1-Bromo-4-(2-iodoethyl)benzene

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-iodoethyl benzene (50.0 g, 0.161 mol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to −70° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2 M solution in THF, 100 ml, 0.200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below −60° C. by external cooling. When the addition is complete, the reaction is stirred at −70° C. for 20 minutes then allowed to warm to room temperature over 1 hour and 20 minutes. The reaction mixture is then cooled to −70° C. and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (˜500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2-ethylphenyl)-furan-2-ylmethanol. maintaining the internal temp below −60° C. by external cooling When the addition the reaction is stirred at −70° C. for 20 minutes to warm to room temperature over 1 hour and 20 minutes The reaction mixture is then cooled to −70° C. On completion of the addition to warm to room temperature stirred at room temperature for 3 hours the mixture is extracted into ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue is further purified by column chromatography on silica gel

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-iodoethyl benzene (50.0 g, 160.8 mmol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to −70° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2M solution in THF, 100 ml, 200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below −60° C. by external cooling. When the addition is complete, the reaction is stirred at −70° C. for 20 minutes then allowed to warm to room temperature over 1 h 20 minutes. The reaction mixture is then cooled to −70° C. and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (−500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2-ethylphenyl)furan-2-ylmethanol (40.7 g). maintaining the internal temp below −60° C. by external cooling When the addition the reaction is stirred at −70° C. for 20 minutes to warm to room temperature over 1 h 20 minutes The reaction mixture is then cooled to −70° C. On completion of the addition to warm to room temperature stirred at room temperature for 3 hours the mixture is extracted into ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue is further purified by column chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (650 mg, 100%) was prepared following the general procedure of step 1, Preparation 2, outlined for 1-bromo-4-(2-iodoethyl)benzene except that 2-(4′-fluorobiphenyl-4-yl)ethanol (430 mg, 1.99 mmol) was used in place of 2-(4-bromophenyl)ethanol. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.23 (t, J=7.69 Hz, 2H) 3.39 (t, J=7.69 Hz, 2H) 7.13 (t, J=8.72 Hz, 2H) 7.24-7.30 (m, 2H) 7.48-7.58 (m, 4H). the general procedure of step 1, Preparation 2

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (650 mg, 100%) was prepared following the general procedure of step 1, Preparation 2, outlined for 1-bromo-4-(2-iodoethyl)benzene except that 2-(4′-fluorobiphenyl-4-yl)ethanol (430 mg, 1.99 mmol) was used in place of 2-(4-bromophenyl)ethanol. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.23 (t, J=7.69 Hz, 2H) 3.39 (t, J=7.69 Hz, 2H) 7.13 (t, J=8.72 Hz, 2H) 7.24-7.30 (m, 2H) 7.48-7.58 (m, 4H). the general procedure of step 1, Preparation 2

