv) in SuperDry MeCN (2.0 ml) for 2 h via a syringe pump at room temperature. After completion of the addition, the resultant solution was stirred overnight. The solvent was removed and the crude residue was subjected to 1 H NMR analysis to calculate the H/D ratio. The crude residue was then subjected to column chromatography to afford the pure product. Experimental procedure for the deuterium-labeling studies of 1f and D2O S6
Under a nitrogen atmosphere, the solution of CuI (0.02 mmol, 0.1 equiv), phenylacetylene 1f (0.20 mmol, 1.0 equiv) and D2O (2 mmol, 10.0 equiv) in SuperDry MeCN (2.0 ml) was stirred at room temperature overnight. The solvent was removed and the crude residue was subjected to 1 H NMR analysis to calculate the H/D ratio. Experimental procedure for the deuterium-labeling studies of 4f and D2O Under a nitrogen atmosphere, the solution of CuI (0.02 mmol, 0.1 equiv), product 4f (0.20 mmol, 1.0 equiv) and D2O (2 mmol, 10.0 equiv) in SuperDry MeCN (2.0 ml) was stirred at room temperature overnight. The solvent was removed and the crude residue was subjected to 1 H NMR analysis to calculate the H/D ratio. Scheme S1: Results with Different Diazo Compounds. S7
Scheme S2: Catalytic Asymmetric Attempts for this Transformation Scheme S3: Failed Examples with Heteroaromatic Substituted Substrates S8
3. X-ray diffraction parameters and data of 4n S9
4. Characterization Data of the Products 2,3,5-triphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4a) Yield: 90% (133 mg). White solid, m.p. 113.1 113.8 C; 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.1 Hz, 2H), 7.46 7.41 (m, 2H), 7.39 7.31 (m, 3H), 7.28 7.14 (m, 8H), 5.79 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 150.11 (s), 146.09 (s), 137.46 (s), 129.56 (s), 129.16 (s), 128.90 (s), 128.70 (s), 128.64 (s), 128.46 (s), 128.07 (s), 127.33 (s), 126.26 (d, J = 0.5 Hz), 126.08 (s), 124.01 (q, J = 286.0 Hz), 101.52 (s), 90.71 (q, J = 31.2 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.84 (s); HRMS (ESI) calcd for C22H17F3NO [M + H] + = 368.1262, found 368.1269 3-(3-bromophenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4b) Yield: 73% (131 mg). White solid, m.p. 93.9 95.2 C; 1 H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.50 (d, J = 6.8 Hz, 2H), 7.42 7.27 (m, 5H), 7.27 7.14 (m, 5H), 7.06 (t, J = 7.9 Hz, 1H), 5.81 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 148.90 (s), 145.69 (s), 137.19 (s), 132.61 (s), 131.18 (s), 130.26 (s), 130.15 (s), 129.10 (s), 128.87 (s), 128.58 (s), 128.46 (s), 126.24 (s), 126.18 (s), 125.99 (s), 123.97 (q, J = 286.0 Hz), 122.71 (s), 102.69 (s), 90.82 (q, J = 31.4 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.76 (s); HRMS (ESI) calcd for C22H16BrF3NO [M + H] + = 446.0367, found 446.0389 3-(4-chlorophenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4c) Yield: 87% (139 mg). White solid, m.p. 141.8 142.4 C; 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 6.6 Hz, 2H), 7.41 7.31 (m, 5H), 7.29 7.18 (m, 7H), 5.80 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 149.08 (s), 145.73 (s), 137.23 (s), 135.48 (s), 129.02 (s), 128.95 (s), 128.79 (s), 128.58 (s), 128.51 (s), 128.37 (s), 127.58 (s), 126.18 (d, J = 2.0 Hz), 123.91 (q, J = 286.0 Hz), 101.93 (s), 90.79 (q, J = 31.4 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.90 (s); HRMS (ESI) calcd for C22H16ClF3NO [M + H] + = 402.0873, found S10
