3-(4-Bromophenyl)prop-2-en-1-ol

Conditions: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one (1.10 g, 5.0 mmol), (2E)-3-(4-bromophenyl)-2-propen-1-ol (1.28 g, 6 mmol), cuprous iodide (476 mg, 3 mmol), potassium carbonate (829 mg, 6 mmol) and DMF (20 mL) was stirred overnight at 155° C. The reaction liquid was cooled to room temperature, then poured into ammonia water, and ethyl acetate was added for extraction. The organic layer was washed with water and saturated saline, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, followed by purification by flash column chromatography (KP-Sil, hexane:ethyl acetate=1:1 to 0:1) to obtain the entitled compound (881 mg). The reaction liquid was cooled to room temperature was added for extraction The organic layer was washed with water and saturated saline dried with anhydrous magnesium sulfate The solvent was concentrated under reduced pressure followed by purification by flash column chromatography (KP-Sil, hexane:ethyl acetate=1:1 to 0:1)

Conditions: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one (1.10 g, 5.0 mmol), (2E)-3-(4-bromophenyl)-2-propen-1-ol (1.28 g, 6 mmol), cuprous iodide (476 mg, 3 mmol), potassium carbonate (829 mg, 6 mmol) and DMF (20 mL) was stirred overnight at 155° C. The reaction liquid was cooled to room temperature, then poured into ammonia water, and ethyl acetate was added for extraction. The organic layer was washed with water and saturated saline, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, followed by purification by flash column chromatography (KP-Sil, hexane:ethyl acetate=1:1 to 0:1) to obtain the entitled compound (881 mg). The reaction liquid was cooled to room temperature was added for extraction The organic layer was washed with water and saturated saline dried with anhydrous magnesium sulfate The solvent was concentrated under reduced pressure followed by purification by flash column chromatography (KP-Sil, hexane:ethyl acetate=1:1 to 0:1)

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

Procedure: tert-Butyl chlorodimethylsilane (1.33 g, 19.5 mmol) was added to a stirred solution of (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol (3.20 g, 15.0 mmol), and imidazole (2.72 g, 18.0 mmol) in dry dichloromethane (75 ml) and the resulting mixture stirred at room temperature for 18 h, a colourless precipitate being formed. The mixture was diluted with dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The aqueous layer was separated, further extracted with dichloromethane (2×100ml) and the combined organic layers washed with brine, dried (MgSO4) and evaporated. The product was purified by column chromatography on silica gel (1% diethyl ether in n-heptane eluent) to give the colourless solid, (E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (4.39 g, 89%). a colourless precipitate being formed The aqueous layer was separated further extracted with dichloromethane (2×100ml) the combined organic layers washed with brine dried (MgSO4) evaporated The product was purified by column chromatography on silica gel (1% diethyl ether in n-heptane eluent)

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

Procedure: tert-Butyl chlorodimethylsilane (1.33 g, 19.5 mmol) was added to a stirred solution of (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol (3.20 g, 15.0 mmol), and imidazole (2.72 g, 18.0 mmol) in dry dichloromethane (75 ml) and the resulting mixture stirred at room temperature for 18 h, a colourless precipitate being formed. The mixture was diluted with dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The aqueous layer was separated, further extracted with dichloromethane (2×100ml) and the combined organic layers washed with brine, dried (MgSO4) and evaporated. The product was purified by column chromatography on silica gel (1% diethyl ether in n-heptane eluent) to give the colourless solid, (E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (4.39 g, 89%). a colourless precipitate being formed The aqueous layer was separated further extracted with dichloromethane (2×100ml) the combined organic layers washed with brine dried (MgSO4) evaporated The product was purified by column chromatography on silica gel (1% diethyl ether in n-heptane eluent)

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

Procedure: The colourless solid (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(4-bromo-phenyl)-acrylate (example 71a) as described for example 52b.

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

Procedure: A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under nitrogen atmosphere was cooled to −10° C., and diethylzinc (235 mL, 1M in hexane, 235 mmol) was added over 5-10 minutes followed by diiodomethane (37.9 mL, 469 mmol). The product from Example 8C (33.0 g, 122 mmol) in 100 mL DCM was added in 5-10 minutes. The temperature was maintained from −5° to −10° C. throughout the additions. The product from Example 8A, (E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 hours. It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) and diluted with ether (900 mL). The organic layer was separated. The aqueous layer was extracted with additional ether. The organic layers were combined and treated with NaOH (2N, 880 mL). To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath. The solution was stirred for 5-10 minutes. The organic layer was separated, washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine, dried and concentrated. The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCI—NH3) m/z 228 (M+H)+. (ee 94%). The temperature was maintained from −5° to −10° C. throughout the additions It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) diluted with ether (900 mL) The organic layer was separated The aqueous layer was extracted with additional ether treated with NaOH (2N, 880 mL) To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath The solution was stirred for 5-10 minutes The organic layer was separated washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine dried concentrated The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane

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

Procedure: A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under nitrogen atmosphere was cooled to −10° C., and diethylzinc (235 mL, 1M in hexane, 235 mmol) was added over 5-10 minutes followed by diiodomethane (37.9 mL, 469 mmol). The product from Example 8C (33.0 g, 122 mmol) in 100 mL DCM was added in 5-10 minutes. The temperature was maintained from −5° to −10° C. throughout the additions. The product from Example 8A, (E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 hours. It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) and diluted with ether (900 mL). The organic layer was separated. The aqueous layer was extracted with additional ether. The organic layers were combined and treated with NaOH (2N, 880 mL). To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath. The solution was stirred for 5-10 minutes. The organic layer was separated, washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine, dried and concentrated. The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCI—NH3) m/z 228 (M+H)+. (ee 94%). The temperature was maintained from −5° to −10° C. throughout the additions It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) diluted with ether (900 mL) The organic layer was separated The aqueous layer was extracted with additional ether treated with NaOH (2N, 880 mL) To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath The solution was stirred for 5-10 minutes The organic layer was separated washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine dried concentrated The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g, 96 mmol) in DCM (300 ml) under nitrogen and cooled to −78° C. was added dropwise DIBAL-H (240 ml, 1M in DCM, 240 mmol) in about 20 minutes. The mixture was stirred at −78° C. for 2 hours. Then, the dry ice bath was removed. The reaction was diluted with DCM (500 mL), quenched with HCl (1N), and partitioned. The combined organic phases were washed with H2O, dried and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 1.43 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (d, J=15 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCI—NH3) m/z 214 (M+H)+. Then, the dry ice bath was removed The reaction was diluted with DCM (500 mL) quenched with HCl (1N) partitioned The combined organic phases were washed with H2O dried concentrated under reduced pressure

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

Procedure: A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under nitrogen atmosphere was cooled to −10° C., and diethylzinc (235 mL, 1M in hexane, 235 mmol) was added over 5-10 minutes followed by diiodomethane (37.9 mL, 469 mmol). The product from Example 34C (33.0 g, 122 mmol) in 100 mL DCM was added in 5-10 minutes. The temperature was maintained from −5° to −10° C. throughout the additions. The product from Example 34A, (E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 hours. It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) and diluted with ether (900 mL). The organic layer was separated. The aqueous layer was extracted with additional ether. The organic layers were combined and treated with NaOH (2N, 880 mL). To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath. The solution was stirred for 5-10 minutes. The organic layer was separated, washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine, dried and concentrated. The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+. (ee 94%). The temperature was maintained from −5° to −10° C. throughout the additions It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) diluted with ether (900 mL) The organic layer was separated The aqueous layer was extracted with additional ether treated with NaOH (2N, 880 mL) To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath The solution was stirred for 5-10 minutes The organic layer was separated washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine dried concentrated The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g, 96 mmol) in DCM (300 ml) under nitrogen and cooled to −78° C. was added dropwise DIBAL-H (240 ml, 1M in DCM, 240 mmol) in about 20 minutes. The mixture was stirred at −78° C. for 2 hours. Then, the dry ice bath was removed. The reaction was diluted with DCM (500 mL), quenched with HCl (1N), and partitioned. The combined organic phases were washed with H2O, dried and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): 1.43 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (d, J=15 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 214 (M+H)+. Then, the dry ice bath was removed The reaction was diluted with DCM (500 mL) quenched with HCl (1N) partitioned The combined organic phases were washed with H2O dried concentrated under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g, 96 mmol) in DCM (300 ml) under nitrogen and cooled to −78° C. was added dropwise DIBAL-H (240 ml, 1M in DCM, 240 mmol) in about 20 minutes. The mixture was stirred at −78° C. for 2 hours. Then, the dry ice bath was removed. The reaction was diluted with DCM (500 mL), quenched with HCl (1N), and partitioned. The combined organic phases were washed with H2O, dried and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CDCl3): 1.43 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (d, J=15 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 214 (M+H)+. Then, the dry ice bath was removed The reaction was diluted with DCM (500 mL) quenched with HCl (1N) partitioned The combined organic phases were washed with H2O dried concentrated under reduced pressure

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

Procedure: The title compound was prepared by the method of A. B. Charette and H. Lebel (Organic Synthesis, 1998, 76, 86-96) substituting trans-3-(4-Bromophenyl)prop-2-en-1-ol (the product from Example 1A) for 3-Phenyl-prop-2-en-1-ol. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+. Lebel (Organic Synthesis, 1998, 76, 86-96)