Supporting Information

Supporting Information Wiley-VCH 2012 69451 Weinheim, Germany Substitution of Two Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis of 3-Fluoropyrazoles** Kohei Fuchibe, Masaki Takahashi, and Junji Ichikawa* anie_201206946_sm_miscellaneous_information.pdf

Table of Contents 1. General Statements p. 2 2. S N 2 -type Reaction of 2-Trifluoromethyl-1-alkenes (Synthesis of 3a) p. 3 3. Synthesis of Tosylhydrazides 5 p. 4 3.1 S N 2 -type Reactions of Boc-Hydrazine and Sequential Tosylation (Conditions A) 3.2 S N 2 -type Reactions of Arylhydrazines and Sequential Tosylation (Conditions B) p. 4 p. 6 4. Synthesis of 3-Fluoropyrazoles 7 (Cyclization of Tosylhydrazides 5) p. 8 5. 1 H, 13 C, and 19 F NMR Spectra of 3a, 5, 6c, and 7 p. 11 6. X ray Crystal Structure of 7c p. 77 1

1. General Statements IR spectra were recorded on Horiba FT-300S spectrometers. NMR spectra were recorded on a Bruker avance 500 spectrometer in CDCl 3 at 500 MHz ( 1 H NMR), at 126 MHz ( 13 C NMR), and at 470 MHz ( 19 F NMR). Chemical shifts were given in ppm relative to internal Me 4 Si (for 1 H NMR: δ = 0.00), CDCl 3 (for 13 C NMR: δ = 77.0), and C 6 F 6 (for 19 F NMR: δ = 0.0). High resolution mass spectroscopy (HRMS) was conducted with a JMS-T100GCV spectrometer. Elemental analyses were performed with a YANAKO MT-3 CHN Corder apparatus. Column chromatography and preparative thin layer chromatography (PTLC) were conducted on silica gel (Silica Gel 60 N, Kanto Chemical Co., Inc. for column chromatography and Wakogel B-5F, Wako Pure Chemical Industries for PTLC, respectively). All the reactions were conducted under argon. Dry tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dichloromethane (CH 2 Cl 2 ) were dried by passing over a column of activated alumina followed by a column of Q-5 scavenger (Engelhard). Pyridine was distilled after being dried with KOH, and stored over molecular sieves 4A. Hexamethylphosphoric triamide (HMPA) was distilled from CaH 2, and stored over molecular sieves 4A. α-trifluoromethylstyrenes were prepared by the reported Wittig reaction of trifluoromethylketones. 1 Boc-hydrazine was prepared by the known method. 2 Silylated 2-trifluoromethyl-1-alkene 1e was prepared by our method. 3 Liquid reagents were purified by distillation and solid reagents were purified by recrystalization. Sodium hydride dispersion in paraffin was rinsed with hexane three times, dried under reduced pressure, and stored in a glovebox under argon. All the reactions were performed under argon. 1 2 3 (a) X. Creary, J. Org. Chem. 1987, 52, 5026; (b) K. V. Alem, G. Belder, G. Lodder, H. Zuilhof, J. Org. Chem. 2005, 70, 179. A. Bredihhin, U. Maeorg, Tetrahedron 2008, 64, 6788. J. Ichikawa, H. Fukui, Y. Ishibashi, J. Org. Chem. 2003, 68, 7800 7805. 2

2. S N 2 -type Reaction of 2-Trifluoromethyl-1-alkenes (Synthesis of 3a) tert-butyl 1-(3,3-difluoro-2-phenylprop-2-en-1-yl)hydrazine-1-carboxylate (3a) Sodium hydride (86 mg, 3.6 mmol) was added to a THF (4.0 ml) solution of α-trifluoromethylstyrene (1a, 344 mg, 2.00 mmol) and Boc-hydrazine (2a, 477 mg, 3.61 mmol) at 0 C. After the mixture was stirred for 1 h at 0 o C, phosphate buffer (ph 7) was added to quench the reaction. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexane AcOEt 4:1) to give 3a as a colorless liquid (520 mg, 92%). IR (neat): ν ~ = 3292, 3062, 2978, 2933, 1718, 1450, 1369, 1252, 1146, 754, 698 cm 1. 1 H NMR: δ 1.36 (9H, s), 3.80 (2H, br s), 4.41 (2H, s), 7.26 7.37 (5H, m). 13 C NMR: δ 28.0, 47.9, 80.7, 90.1 (dd, J CF = 19, 14 Hz), 127.6, 128.3, 128.7, 131.6, 154.5 (dd, J CF = 292, 292 Hz), 156.3. 19 F NMR: δ 71.5 (1F, br d, J = 29 Hz), 73.3 (1F, br d, J = 29 Hz). Elemental analysis: Calcd. for C 14 H 18 F 2 N 2 O 2 : C, 59.14; H, 6.38; N, 9.85. Found: C, 58.82; H, 6.22; N, 9.83. 3

3. Synthesis of Tosylhydrazides 5 3.1 S N 2 -type Reactions of Boc-Hydrazine and Sequential Tosylation (Conditions A) N -(3,3-Difluoro-2-phenylprop-2-en-1-yl)-N -tert-butoxycarbonyl-p-toluenesulfonohydrazide (5a) Sodium hydride (43 mg, 1.8 mmol) was added to a THF (2.0 ml) solution of α-trifluoromethylstyrene (1a, 172 mg, 1.0 mmol) and Boc-hydrazine (2a, 239 mg, 1.80 mmol) at 0 C. After the mixture was stirred for 1 h at 0 o C, phosphate buffer (ph 7) was added to quench the reaction. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was transferred to a reaction flask for the following tosylation step with ethyl acetate. Ethyl acetate was removed in vacuo and the residue was azeotropically dehydrated with pyridine under reduced pressure three times to give crude 3a. Tosyl chloride (515 mg, 2.70 mmol) was added to a pyridine (2.0 ml) solution of the crude 3a at room temperature. After the mixture was stirred for 2.5 h at room temperature, phosphate buffer (ph 7) was added to quench the reaction. The mixture was filtered, and organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexane AcOEt 4:1) on silica gel. After removal of the solvent under reduced pressure, hexane was added to the viscous liquid. The obtained solid was washed with hexane three times, and tosylhydrazide 5a was obtained as a white powder (390 mg, 89%, two steps). IR (neat): ν ~ = 3064, 2921, 1340, 1241, 1151, 1103, 763, 739 cm 1. 1 H NMR: δ 0.99 (9H, s), 2.38 (3H, s), 4.53 (2H, br s), 6.69 (1H, br s), 7.12 7.30 (5H, m), 7.32 (2H, d, J = 7.0 Hz), 7.71 (2H, d, J = 7.9 Hz). 13 C NMR: δ 21.5, 27.3, 48.3, 82.6, 89.2 (dd, J CF = 19, 16 Hz), 127.9, 128.5, 128.6, 129.0, 129.4, 131.1, 133.7, 144.4, 154.0, 154.9 (dd, J CF = 293, 293 Hz). 19 F NMR: δ 72.5 7.33 (1F, m), 73.6 74.7 (1F, m). Elemental analysis: Calcd. for C 21 H 24 F 2 N 2 O 4 S: C, 57.52; H, 5.52; N, 6.39. Found: C, 57.62; H, 5.55; N, 6.40. N -[3,3-Difluoro-2-(p-methoxyphenyl)prop-2-en-1-yl]-N -tert-butoxycarbonyl-p-toluenesulfonohydrazide (5b) Tosylhydrazide 5b was synthesized by the method described for 5a (white powder). IR (neat): ν ~ = 3255, 2981, 1708, 1514, 1338, 1228, 1159, 1134, 1089 cm 1. 1 H NMR: δ 1.03 (9H, s), 2.39 (3H, s), 3.78 (3H, br s), 4.49 (2H, br s), 6.65 (1H, br s), 6.85 (2H, d, J = 8.5 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.71 (2H, d, J = 8.5 Hz). 13 C NMR: δ 21.5, 27.4, 48.3, 55.2, 82.6, 88.7 (dd, J CF = 19, 17 Hz), 114.0, 123.1, 128.6, 129.4, 130.1 (dd, J CF = 2, 2 Hz), 133.9, 144.4, 154.0, 154.8 (dd, J CF = 292, 292 Hz), 159.2. 19 F NMR: δ 71.9-72.5(1F, m), 72.9 73.6 (1F, m). Elemental analysis: Calcd. for C 22 H 26 F 2 N 2 O 5 S: C, 56.40; H, 5.59; N, 5.98. Found: C, 56.32; H, 5.65; N, 6.03. 4