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (549 mg, 74.5%) was prepared from 2-(4′-fluoro-2-methoxybiphenyl-4-yl)ethanol (which may be made as described in Preparation Number 5) following the general procedure described in Preparation 2, Step 1 for 1-bromo-4-(2-iodoethyl)benzene. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.11 (t, J=8.00 Hz, 2H) 3.33 (t, J=7.81 Hz, 2H) 3.90 (s, 3H) 6.66-6.73 (m, 4H) 6.87 (d, J=8.59 Hz, 2H) 7.27 (s, 1H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 1-bromo-4-(2-iodo-ethyl)-benzene (25.0 g, 80 mmol) and (+/−)-2-methanesulfonyl-propionic acid ethyl ester (15.9 g, 88.4 mmol) in DMF (100 mL) with solid Cs2CO3 (52.4 g, 161 mmol) was stirred overnight at room temperature. After 16 hours the reaction was poured into water (500 mL). The resulting suspension was stirred for 2 h. The mixture was extracted with diethylether (2×). The organic layers were combined and washed with water then brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 9:1-8:2) afforded the title compound as a white solid (21.0 g, 72%). 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.22 Hz, 3H) 1.70 (s, 3H) 2.14-2.24 (m, 1H) 2.42-2.55 (m, 2H) 2.68-2.78 (m, 1H) 3.04 (s, 3H) 4.25-4.31 (m, 2H) 7.07 (d, J=8.20 Hz, 2H) 7.43 (d, J=8.20 Hz, 2H) The resulting suspension was stirred for 2 h The mixture was extracted with diethylether (2×) washed with water brine, dried (Na2SO4) concentrated in vacuo Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 9:1-8:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 1-bromo-4-(2-iodo-ethyl)-benzene (25.0 g, 80 mmol) and (+/−)-2-methanesulfonyl-propionic acid ethyl ester (15.9 g, 88.4 mmol) in DMF (100 mL) with solid Cs2CO3 (52.4 g, 161 mmol) was stirred overnight at room temperature. After 16 hours the reaction was poured into water (500 mL). The resulting suspension was stirred for 2 h. The mixture was extracted with diethylether (2×). The organic layers were combined and washed with water then brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 9:1-8:2) afforded the title compound as a white solid (21.0 g, 72%). 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.22 Hz, 3H) 1.70 (s, 3H) 2.14-2.24 (m, 1H) 2.42-2.55 (m, 2H) 2.68-2.78 (m, 1H) 3.04 (s, 3H) 4.25-4.31 (m, 2H) 7.07 (d, J=8.20 Hz, 2H) 7.43 (d, J=8.20 Hz, 2H) The resulting suspension was stirred for 2 h The mixture was extracted with diethylether (2×) washed with water brine, dried (Na2SO4) concentrated in vacuo Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 9:1-8:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-(4-bromophenyl)ethanol (40.0 g, 0.199 mol) in dichloromethane (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.329 mmol), triphenylphosphine (66.5 g, 0.254 mol), and iodine (65.0 g, 0.26 mol) in dichloromethane (50 mL) at 0° C. When the addition was complete it was warmed to rt. After 1 hour the reaction was filtered through celite, the filtrate was washed with saturated aqueous sodium thiosufate (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (heptane/ethyl acetate 4:1) afforded the title compound as a yellow-white solid (59.09 g, 60%). 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 3.14 (t, J=7.69 Hz, 2H) 3.33 (t, J=7.69 Hz, 2H) 7.08 (d, J=7.89 Hz, 2H) 7.45 (d, J=8.31 Hz, 2H) When the addition After 1 hour the reaction was filtered through celite the filtrate was washed with saturated aqueous sodium thiosufate (2×100 mL), brine (100 mL) dried over MgSO4 filtered concentrated in vacuo Purification by flash column chromatography on silica gel (heptane/ethyl acetate 4:1)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-iodoethyl benzene (50.0 g, 0.161 mol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to −70° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2 M solution in THF, 100 ml, 0.200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below −60° C. by external cooling. When the addition is complete, the reaction is stirred at −70° C. for 20 minutes then allowed to warm to room temperature over 1 hour and 20 minutes. The reaction mixture is then cooled to −70° C. and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (˜500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2-ethylphenyl)-furan-2-ylmethanol. maintaining the internal temp below −60° C. by external cooling When the addition the reaction is stirred at −70° C. for 20 minutes to warm to room temperature over 1 hour and 20 minutes The reaction mixture is then cooled to −70° C. On completion of the addition to warm to room temperature stirred at room temperature for 3 hours the mixture is extracted into ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue is further purified by column chromatography on silica gel

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-iodoethyl benzene (50.0 g, 160.8 mmol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to −70° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2M solution in THF, 100 ml, 200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below −60° C. by external cooling. When the addition is complete, the reaction is stirred at −70° C. for 20 minutes then allowed to warm to room temperature over 1 h 20 minutes. The reaction mixture is then cooled to −70° C. and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (−500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2-ethylphenyl)furan-2-ylmethanol (40.7 g). maintaining the internal temp below −60° C. by external cooling When the addition the reaction is stirred at −70° C. for 20 minutes to warm to room temperature over 1 h 20 minutes The reaction mixture is then cooled to −70° C. On completion of the addition to warm to room temperature stirred at room temperature for 3 hours the mixture is extracted into ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue is further purified by column chromatography on silica gel

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-iodoethyl benzene (50.0 g, 160.8 mmol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to −70° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2M solution in THF, 100 ml, 200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below −60° C. by external cooling. When the addition is complete, the reaction is stirred at −70° C. for 20 minutes then allowed to warm to room temperature over 1 h 20 minutes. The reaction mixture is then cooled to −70° C. and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (−500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2-ethylphenyl)furan-2-ylmethanol (40.7 g). maintaining the internal temp below −60° C. by external cooling When the addition the reaction is stirred at −70° C. for 20 minutes to warm to room temperature over 1 h 20 minutes The reaction mixture is then cooled to −70° C. On completion of the addition to warm to room temperature stirred at room temperature for 3 hours the mixture is extracted into ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue is further purified by column chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-(4-bromophenyl)ethanol (20.0 g, 100 mol) in CH2Cl2 (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.33 mmol), PPh3 (33.3 g, 127 mmol), and I2 (32.5 g, 130 mmol) in CH2Cl2 (50 mL) at 0° C., and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous sodium thiosulfate (2×50 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE) to yield 1-bromo-4-(2-iodoethyl)benzene (9.2, 22.7 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.13 (t, J=7.6 Hz, 2H), 3.32 (t, J=7.6 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H). The reaction mixture was washed with saturated aqueous sodium thiosulfate (2×50 mL), brine dried over Na2SO4 filtered concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE)