Palladium Catalyzed Iodofluorination of Alkenes using Fluoro-Iodoxole Reagent

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1 Supporting Information Palladium Catalyzed Iodofluorination of Alkenes using Fluoro-Iodoxole Reagent Nadia O. Ilchenko, Miguel A. Cortés and Kálmán J. Szabó* Stockholm University, Arrhenius Laboratory, Department of Organic Chemistry SE Stockholm, Sweden. Fax: Contents: General information Experimental Procedure and Spectral Data References S1 S1-S7 S8 1 H, 13 C and 19 F NMR spectra S9-S59 S1

2 General information Hypervalent iodine reagent 1 1 and α-methyl styrene 2m-n 2 were prepared according to literature procedures. All other chemicals were obtained from commercial sources and used as received. 1 H NMR, 13 C NMR and 19 F NMR spectra were recorded in CDCl 3 (internal standard 7.26 ppm, 1 H; 77.2 ppm, 13 C) using 400 MHz spectrometers. NMR yields were calculated using trifluorotoluene as an internal standard. For column chromatography, silica gel (35-70 microns) was used. Unless otherwise stated, all the reactions were performed under Argon atmosphere. We were not able to obtain high-resolution mass data for products 3a-q probably because of the easy cleavage of the carbon-iodine bond. Therefore, we provide EI mass data in the characterization. Experimental Procedures and Spectral Data General procedure for iodofluorination of alkenes Fluoroiodane reagent 1 (28.0 mg, 0.1 mmol), the corresponding alkene 2a-p (0.1 mmol) and palladium catalyst (4a-c) (0.020 mmol) were mixed in CDCl 3 (0.5 ml). This mixture was stirred at 40 o C for 18 h, unless otherwise stated. The products were isolated by silica gel column chromatography. (2-Fluoro-3-iodopropyl)benzene (3a) This product was prepared according to the above general procedure using Pd(MeCN) 4 (BF 4 ) 2 (4a) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (20 mg, 76%). The NMR data obtained for 3a are in agreement with literature values. 3 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 5H), (m, 1H), (m, 2H), 3.09 (dd, J HF = 20.9, J = 6.0 Hz, 2H). 13 C-NMR (100 MHz, CDCl 3 ) δ (d, J CF = 5.3 Hz), 129.4, 128.7, 127.1, 92.1 (d, J CF = Hz), 40.7 (d, J CF = 21.0 Hz), 6.3 (d, J CF = 24.3 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 264 (M+, 100), 137 (7), 117 (50), 91 (42), 65 (9). anti-(1-fluoro-2-iodopropyl)benzene (3b) S2

3 This product was prepared according to the above general procedure using PdCl 2 (MeCN) 2 (4c) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (24 mg, 77%). The NMR data obtained for 3b are in agreement with literature values. 4 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 5H), 5.52 (dd, J = 46.4, 6.0 Hz, 1H), (m, 1H), 1.91 (dd, J = 7.0, 0.8 Hz, 3H). 13 C-NMR (100 MHz, CDCl 3 ) δ 137.3, (d, J CF = 1.8 Hz), 128.6, (d, J CF = 6.8 Hz), 97.5 (d, J CF = Hz), 27.3 (d, J CF = 26.1 Hz), 22.7 (d, J CF = 4.3 Hz). 19 F- NMR (377 MHz, CDCl 3 ) δ (dd, J HF = 46.3, 17.3 Hz). (EI) m/z (rel intens) 137 (M-I, 100), 118 (10), 117 (71), 115 (79), 109 (42). anti-(1-fluoro-2-iodobutyl)benzene (3c) This product was prepared according to the above general procedure using Pd(MeCN) 4 (BF 4 ) 2 (4a) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (20 mg, 76%). 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 5H), 5.58 (dd, J = 46.5, 7.0 Hz, 1H), (m, 1H), (m, 2H), 1.08 (t, J = 7.2 Hz, 3H). 13 C-NMR (100 MHz, CDCl 3 ) δ (d, J CF = 20.6 Hz), (d, J CF = 2.0 Hz), 128.3, (d, J CF = 6.3 Hz), 96.3 (d, J CF = Hz), 39.9 (d, J CF = 25.1 Hz), 27.4 (d, J CF = 3.8 Hz), F-NMR (377 MHz, CDCl 3 ) δ (dd, J HF = 46.6, 14.9 Hz). (EI) m/z (rel intens) 151 (M-I, 30), 131 (15), 122 (16), 109 (67), 91 (100). (3-Fluoro-4-iodobutyl)benzene (3d) This product was prepared according to the above general procedure using Pd(OAc) 2 (4b) as catalyst at 50 o C. The compound was isolated as a colorless oil using pentane:dichloromethane 20:1 as eluent system (17 mg, 58%). 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 3H), (m, 1H), (m, 2H), (m, 2H), (m, 2H). 13 C-NMR (100 MHz, CDCl 3 ) δ 140.6, (d, J CF = 13.4 Hz), 126.2, 91.2 (d, J CF = Hz), 36.6 (d, J CF = 20.7 Hz), 30.9 (d, J CF = 3.9 Hz), 6.7 (d, J CF = 24.5 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 278 (M+, 7), 132 (11), 131 (100), 92 (11), 91 (84). 1-(2-Fluoro-3-iodopropyl)-4-methoxybenzene (3e) This product was prepared according to the above general procedure S3

4 using Pd(OAc) 2 (4b) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (23 mg, 78%). 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 1H), 3.80 (s, 3H), (m, 2H), 3.03 (dd, J HF = 20.8, J = 6.0 Hz, 2H). 13 C-NMR (100 MHz, CDCl 3 ) δ 158.7, 130.4, 114.1, 92.3 (d, J CF = Hz), 55.3, 39.8 (d, J CF = 21.2 Hz), 6.3 (d, J CF = 24.3 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 294 (M+, 31), 148 (1), 122 (9), 121 (100), 77 (9). 1-(2-Fluoro-3-iodopropyl)-2-methoxybenzene (3f) This product was prepared according to the above general procedure using Pd(OAc) 2 (4b) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (16 mg, 53%). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), 6.91 (m, 1H), 6.87 (m, 1H), 4.70 (m, 1H), 3.83 (s, 3H), (m, 2H), 3.07 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 157.4, 131.4, 128.5, 124.0, 120.6, 110.3, 90.9 (d, J CF = Hz), 55.3, 36.1 (d, J CF = 22.2 Hz), 7.6 (d, J CF = 23.4 Hz). 19 F NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 294 (M+, 68), 167 (5), 148 (2), 121 (100), 91 (65). 4-(2-Fluoro-3-iodopropyl)-1,2-dimethoxybenzene (3g) This product was prepared according to the above general procedure using Pd(OAc) 2 (4b) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (21 mg, 64%). The NMR data obtained for 3g are in agreement with literature values. 5 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 3H), 4.63 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), (m, 2H), 3.03 (m, 2H). 13 C- NMR (100 MHz, CDCl 3 ) δ 148.9, 148.1, 127.9, 121.5, 112.6, 111.3, 92.2 (d, J CF = Hz), 55.91, 55.89, 40.2 (d, J CF = 21.0 Hz), 6.3 (d, J CF = 24.4 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 324 (M+, 44), 197 (5), 177 (4), 152 (11), 151 (100). 1-(2-Fluoro-3-iodopropyl)-4-methylbenzene (3h) This product was prepared according to the above general procedure using Pd(OAc) 2 (4b) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (14 mg, 51%). 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 4H), (m, 1H), (m, 2H), 3.04 (m, 2H), S4

5 2.33 (s, 3H). 13 C-NMR (100 MHz, CDCl 3 ) δ 136.7, (d, J CF = 5.5 Hz), (d, J CF = 6.6 Hz), 92.2 (d, J CF = Hz), 40.3 (d, J CF = 21.2 Hz), 21.1, 6.4 (d, J CF = 24.2 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 278 (M+, 30), 151 (2), 132 (2), 105 (100), 79 (15). 1-(2-Fluoro-3-iodopropyl)-2-methylbenzene (3i) This product was prepared according to the above general procedure using Pd(OAc) 2 (4b) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (14 mg, 51%). 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 4H), (m, 1H), (m, 2H), 3.09 (m, 2H), 2.35 (s, 3H). 13 C-NMR (100 MHz, CDCl 3 ) δ 136.6, (d, J CF = 5.1 Hz), 130.6, 130.1, 127.2, 126.2, 91.8 (d, J CF = Hz), 38.2 (d, J CF = 21.4 Hz), 19.5 (d, J CF = 32.8 Hz), 6.7 (d, J CF = 24.2 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 278 (M+, 49), 132 (5), 117 (2), 105 (100), 79 (20). 1-Fluoro-4-(2-fluoro-3-iodopropyl)benzene (3j) This product was prepared according to the above general procedure using Pd(MeCN) 4 (BF 4 ) 2 (4a) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (15 mg, 53%). 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 1H), 3.27 (m, 2H), 3.07 (m, 2H). 13 C-NMR (100 MHz, CDCl 3 ) δ (d, J CF = Hz), (d, J CF = 4.4 Hz), (d, J CF = 8.1 Hz), (d, J CF = 21.3 Hz), 92.0 (d, J CF = Hz), 39.8 (d, J CF = 21.2 Hz), 5.8 (d, J CF = 24.5 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m), (m). (EI) m/z (rel intens) 282 (M+, 35), 155 (4), 136 (3), 127 (1), 109 (100). 1-(2-Fluoro-3-iodopropyl)-4-(trifluoromethyl)benzene (3k) This product was prepared according to the above general procedure using Pd(MeCN) 4 (BF 4 ) 2 (4a) as catalyst. The compound was isolated as a green oil using pentane:diethyl ether 100:1 as eluent system (12 mg, 48%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), (m, 1H), 3.29 (m, 2H), 3.17 (m, 2H). 13 C-NMR (100 MHz, CDCl 3 ) δ (d, J CF = 3.7 Hz), 129.8, (q, J CF = 32.5 Hz) (q, J CF = 3.8 Hz), (q, J CF = Hz), 91.6 (d, J CF = S5

6 Hz), 40.4 (d, J CF = 21.2 Hz), 5.5 (d, J CF = 24.8 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (s), (m). (EI) m/z (rel intens) 332 (M+, 40), 313 (3), 205 (73), 186 (11), 127 (4). 1-Bromo-2-(2-fluoro-3-iodopropyl)benzene (3l) This product was prepared according to the above general procedure using Pd(MeCN) 4 (BF 4 ) 2 (4a) as catalyst. The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (18 mg, 53%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.57 (dd, J = 8.0, 1.3 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 4H). 13 C-NMR (100 MHz, CDCl 3 ) δ 135.4, 133.0, 131.9, 128.9, 127.7, 124.7, 90.5 (d, J CF = Hz), 41.4 (d, J CF = 21.9 Hz), 6.6 (d, J CF = 23.7 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 343 (M+, 9), 263 (7), 215 (96), 195 (15), 136 (4). (2-Fluoro-1-iodopropan-2-yl)benzene (3m) This product was prepared according to the above general procedure using Pd(OAc) 2 (4b) as catalyst at 50 o C. The compound was isolated as a colorless oil using pentane:dichloromethane 20:1 as eluent system (16 mg, 61%). The NMR data obtained for 3m are in agreement with literature values. 6 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 5H), 3.59 (d, J = 20.2 Hz, 2H), 1.86 (d, J = 21.8 Hz, 3H). 13 C-NMR (100 MHz, CDCl 3 ) δ (d, J CF = 21.9 Hz), (d, J CF = 1.6 Hz), (d, J CF = 12.5 Hz), (d, J CF = 9.1 Hz), 94.4 (d, J CF = Hz), 26.9 (d, J CF = 24.4 Hz), 15.5 (d, J CF = 28.2 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (sext, J HF = 21.4 Hz). (EI) m/z (rel intens) 137 (M-I, 100), 118 (8), 117 (50), 115 (41), 103 (24). 2-(2-Fluoro-1-iodopropan-2-yl)naphthalene (3n) This product was prepared according to the above general procedure using PdCl 2 (MeCN) 2 (4c) as catalyst at 50 o C. The compound was isolated as a colorless oil using pentane:dichloromethane 20:1 as eluent system (17 mg, 54%). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 1H), (m, 2H), 1.95 (d, J = 21.7 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J CF = 21.9 Hz), (d, J CF = 1.5 Hz), (d, J CF = 0.9 Hz), (d, J CF = 1.4 Hz), 128.3, 127.6, 126.5, 126.4, (d, J CF = 10.0 Hz), (d, J CF = 8.2 Hz), 94.6 (d, J CF = Hz), 26.9 (d, J CF = 24.5 Hz), 15.3 (d, J CF = 28.1 Hz). 19 F NMR (377 MHz, CDCl 3 ) δ - S6