N -[2-(p-Bromophenyl)-3,3-difluoroprop-2-en-1-yl]-N -tert-butoxycarbonyl-p-toluenesulfonohydrazide (5c) Tosylhydrazide 5c was synthesized by the method described for 5c (white powder). IR (neat): ν ~ = 3238, 2979, 1716, 1340, 1244, 1163, 1136, 1007 cm 1. 1 H NMR: δ 1.02 (9H, s), 2.39 (3H, s), 4.52 (2H, br s), 6.71 (1H, br s), 7.17 (2H, d, J = 8.3 Hz), 7.27 (2H, d, J = 7.6 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.69 (2H, d, J = 7.6 Hz). 13 C NMR: δ 21.4, 27.3, 47.7, 82.8, 88.6 (dd, J CF = 20, 16 Hz), 122.0, 128.6, 129.4, 130.1, 130.6 (dd, J CF = 3, 3 Hz), 131.6, 133.7, 144.5, 153.7, 154.9 (dd, J CF = 294, 294 Hz). 19 F NMR: δ 73.7 74.5 (1F, m), 74.6 75.5 (1F, m). Elemental analysis: Calcd. for C 21 H 23 BrF 2 N 2 O 4 S: C, 48.75; H, 4.48; N, 5.41. Found: C, 48.91; H, 4.45; N, 5.43. N -{3,3-Difluoro-2-[p-(trifluoromethyl)phenyl]prop-2-en-1-yl}-N -tert-butoxycarbonyl-p-toluenesulfonohydrazide (5d) Tosylhydrazide 5d was synthesized by the method described for 5a (white powder). IR (neat): ν ~ = 3234, 2983, 1716, 1322, 1246, 1161, 1126, 1012 cm 1. 1 H NMR: δ 1.01 (9H, s), 2.39 (3H, s), 4.61 (2H, br s), 6.71 (1H, br s), 7.27 (2H, d, J = 7.9 Hz), 7.44 (2H, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.0 Hz), 7.68 (2H, d, J = 8.1 Hz). 13 C NMR: δ 21.5, 27.3, 47.6, 83.0, 88.7 (dd, J CF = 20, 16 Hz), 123.9 (q, J CF = 272 Hz), 125.4 (d, J CF = 4 Hz), 128.7, 129.4 (dd, J CF = 3 Hz), 129.5, 130.1 (q, J CF = 33 Hz), 133.7, 135.2, 144.6, 153.8, 155.3 (dd, J CF = 295, 295 Hz). 19 F NMR: δ 76.0 (1F, d, J = 28 Hz), 76.5 (1F, d, J = 28 Hz), 99.1 (3F, s). Elemental analysis: Calcd. for C 22 H 23 F 5 N 2 O 4 S: C, 52.17; H, 4.58; N, 5.53. Found: C, 52.29; H, 4.73; N, 5.44. N -[3,3-Difluoro-2-(dimethylphenylsilyl)prop-2-en-1-yl]-N -tert-butoxycarbonyl-p-toluenesulfonohydrazide (5i) Tosylhydrazide 5i was synthesized by the method described for 5a (white powder). IR (neat): ν ~ = 3253, 2979, 1684, 1340, 1161, 812, 669 cm 1. 1 H NMR: δ 0.49 (6H, s), 1.10 (9H, s), 2.38 (3H, s), 4.06 (1H, br s), 4.48 (1H, br s), 6.18 (1H, br s), 7.25 (2H, d, J = 7.3 Hz), 7.37 (3H, d, J = 6.5 Hz), 7.50 (2H, d, J = 5.8 Hz), 7.68 (2H, d, J = 8.1 Hz). 13 C NMR: δ 2.38, 21.5, 27.5, 46.3, 78.1 (d, J CF = 22 Hz), 82.5, 128.0, 128.6, 129.4, 129.5, 133.5, 134.1, 136.7, 144.3, 153.5, 158.1 (dd, J CF = 312, 288 Hz). 19 F NMR: δ 90.0 (1F, br s), 94.6 (1F, br s). Elemental analysis: Calcd. for C 23 H 30 F 2 N 2 O 4 SSi: C, 55.62; H, 6.09; N, 5.64. Found: C, 55.67; H, 6.17; N, 5.76. 5

3.2 S N 2 -type Reactions of Arylhydrazines and Sequential Tosylation (Conditions B) N -(3,3-Difluoro-2-phenylprop-2-en-1-yl)-N -phenyl-p-toluenesulfonohydrazide (5e) Butyllithium (2.25 ml, 1.60 M in hexane, 3.60 mmol) was added to a THF (8.0 ml) solution of phenylhydrazine (2b, 389 mg, 3.60 mmol) at 78 C. After the mixture was stirred for 30 min at the same temperature, a THF (2.0 ml) solution of α-trifluoromethylstyrene (1a, 344 mg, 2.00 mmol) was added. After the mixture was allowed to warm to 55 C over 1.5 h, phosphate buffer (ph 7) was added to quench the reaction. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was transferred to a reaction flask for the following tosylation step with ethyl acetate. Ethyl acetate was removed in vacuo and the residue was azeotropically dehydrated with pyridine under reduced pressure three times to give crude 3e. Tosyl chloride (1.03 g, 5.40 mmol), 4-dimethylaminopyridine (DMAP, 48 mg, 0.40 mmol), and pyridine (330 µl, 3.60 mmol) were added to a dichloromethane (0.4 ml) solution of the crude 3e at 0 o C. After the mixture was stirred for 2.5 h at 0 o C, phosphate buffer (ph 7) was added to quench the reaction. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexane AcOEt 4:1) on silica gel. After removal of the solvent under reduced pressure, hexane was added to the viscous liquid. The obtained solid was washed with hexane three times, and tosylhydrazide 5e was obtained as a white powder (390 mg, 63%, two steps). IR (neat): ν ~ = 3238, 3032, 1731, 1597, 1329, 1238, 1155, 750 cm 1. 1 H NMR: δ 2.36 (3H, s), 4.40 (2H, br s), 5.85 (1H, s), 6.70 (2H, d, J = 8.0 Hz), 6.83 (1H, dd, J = 7.2, 7.2 Hz), 7.07 7.12 (4H, m), 7.18 (2H, d, J = 8.1 Hz), 7.28 7.35 (3H, m), 7.65 (2H, d, J = 8.3 Hz). 13 C NMR: δ 21.5, 52.7(d, J CF = 3), 88.8 (dd, J CF = 19, 15 Hz), 115.7, 121.4, 128.0, 128.2, 128.8 (br s), 129.4, 131.6 (dd, J CF = 4, 2 Hz), 135.6, 144.1, 147.3, 154.6 (dd, J CF = 293, 291 Hz). 19 F NMR: δ 73.4 (1F, d, J = 35 Hz), 74.0 (1F, d, J = 35 Hz). Elemental analysis: Calcd. for C 22 H 20 F 2 N 2 O 2 S: C, 63.75; H, 4.86; N, 6.76. Found: C, 63.87; H, 4.95; N, 6.78. N -(3,3-Difluoro-2-phenylprop-2-en-1-yl)-N -(p-tolyl)-p-toluenesulfonohydrazide (5f) Tosylhydrazide 5f was synthesized by the method described for 5e (white powder). IR (neat): ν ~ = 3228, 3060, 1726, 1495, 1330, 1238, 1157, 1093 cm 1. 1 H NMR: δ 2.22 (3H, s), 2.37 (3H, s), 4.33 (2H, s), 5.80 (1H, s), 6.61 (2H, d, J = 8.5 Hz), 6.91 (2H, d, J = 8.5 Hz), 7.11 (2H, d, J = 7.6 Hz), 7.17 (2H, d, J = 8.2 Hz), 7.30 7.34 (3H, m), 7.62 (2H, d, J = 8.2 Hz). 13 C NMR: δ 20.4, 21.5, 53.2 (d, J = 4 Hz), 88.9 (dd, J CF = 19, 15 Hz), 116.5, 128.06, 128.12, 128.7, 128.8 (dd, J CF = 3, 3 Hz), 129.4, 131.3, 131.8 (dd, J CF = 4, 4 Hz), 135.6, 143.9, 145.1, 154.6 (dd, J CF = 294, 291 Hz). 19 F NMR: δ 73.4 (1F, d, J = 33 Hz), 73.9 (1F, d, J = 33 Hz). Elemental analysis: Calcd. for C 23 H 22 F 2 N 2 O 2 S: C, 64.47; H, 5.18; N, 6.54. Found: C, 64.24; H, 5.21; N, 6.38. 6