402.0869 3-(4-bromophenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4d) Yield: 69% (123 mg). White solid, m.p. 130.9 131.5 C; 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 6.5 Hz, 2H), 7.36 (t, J = 7.0 Hz, 5H), 7.31 7.10 (m, 7H), 5.80 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 149.18 (s), 145.74 (s), 137.23 (s), 131.92 (s), 129.06 (s), 128.82 (s), 128.54 (s), 128.41 (s), 128.05 (s), 126.19 (s), 123.93 (q, J = 286.0 Hz), 123.78 (s), 102.03 (s), 90.83 (q, J = 31.2 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.81 (s); HRMS (ESI) calcd for C22H16BrF3NO [M + H] + = 446.0367, found 446.0362 2,5-diphenyl-3-(p-tolyl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4e) Yield: 94% (144 mg). White solid, m.p. 119.3 120.0 C; 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 6.8 Hz, 2H), 7.35 7.22 (m, 7H), 7.20 7.10 (m, 3H), 7.01 (d, J = 7.7 Hz, 2H), 5.75 (s, 1H), 2.22 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 150.17 (s), 146.34 (s), 139.79 (s), 137.65 (s), 129.41 (s), 128.94 (s), 128.73 (s), 128.51 (s), 128.08 (s), 127.29 (s), 126.34 (s), 126.16 (s), 124.17 (q, J = 286.1 Hz), 100.83 (s), 90.77 (q, J = 31.2 Hz), 21.34 (s); 19 F NMR (376 MHz, CDCl3) δ -77.76 (s); HRMS (ESI) calcd for C23H19F3NO [M + H] + = 382.1419, found 382.1405 3-(4-methoxyphenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4f) Yield: 96% (153 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 6.8 Hz, 2H), 7.42 7.28 (m, 5H), 7.26 7.14 (m, 5H), 6.91 6.66 (m, 2H), 5.70 (s, 1H), 3.72 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 160.46 (s), 149.65 (s), 146.29 (s), 137.63 (s), 128.87 (s), 128.75 (s), 128.64 (s), 128.42 (s), 128.01 (s), 126.26 (d, J = 0.8 Hz), 126.11 (s), 124.05 (q, J = 286.0 Hz), 121.53 (s), 114.03 (s), 99.93 (s), 90.69 (q, J = 31.1 Hz), 55.24 (s); 19 F NMR (376 MHz, CDCl3) δ -77.92 (s); HRMS S11
(ESI) calcd for C23H19F3NO2 [M + H] + = 398.1368, found 398.1365 5-([1,1'-biphenyl]-4-yl)-2,3-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4g) Yield: 84% (149 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 9.3 Hz, 6H), 7.49 7.38 (m, 4H), 7.31 (dd, J = 24.5, 5.3 Hz, 3H), 7.20 (dd, J = 17.2, 11.7 Hz, 6H), 5.81 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 150.24 (s), 146.14 (s), 141.64 (s), 140.46 (s), 136.43 (s), 129.64 (s), 129.19 (s), 128.99 (s), 128.90 (s), 128.70 (s), 128.18 (s), 127.66 (s), 127.39 (s), 127.27 (s), 127.22 (s), 126.77 (s), 126.18 (s), 124.11 (q, J = 286.7 Hz), 101.48 (s), 90.73 (q, J = 31.8 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.70 (d, J = 10.7 Hz); HRMS (ESI) calcd for C28H21F3NO [M + H] + = 444.1575, found 444.1550 5-(4-bromophenyl)-2,3-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4h) Yield: 54% (97 mg). White solid, m.p. 125.1 126.2 C; 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.3 Hz, 2H), 7.44 7.33 (m, 4H), 7.20 (dd, J = 17.6, 9.5 Hz, 8H), 5.74 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 150.50 (s), 145.91 (s), 136.65 (s), 131.71 (s), 129.76 (s), 129.04 (s), 128.94 (s), 128.73 (s), 128.34 (s), 128.07 (s), 127.36 (s), 126.15 (s), 123.81 (q, J = 284.2 Hz), 123.14 (s), 90.44 (q, J = 31.5 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.85 (s); HRMS (ESI) calcd for C22H16BrF3NO [M + H] + = 446.0367, found 446.0374 2-(3,5-diphenyl-5-(trifluoromethyl)isoxazol-2(5H)-yl)benzonitrile (4i) Yield: 76% (120 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 7.1 Hz, 2H), 7.49 7.41 (m, 2H), 7.40 7.32 (m, 3H), 7.31 7.19 (m, 5H), 7.03 (d, J = 7.6 Hz, 1H), 5.89 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 148.75 (s), 148.28 (s), 136.67 (s), 133.69 (s), 133.25 (s), 130.10 (s), 128.97 (s), 128.95 (s), 128.63 (s), 128.39 S12
(s), 127.17 (s), 126.19 (s), 125.72 (s), 123.57 (q, J = 285.9 Hz), 116.66 (s), 112.70 (s), 103.50 (s), 91.03 (q, J = 31.5 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.78 (s); HRMS (ESI) calcd for C23H16F3N2O [M + H] + = 415.1034, found 415.1024 3,5-diphenyl-2-(m-tolyl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4j) Yield: 94% (144 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.2 Hz, 2H), 7.45 7.39 (m, 2H), 7.37 7.28 (m, 3H), 7.20 (dd, J = 6.5, 3.5 Hz, 3H), 7.13 (s, 1H), 7.00 (ddd, J = 20.2, 16.8, 7.4 Hz, 3H), 5.77 (s, 1H), 2.18 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 150.27 (s), 146.05 (s), 138.94 (s), 137.66 (s), 129.59 (s), 129.27 (s), 129.12 (s), 128.76 (s), 128.70 (d, J = 1.2 Hz), 128.53 (s), 127.38 (s), 127.23 (s), 126.37 (s), 124.20 (q, J = 286.1 Hz), 123.10 (s), 101.43 (s), 90.77 (q, J = 31.2 Hz); 19 F NMR (376 MHz, CDCl3) δ -77.67 (s); HRMS (ESI) calcd for C23H19F3NO [M + H] + = 382.1419, found 382.1410 3,5-diphenyl-2-(p-tolyl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4k) Yield: 88% (134 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.2 Hz, 2H), 7.45 7.39 (m, 2H), 7.38 7.30 (m, 3H), 7.26 7.20 (m, 3H), 7.15 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 5.77 (s, 1H), 2.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 150.35 (s), 143.50 (s), 138.37 (s), 137.67 (s), 129.61 (s), 129.48 (s), 129.22 (s), 128.67 (s), 128.60 (s), 128.47 (s), 127.35 (s), 126.38 (s), 126.28 (d, J = 0.8 Hz), 124.11 (q, J = 286.1 Hz), 101.19 (s), 90.60 (q, J = 31.2 Hz), 21.14 (s); 19 F NMR (376 MHz, CDCl3) δ -77.83 (s); HRMS (ESI) calcd for C23H19F3NO [M + H] + = 382.1419, found 382.1427 methyl 4-(3,5-diphenyl-5-(trifluoromethyl)isoxazol-2(5H)-yl)benzoate (4l) S13
Yield: 88% (150 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 7.1 Hz, 2H), 7.48 7.42 (m, 2H), 7.35 (dt, J = 15.1, 5.1 Hz, 3H), 7.30 7.24 (m, 3H), 7.20 (d, J = 8.7 Hz, 2H), 5.84 (s, 1H), 3.80 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 166.38 (s), 150.34 (s), 149.13 (s), 136.74 (s), 130.36 (s), 129.99 (s), 129.14 (s), 128.96 (s), 128.92 (s), 128.59 (s), 128.15 (s), 127.28 (s), 126.28 (s), 123.84 (q, 286.0 Hz), 123.53 (s), 102.70 (s), 90.89 (q, J = 31.4 Hz), 52.07 (s); 19 F NMR (376 MHz, CDCl3) δ -77.89 (s); HRMS (ESI) calcd for C24H19F3NO3 [M + Na] + = 448.1136, found 448.1123 1-(4-(3,5-diphenyl-5-(trifluoromethyl)isoxazol-2(5H)-yl)phenyl)ethan-1-one (4m) Yield: 91% (149 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.49 7.42 (m, 2H), 7.39 7.25 (m, 6H), 7.20 (d, J = 8.6 Hz, 2H), 5.84 (s, 1H), 2.46 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.98 (s), 150.38 (s), 148.98 (s), 136.63 (s), 134.88 (s), 130.04 (s), 129.15 (s), 128.99 (s), 128.96 (s), 128.60 (s), 127.27 (s), 126.29 (s), 123.80 (q, J = 286.1 Hz), 123.32 (s), 102.79 (s), 90.84 (q, J = 31.4 Hz), 26.47 (s); 19 F NMR (376 MHz, CDCl3) δ -77.91 (s); HRMS (ESI) calcd for C24H19F3NO2 [M + H] + = 410.1368, found 410.1364 2-(4-nitrophenyl)-3,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4n) Yield: 47% (78 mg). Yellow solid, m.p. 123.0 124.4 C; 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 9.1 Hz, 2H), 7.53 (d, J = 6.9 Hz, 2H), 7.48 (dd, J = 7.6, 1.6 Hz, 2H), 7.44 7.31 (m, 6H), 7.17 (d, J = 9.1 Hz, 2H), 5.85 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 151.71 (s), 148.10 (s), 144.59 (s), 135.88 (s), 130.43 (s), 129.20 (s), 128.96 (s), 128.68 (s), 127.26 (s), 126.27 (d, J = 0.8 Hz), 124.47 (s), 123.51 (q, J = 286.1 Hz), 121.67 (s), 103.82 (s), 90.81 (q, J = 31.6 Hz); 19 F NMR (376 MHz, CDCl3) δ -78.09 (s); HRMS (ESI) calcd for C22H16F3N2O3 [M + H] + = 413.1113, found 413.1101 S14
2,5-diphenyl-3-(thiophen-2-yl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4o) Yield: 73% (109 mg). Colourless oil; 1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 6.9 Hz, 2H), 7.41 7.25 (m, 8H), 7.21 (dd, J = 5.0, 1.0 Hz, 1H), 6.98 (dd, J = 3.7, 1.0 Hz, 1H), 6.86 (dd, J = 5.0, 3.7 Hz, 1H), 5.79 (s, 1H); 13 C NMR (126 MHz, CDCl3) δ 146.05 (s), 144.37 (s), 137.26 (s), 130.41 (s), 129.01 (s), 128.82 (s), 128.78 (s), 128.48 (s), 127.87 (s), 127.49 (s), 127.14 (s), 126.78 (s), 126.26 (s), 123.95 (dd, J = 572.1, 286.0 Hz), 100.94 (s), 90.82 (q, J = 31.4 Hz); 19 F NMR (471 MHz, CDCl3) δ -77.78 (s); HRMS (ESI) calcd for C20H14F3NOS [M + H] + = 373.3932, found 373.3928 2,2,2-trifluoro-N,1-diphenylethan-1-imine oxide (5) Yield: 78% (83 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.35 7.26 (m, 4H), 7.26 7.21 (m, 3H), 7.17 (d, J = 7.2 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 130.62 (s), 130.00 (s), 128.96 (dd, J = 68.4, 24.5 Hz), 128.89 (s), 128.62 (s), 124.10 (s); 19 F NMR (376 MHz, CDCl3) δ -65.08 (s); HRMS (ESI) calcd for C14H10F3NO [M + H] + = 266.0793, found 266.0792. (4,4,4-trifluorobuta-1,2-diene-1,3-diyl)dibenzene (6) 5 Yield: 81% (84 mg). Colourless oil; 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.5 Hz, 2H), 7.40 7.28 (m, 8H), 6.91 (d, J = 2.5 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 207.03 (s), 131.03 (s), 129.39 (s), 129.12 (s), 128.89 (s), 128.73 (s), 128.56 (s), 127.65 (s), 127.13 (d, J = 0.9 Hz), 124.54 (t, J = 274.9 Hz), 105.68 (q, J = 34.4 Hz), 102.80 (s); 19 F NMR (376 MHz, CDCl3) δ -60.03 (d, J = 1.5 Hz). (4,4,4-trifluorobut-1-yne-1,3-diyl)dibenzene (7) 3b Yield: 57% (59 mg). White solid; 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 6.9 Hz, 1H), 7.57 (dd, J = 13.3, 7.7 Hz, 3H), 7.44 (dt, J = 14.6, 6.8 Hz, 4H), 7.33 (t, J = 7.0 Hz, 1H), 6.41 (s, 1H), 4.24 (dd, J = 17.6, 8.6 Hz, 1H); 13 C S15