7 (sext, J = 21.3 Hz). (EI) m/z (rel intens) 187 (M-I, 5), 168 (23), 167 (100), 165 (53), 152 (40). 1-bromo-4-(2-Fluoro-1-iodopropan-2-yl)benzene (3o) This product was prepared according to the above general procedure using PdCl 2 (MeCN) 2 (4c) as catalyst at 60 o C. The compound was isolated as a colorless oil using pentane:dichloromethane 20:1 as eluent system (16 mg, 64%). 1 H-NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 3.55 (dd, J = 19.9, 2.9 Hz, 2H), 1.84 (d, J = 21.7 Hz, 3H). 13 C-NMR (100 MHz, CDCl 3 ) δ (d, J CF = 22.4 Hz), (d, J CF = 1.4 Hz), (d, J CF = 9.1 Hz), (d, J CF = 1.7 Hz), 94.2 (d, J CF = Hz), 26.7 (d, J CF = 24.5 Hz), 14.7 (d, J CF = 28.2 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (sext, J HF = 21.3 Hz). (EI) m/z (rel intens) 343 (M+, 10), 217 (94), 215 (100), 136 (66), 117 (9). trans-1-fluoro-2-iodocyclohexane (3p) This product was prepared according to the above general procedure using PdCl 2 (MeCN) 2 (4c) as catalyst (0.005 mmol). The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (9 mg, 40%). The NMR data obtained for 3p are in agreement with literature values. 7 1 H-NMR (400 MHz, CDCl 3 ) δ 4.56 (dtd, J = 47.6, 8.8, 4.2 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H). 13 C-NMR (100 MHz, CDCl 3 ) δ 94.6 (d, J CF = Hz), 36.5, 30.8, 30.7, 26.2, 22.8 (d, J CF = 8.5 Hz). 19 F-NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 228 (M+, 44), 264 (75), 249 (63), 102 (100), 101 (17). 1-Fluoro-2-iodocycloheptane (3q) This product was prepared according to the above general procedure using PdCl 2 (MeCN) 2 (4c) as catalyst (0.005 mmol). The compound was isolated as a colorless oil using pentane:diethyl ether 100:1 as eluent system (12 mg, 50%). The NMR data obtained for 11b are in agreement with literature values. 8 1 H NMR (400 MHz, CDCl 3 ) δ 4.84 (dtd, J = 45.9, 7.5, 3.2 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 99.2 (d, J CF = Hz), 35.4 (d, J CF = 5.5 Hz), 34.9 (d, J CF = 23.0 Hz), 31.7 S7

8 (d, J CF = 21.7 Hz), 27.1, 26.8, 20.5 (d, J CF = 8.3 Hz). 19 F NMR (377 MHz, CDCl 3 ) δ (m). (EI) m/z (rel intens) 115 (M-I, 3), 264 (70), 249 (100), 127 (1), 96 (1). References 1. (a) Geary, G. C.; Hope, E. G.; Singh, K.; Stuart, A. M., Chem. Commun. 2013, ; (b) Matoušek, V.; Pietrasiak, E.; Schwenk, R.; Togni, A., J. Org. Chem. 2013, 78, Phan, D. H. T.; Kou, K. G. M.; Dong, V. M., J. Am. Chem. Soc. 2010, 132, Barluenga, J.; Campos, P. J.; Gonzalez, J. M.; Suarez, J. L.; Asensio, G.; Asensio, G., J. Org. Chem. 1991, 56, Yoshino, H.; Matsubara, S.; Oshima, K.; Matsumoto, K.; Hagiwara, R.; Ito, Y., J. Fluorine Chem. 2005, 126, Khrimian, A. P.; DeMilo, A. B.; Waters, R. M.; Liquido, N. J.; Nicholson, J. M., J. Org. Chem. 1994, 59, Crespo, L. T. C.; Ribeiro, R. d. S.; de Mattos, M. C. S.; Esteves, P. M., Synthesis 2010, 2010, Yoshino, H.; Matsumoto, K.; Hagiwara, R.; Ito, Y.; Oshima, K.; Matsubara, S., J. Fluorine Chem. 2006, 127, Rozen, S.; Brand, M., J. Org. Chem. 1985, 50, S8

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