N -(3,3-Difluoro-2-phenylprop-2-en-1-yl)-N -(o-tolyl)-p-toluenesulfonohydrazide (5g) Tosylhydrazide 5g was synthesized by the method described for 5e (white powder). IR (neat): ν ~ = 3234, 3031, 1731, 1509, 1331, 1238, 1159, 812 cm 1. 1 H NMR: δ 1.90 (3H, s), 2.33 (3H, s), 4.11 (2H, s), 6.36 (1H, s), 6.87 6.93 (3H, m), 7.00 (1H, t, J = 8.2 Hz), 7.10 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.24 7.32 (3H, m), 7.56 (2H, d, J = 8.2 Hz). 13 C NMR: δ 17.6, 21.5, 54.6, 88.5 (dd, J CF = 19, 14 Hz), 122.0, 125.5, 126.1, 127.7, 128.0, 128.4 (dd, J CF = 3, 3 Hz), 128.5, 129.1, 130.8, 132.3, 132.5, 135.6, 143.6, 146.5, 155.5 (dd, J CF = 295, 295 Hz). 19 F NMR: δ 74.3 (1F, d, J = 33 Hz), 74.4 (1F, d, J = 33 Hz). Elemental analysis: Calcd. for C 23 H 22 F 2 N 2 O 2 S: C, 64.47; H, 5.18; N, 6.54. Found: C, 64.33; H, 5.25; N, 6.54. N -(3,3-Difluoro-2-phenylprop-2-en-1-yl)-N -[p-(trifluoromethyl)phenyl]-p-toluenesulfonohydrazide (5h) Tosylhydrazide 5h was synthesized by the method described for 5e at 98 o C (white powder). IR (neat): ν ~ = 3232, 1724, 1495, 1329, 1238, 1157, 1093, 760, 663 cm 1. 1 H NMR: δ 2.38 (3H, s), 4.50 (2H, br s), 5.91 (1H, s), 6.73 (2H, d, J = 8.6 Hz), 7.06 (2H, m), 7.22 (2H, d, J = 8.2 Hz), 7.28 7.38 (5H, m), 7.66 (2H, d, J = 8.2 Hz). 13 C NMR: δ 21.5, 51.6 (d, J CF = 3.4 Hz), 88.4 (dd, J CF = 19, 16 Hz), 114.1, 122.5 (q, J CF = 33 Hz), 124.3 (q, J CF = 272 Hz), 126.1 (q, J CF = 4 Hz), 128.0, 128.7, 128.8 (dd, J CF = 2, 2 Hz), 129.1, 129.7, 131.0 (q, J CF = 2 Hz), 135.4, 144.7, 152.2, 154.5 (dd, J CF = 291, 291 Hz). 19 F NMR: δ 73.5 (1F, d, J = 35 Hz), 74.5 (1F, d, J = 35 Hz), 100.1 (3F, s). Elemental analysis: Calcd. for C 23 H 19 F 5 N 2 O 2 S C, 57.26; H, 3.97; N, 5.81 Found: C, 57.36; H, 4.01; N, 5.71. N -[3,3-Difluoro-2-(dimethylphenylsilyl)prop-2-en-1-yl]-N -phenyl-p-toluenesulfonohydrazide (5j) Tosylhydrazide 5j was synthesized by the method described for 5e (white powder). IR (neat): ν ~ = 3240, 3068, 1689, 1596, 1496, 1334, 1232, 1157, 812, 660 cm 1. 1 H NMR: δ 0.31 (6H, s), 2.33 (3H, s), 4.03 (2H, br s), 5.57 (1H, s), 6.46 (2H, d, J = 8.8 Hz), 6.75 (1H, t, J = 7.3 Hz), 6.99 (2H, dd, J = 8.8, 7.4 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.38 7.47 (5H, m), 7.52 (2H, d, J = 8.3 Hz). 13 C NMR: δ 2.68, 21.4, 51.3 (d, J = 9 Hz), 78.3 (dd, J CF = 26, 6 Hz), 115.8, 120.9, 127.8, 128.3, 128.5, 129.3, 129.8, 133.8, 136.3, 136.4, 143.7, 146.8, 157.5 (dd, J CF = 311, 287 Hz). 19 F NMR: δ 90.0 (1F, d, J = 28 Hz), 94.6 (1F, d, J = 28 Hz). Elemental analysis: Calcd. for C 24 H 26 F 2 N 2 O 2 SSi: C, 60.99; H, 5.54; N, 5.93. Found: C, 60.86; H, 5.70; N, 5.88. 7

4. Synthesis of 3-Fluoropyrazoles 7 (Cyclization of Tosylhydrazides 5) tert-butyl 3-fluoro-4-phenyl-1H-pyrazole-1-carboxylate (7a) Sodium hydride (24 mg, 1.0 mmol) was added to a DMF (0.92 ml) solution of tosylhydrazide 5a (200 mg, 0.456 mmol) at room temperature. After the mixture was stirred for 5 h at room temperature, phosphate buffer (ph 7) was added to quench the reaction. Organic materials were extracted with ethyl acetate three times. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexane AcOEt 10:1) on silica gel to give fluoropyrazole 7a (104 mg, 86%) and fluoropyrazoline 6a (23 mg, 12%) as colorless liquids. 7a: IR (neat): ν ~ = 2981, 1516, 1371, 1236, 1151, 964, 758 cm 1. 1 H NMR: δ 1.66 (9H, s), 7.32 (1H, dd, J = 7.6, 7.6 Hz), 7.41 (2H, dd, J = 7.6, 7.6 Hz), 7.56 (2H, d, J = 7.6 Hz), 8.19 (1H, d, J = 2.9 Hz). 13 C NMR: δ 27.8, 86.1, 111.1 (d, J CF = 19 Hz), 126.4 (d, J CF = 3 Hz), 127.9, 128.2 (d, J CF = 4 Hz), 128.5, 128.9, 147.0, 162.3 (d, J CF = 295 Hz). 19 F NMR: δ 38.9 (1F, s). Elemental analysis: Calcd. for C 14 H 15 FN 2 O 2 C, 64.11; H, 5.76; N, 10.68. Found: C, 64.23; H, 5.77; N, 10.74. tert-butyl 3-fluoro-4-(p-methoxyphenyl)-1H-pyrazole-1-carboxylate (7b) Fluoropyrazole 7b was synthesized by the method described for 7a (white powder). IR (neat): ν ~ = 2981, 1747, 1594, 1487, 1367, 1230, 1149, 962, 841 cm 1. 1 H NMR: δ 1.66 (9H, s), 3.83 (3H, s) 6.94 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7 Hz), 8.10 (1H, d, J = 3.0 Hz). 13 C NMR: δ 27.9, 55.3, 85.9, 110.9 (d, J CF = 19 Hz), 114.4, 120.6 (d, J CF = 5 Hz), 127.70 (d, J CF = 3 Hz), 127.72 (d, J CF = 2 Hz), 147.1, 159.3, 162.5 (d, J CF = 256 Hz). 19 F NMR: δ 38.4 (1F, s). Elemental analysis: Calcd. for C 15 H 17 FN 2 O 3 C, 61.63; H, 5.86; N, 9.58. Found: C, 61.32; H, 5.78; N, 9.42. tert-butyl 4-(p-bromophenyl)-3-fluoro-1H-pyrazole-1-carboxylate (7c) and 2-tert-butoxycarbonyl-zw4-(p-bromophenyl)-5-fluoro-1-p-toluenesulfonyl-2,3-dihydropyrazole (6c) Fluoropyrazole 7c and fluoropyrazoline 6c were synthesized by the method described for 7a (white powder). These compounds were separated from each other by column chromatography (SiO 2 ). 7c: IR (neat): ν ~ = 2981, 1749, 1516, 1371, 1236, 1151, 966 cm 1. 1 H NMR: δ 1.66 (9H, s), 7.43 (2H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 8.19 (1H, d, J = 2.9 Hz). 13 C NMR: δ 27.8, 86.3, 110.1 (d, J CF = 19 Hz), 121.9, 127.2 (d, J CF = 5 Hz), 127.9 (d, J CF = 3 Hz), 128.5, 132.1, 146.9, 162.2 (d, J CF = 257 Hz). 19 F NMR: δ 38.9 (1F, s). Elemental analysis: Calcd. for C 14 H 14 BrFN 2 O 2 C, 49.29; H, 4.14; N, 8.21. Found: C, 49.62; H, 4.21; N, 8.13. 6c: IR (neat): ν ~ = 2981, 1701, 1392, 1146, 750, 590 cm 1. 1 H NMR: δ 1.48 (9H, s), 2.43 (3H, s), 4.49 (1H, d, J = 13.0 Hz), 5.18 (1H, d, J = 13.0 Hz), 7.24 (2H, d, J = 8.7 Hz), 7.26, (2H, d, J = 8.7 Hz), 7.51 (4H, d, J = 8.7 Hz). 13 C NMR: δ 21.7, 28.1, 57.0, 82.9, 124.6, 126.7, 129.7, 129.8 (d, J CF = 5 Hz), 130.2, 130.9, 132.1 (d, J CF = 14 Hz), 132.2, 146.5, 156.7 (d, J CF = 281 Hz). 19 F NMR: δ 38.9 (1F, s). Elemental analysis: Calcd. for C 21 H 22 BrFN 2 O 4 S C, 50.71; H, 4.46; N, 5.63. Found: C, 51.08; H, 4.60; N, 5.75. 8