NMR (100 MHz, CDCl3) δ 149.38 (s), 144.19 (s), 138.74 (s), 134.59 (s), 128.76 (s), 128.50 (d, J = 8.9 Hz), 127.78 (s), 126.37 (s), 124.78 (d, J = 14.6 Hz), 121.22 (s), 52.69 (q, J = 29.6 Hz); 19 F NMR (376 MHz, CDCl3) δ -67.22 (d, J = 5.2 Hz). 5. Notes and References 1. Priewisch, B.; Rück-Braun, K. J. Org. Chem. 2005, 70, 2350. 2. Emer, E.; Twilton, J.; Tredwell, M.; Calderwood, S.; Collier, T. L.; Liégault, B.; Taillefer, M.; Gouverneur, V. Org. Lett. 2014, 16, 6004. 3. (a) Ko, S-J.; Lim, J.; Jeon, N.; Won, K.; Ha, D-C.; Kim, B.; Lee, H. Tetrahedron Asymmetry, 2009, 20, 1109. (b) Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang J. Org. Lett. 2015, 17, 2474. 4. SuperDry MeCN: Acetonitrile 99.9%, Extra dry with molecular sieves, Water < 50ppm, in resealable bottle, Energy Chemical. 5. Chu, W-D.; Zhang, L.; Zhang, Z.; Zhou, Q.; Mo, F.; Zhang, Yan.; Wang, J. J. Am. Chem. Soc. 2016, 138, 14558. S16
6. NMR spectra of the Products 2,3,5-triphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4a) 1 H NMR spectrum of (4a) 13 C NMR spectrum of (4a) S17
19 F NMR spectrum of (4a) 3-(3-bromophenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4b) 1 H NMR spectrum of (4b) 13 C NMR spectrum of (4b) S18
19 F NMR spectrum of (4b) 3-(4-chlorophenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4c) 1 H NMR spectrum of (4c) S19
13 C NMR spectrum of (4c) 19 F NMR spectrum of (4c) S20
3-(4-bromophenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4d) 1 H NMR spectrum of (4d) 13 C NMR spectrum of (4d) S21
19 F NMR spectrum of (4d) 2,5-diphenyl-3-(p-tolyl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4e) 1 H NMR spectrum of (4e) S22
13 C NMR spectrum of (4e) 19 F NMR spectrum of (4e) S23
3-(4-methoxyphenyl)-2,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4f) 1 H NMR spectrum of (4f) 13 C NMR spectrum of (4f) S24
19 F NMR spectrum of (4f) 5-([1,1'-biphenyl]-4-yl)-2,3-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4g) 1 H NMR spectrum of (4g) S25
13 C NMR spectrum of (4g) 19 F NMR spectrum of (4g) S26
5-(4-bromophenyl)-2,3-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4h) 1 H NMR spectrum of (4h) 13 C NMR spectrum of (4h) S27
19 F NMR spectrum of (4h) 2-(3,5-diphenyl-5-(trifluoromethyl)isoxazol-2(5H)-yl)benzonitrile (4i) 1 H NMR spectrum of (4i) S28
13 C NMR spectrum of (4i) 19 F NMR spectrum of (4i) S29
3,5-diphenyl-2-(m-tolyl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4j) 1 H NMR spectrum of (4j) 13 C NMR spectrum of (4j) S30
19 F NMR spectrum of (4j) 3,5-diphenyl-2-(p-tolyl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4k) 1 H NMR spectrum of (4k) S31
13 C NMR spectrum of (4k) 19 F NMR spectrum of (4k) S32
methyl 4-(3,5-diphenyl-5-(trifluoromethyl)isoxazol-2(5H)-yl)benzoate (4l) 1 H NMR spectrum of (4l) 13 C NMR spectrum of (4l) S33
19 F NMR spectrum of (4l) 1-(4-(3,5-diphenyl-5-(trifluoromethyl)isoxazol-2(5H)-yl)phenyl)ethan-1-one (4m) 1 H NMR spectrum of (4m) S34
13 C NMR spectrum of (4m) 19 F NMR spectrum of (4m) S35
2-(4-nitrophenyl)-3,5-diphenyl-5-(trifluoromethyl)-2,5-dihydroisoxazole (4n) 1 H NMR spectrum of (4n) 13 C NMR spectrum of (4n) S36
19 F NMR spectrum of (4n) 2,5-diphenyl-3-(thiophen-2-yl)-5-(trifluoromethyl)-2,5-dihydroisoxazole (4o) 1 H NMR spectrum of (4o) S37
13 C NMR spectrum of (4o) 19 F NMR spectrum of (4o) S38
2,2,2-trifluoro-N,1-diphenylethan-1-imine oxide (5) 1 H NMR spectrum of (5) 13 C NMR spectrum of (5) S39
19 F NMR spectrum of (6) (4,4,4-trifluorobuta-1,2-diene-1,3-diyl)dibenzene (6) 1 H NMR spectrum of (6) S40
13 C NMR spectrum of (6) 19 F NMR spectrum of (6) S41
(4,4,4-trifluorobut-1-yne-1,3-diyl)dibenzene (7) 1 H NMR spectrum of (7) 13 C NMR spectrum of (7) S42
19 F NMR spectrum of (7) S43
S44