tert-butyl 3-fluoro-4-[p-(trifluoromethyl)phenyl]-1H-pyrazole-1-carboxylate (7d) Fluoropyrazole 7d was synthesized by the method described for 7a (colorless liquid). IR (neat): ν ~ = 2981, 1754, 1531, 1323, 1109, 1068, 966 cm 1. 1 H NMR: δ 1.67 (9H, s), 7.64 7.73 (4H, m), 8.27 (1H, d, J = 2.8 Hz). 13 C NMR: δ 27.8, 86.6, 109.8 (d, J CF = 19 Hz), 123.9 (q, J CF = 272 Hz), 126.0 (q, J CF = 4 Hz), 126.5 (d, J CF = 3 Hz), 129.2, 129.8 (q, J CF = 33 Hz), 131.9 (d, J CF = 4 Hz), 146.8, 162.3 (d, J CF = 257 Hz). 19 F NMR: δ 39.2 (1F, s), 99.0 (3F, s). Elemental analysis: Calcd. for C 15 H 14 F 4 N 2 O 2 C, 54.55; H, 4.27; N, 8.48. Found: C, 54.71.; H, 4.29; N, 8.51. 3-Fluoro-1,4-diphenyl-1H-pyrazole (7e) Fluoropyrazole 7e was synthesized by the method described for 7a (white powder). IR (neat): ν ~ = 3014, 1599, 1514, 1479, 1408, 1215, 1063, 746, 688 cm 1. 1 H NMR: δ 7.23 7.30 (2H, m), 7.39 (2H, dd, J = 7.9, 7.9 Hz), 7.43 (2H, dd, J = 7.6, 7.6 Hz), 7.57 (2H, d, J = 7.6 Hz), 7.62 (2H, d, J = 7.7 Hz), 7.97 (1H, d, J = 2.4 Hz). 13 C NMR: δ 108.2 (d, J CF = 18 Hz), 118.2, 124.7, 126.0 (d, J CF = 3 Hz), 126.5, 127.1, 128.9, 129.4 (d, J CF = 5 Hz), 129.5 139.4, 161.9 (d, J CF = 250 Hz). 19 F NMR: δ 32.5 (1F, s). HRMS (ESI): m/z Calcd. for C 15 H 11 FN 2 ([M] + ) 238.0906, Found 238.0915. 3-Fluoro-4-phenyl-1-p-tolyl-1H-pyrazole (7f) Fluoropyrazole 7f was synthesized by the method described for 7a (white powder). IR (neat): ν ~ = 3039, 2918, 1575, 1518, 1383, 1259, 1207, 810, 754 cm 1. 1 H NMR: δ 2.39 (3H, s), 7.26 (2H, d, J = 8.5 Hz), 7.29 (1H, t, J = 7.5 Hz), 7.41 (2H, t, J = 7.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 7.5 Hz), 7.98 (1H, d, J = 2.5 Hz). 13 C NMR: δ 20.9, 107.9 (d, J CF = 18 Hz), 118.3, 124.7, 126.1 (d, J CF = 3 Hz), 127.0, 128.9, 129.6 (d, J CF = 5 Hz), 130.0, 136.5, 137.2, 161.8 (d, J CF = 249 Hz). 19 F NMR: δ 32.1 (1F, s). Elemental analysis: Calcd. for C 16 H 13 FN 2 C, 76.17; H, 5.19; N, 11.10 Found: C, 76.03; H, 5.37; N, 10.97. 3-Fluoro-4-phenyl-1-o-tolyl-1H-pyrazole (7g) Fluoropyrazole 7g was synthesized by the method described for 7a (white powder). IR (neat): ν ~ = 3037, 2923, 1581, 1511, 1378, 1263, 1191, 949, 755 cm 1. 1 H NMR: δ 2.33 (3H, s), 7.23 7.33 (5H, m), 7.39 (2H, t, J = 7.9 Hz), 7.58 (2H, d, J = 7.6 Hz), 7.66 (1H, d, J = 2.5 Hz). 13 C NMR: δ 18.1, 106.8 (d, J CF = 17 Hz), 125.9, 126.0 (d, J CF = 3 Hz), 126.7, 126.8, 128.6, 128.9, 129.0, 129.7 (d, J CF = 5 Hz), 131.4, 133.6, 139.2, 161.3 (d, J CF = 249 Hz). 19 F NMR: δ 30.8 (1F, s). Elemental analysis: Calcd. for C 16 H 13 FN 2 C, 76.17; H, 5.19; N, 11.10 Found: C, 76.11; H, 5.53; N, 11.09. 3-Fluoro-4-phenyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrazole (7h) Fluoropyrazole 7h was synthesized by the method described for 5a (white powder). IR (neat): ν ~ = 2920, 1614, 1448, 1327, 1217, 1111, 771 cm 1. 1 H NMR: δ 7.33 (1H, dd, J = 7.7, 7.7 Hz), 7.44 (2H, dd, J = 7.6, 7.6 Hz), 7.60 (2H, d, J = 7.6 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 8.09 (1H, d, J = 2.4 Hz). 13 C 9

NMR: δ 109.7 (d, J CF = 18 Hz), 117.9, 123.8 (q, J CF = 273 Hz), 124.8, 126.2 (d, J CF = 3 Hz), 126.9 (q, J CF = 4 Hz), 127.5, 128.4 (q, J CF = 33 Hz), 128.9 (d, J CF = 5 Hz), 129.0, 141.8, 162.4 (d, J CF = 252 Hz). 19 F NMR: δ 34.1 (1F, s), 99.4 (3F, s). HRMS (ESI): m/z Calcd. for C 16 H 10 F 4 N 2 ([M] + ) 306.0780, Found 306.0787. tert-butyl 3-fluoro-1H-pyrazole-1-carboxylate (7i) Fluoropyrazole 7i was synthesized by the method described for 7a (colorless liquid). Because this compound is volatile, ether and pentane were used for extraction and column chromatography, respectively. IR (neat): ν ~ = 2983, 1751, 1560, 1371, 1142, 958, 762 cm 1. 1 H NMR: δ 1.64 (9H, s), 6.04 (1H, dd, J = 6.0, 2.9 Hz), 8.00 (1H, dd, J = 2.9, 2.9 Hz). 13 C NMR: δ 27.8, 86.0, 95.3 (d, J CF = 26 Hz), 132.6, 147.0, 165.2 (d, J CF = 253 Hz). 19 F NMR: δ 39.5 (1F, s). HRMS (ESI): m/z Calcd. for C 8 H 11 FN 2 NaO 2 ([M+Na] + ) 209.0702, Found 209.0698. 3-Fluoro-1-phenyl-1H-pyrazole (7j) Fluoropyrazole 7j was synthesized by the method described for 7a (white powder). IR (neat): ν ~ = 3153, 2927, 1600, 1541, 1479, 1398, 1238, 1049, 737, 687 cm 1. 1 H NMR: δ 6.02 (1H, dd, J = 5.7, 2.6 Hz), 7.28 (1H, dddd, J = 12.4, 12.4, 1.0, 1.0 Hz), 7.44 (2H, dd, J = 9.0, 9.0 Hz), 7.60 (2H, dd, J = 9.0, 1.0 Hz), 7.75 (1H, dd, J = 2.5, 2.5 Hz). 13 C NMR: δ 92.2 (d, J CF = 25 Hz), 118.4, 126.4, 128.1, 129.5, 139.6, 164.9 (d, J CF = 245 Hz). 19 F NMR: δ 33.0 (1F, d, J = 1 Hz). HRMS (ESI): m/z Calcd. for C 9 H 7 FN 2 ([M] + ) 162.0593, Found 162.0597. 10

5. 1 H, 13 C, and 19 F NMR Spectra of 3a, 5, 6c, and 7 3a ( 1 H NMR) 11

3a ( 13 C NMR) 12

3a ( 19 F NMR) 13

5a ( 1 H NMR) 14

5a ( 13 C NMR) 15

5a ( 19 F NMR) 16

5b ( 1 H NMR) 17

5b ( 13 C NMR) 18

5b ( 19 F NMR) 19

5c ( 1 H NMR) 20

5c ( 13 C NMR) 21

5c ( 19 F NMR) 22

5d ( 1 H NMR) 23

5d ( 13 C NMR) 24

5d ( 19 F NMR) 25

5e ( 1 H NMR) 26

5e ( 13 C NMR) 27

5e ( 19 F NMR) 28

5f ( 1 H NMR) 29

5f ( 13 C NMR) 30

5f ( 19 F NMR) 31

5g ( 1 H NMR) 32

5g ( 13 C NMR) 33

5g ( 19 F NMR) 34

5h ( 1 H NMR) 35

5h ( 13 C NMR) 36

5h ( 19 F NMR) 37

5i ( 1 H NMR) 38

5i ( 13 C NMR) 39

5i ( 19 F NMR) 40

5j ( 1 H NMR) 41

5j ( 13 C NMR) 42

5j ( 19 F NMR) 43

6c ( 1 H NMR) 44

6c ( 13 C NMR) 45

6c ( 19 F NMR) 46

7a ( 1 H NMR) 47

7a ( 13 C NMR) 48

7a ( 19 F NMR) 49

7b ( 1 H NMR) 50

7b ( 13 C NMR) 51

7b ( 19 F NMR) 52

7c ( 1 H NMR) 53

7c ( 13 C NMR) 54

7c ( 19 F NMR) 55

7d ( 1 H NMR) 56

7d ( 13 C NMR) 57

7d ( 19 F NMR) 58

7e ( 1 H NMR) 59

7e ( 13 C NMR) 60

7e ( 19 F NMR) 61

7f ( 1 H NMR) 62

7f ( 13 C NMR) 63

7f ( 19 F NMR) 64

7g ( 1 H NMR) 65

7g ( 13 C NMR) 66

7g ( 19 F NMR) 67

7h ( 1 H NMR) 68

7h ( 13 C NMR) 69

7h ( 19 F NMR) 70

7i ( 1 H NMR) 71

7i ( 13 C NMR) 72

7i ( 19 F NMR) 73

7j ( 1 H NMR) 74

7j ( 13 C NMR) 75

7j ( 19 F NMR) 76

6. X Ray Crystal Structure of 7c CCDC 889343 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystal Data Collection Parameters for 7c ---------------------------------------------------------------------------- formula C 14 H 14 Br F N 2 O 2 crystal system triclinic space group P -1 R, R w (I > 2σ(I)) 0.0223, 0.0556 R1, wr2 (all data) 0.0241, 0.0614 GOF on F 2 1.101 a (Å) 8.1204(17) b (Å) 9.050(2) c (Å) 10.942(2) α (deg) 91.016(2) β (deg) 103.435(2) γ (deg) 113.477(2) V (Å 3 ) 711.9(3) Z 2 T (K) 296.(2) crystal size (mm) 0.70, 0.70, 0.60 2θ min, 2θ max (deg) 4.945, 54.9806 no. refln measured (unique) 4004 no. refln measured (I > 2σ(I)) 3063 no. parameters 2913 ---------------------------------------------------------------------------- 77