1-bromo-3-but-3-enylbenzene

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 1-bromo-3-(but-3-en-1-yl)benzene (CA46) (7.51 g, 35.6 mmol) in hexanes (80 mL) was added (1S,5S)-9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 74.7 mL, 37.4 mmol). The reaction was allowed to stir at room temperature overnight. To the resulting clear solution sodium hydroxide (6.0 M, 5.93 mL, 35.6 mmol) was added dropwise. The reaction was placed in an ice water bath and hydrogen peroxide (13.8 mL, 135 mmol) was added. The resulting mixture was then heated to an internal temperature of 50° C. for overnight. The reaction mixture was cooled to room temperature. The biphasic solution was partitioned, and the organic layer was washed with sodium bisulfite, and brine solution. The combined aqueous layers were made basic with saturated sodium carbonate, and extracted with diethyl ether (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The liquid was loaded on to silica and purified by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent providing the title compound as a clear liquid (7.50 g, 90%): 1H NMR (400 MHz, DMSO-d6) δ 7.40 (t, J=1.9 Hz, 1H), 7.37 (dt, J=7.6, 1.8 Hz, 1H), 7.28-7.17 (m, 2H), 4.39 (t, J=5.2 Hz, 1H), 3.40 (td, J=6.5, 5.2 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.65-1.51 (m, 2H), 1.49-1.35 (m, 2H); EIMS m/z 228 ([M]+). The reaction was placed in an ice water bath The resulting mixture was then heated to an internal temperature of 50° C. for overnight The reaction mixture was cooled to room temperature The biphasic solution was partitioned the organic layer was washed with sodium bisulfite, and brine solution extracted with diethyl ether (2×100 mL) The combined organics were dried over magnesium sulfate filtered concentrated purified by flash column chromatography

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

Procedure: To a solution of 1-bromo-3-(bromomethyl)benzene (10.0 g, 40.0 mmol) in tetrahydrofuran (50 mL), under an inert atmosphere was added allylmagnesium bromide (1.0 M in diethyl ether, 40.0 mL, 40.0 mmol). The reaction was allowed to reflux overnight. The reaction was quenched with sulfuric acid (2 M, 45 mL). The resulting biphasic solution was solution was partitioned. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 100% hexanes as eluent providing the title compound as a clear liquid (7.51 g, 71%, ˜80% pure): 1H NMR (400 MHz, DMSO-d6) δ 7.42 (ddd, J=2.1, 1.4, 0.7 Hz, 1H), 7.37 (dt, J=7.1, 2.1 Hz, 1H), 7.28-7.18 (m, 2H), 5.81 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.09-4.90 (m, 2H), 2.67 (dd, J=8.6, 6.8 Hz, 2H), 2.32 (tdt, J=7.7, 6.5, 1.5 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 144.35, 137.61, 131.05, 130.28, 128.62, 127.44, 121.53, 115.37, 34.59, 33.91; EIMS m/z 210 ([M]+). to reflux overnight The reaction was quenched with sulfuric acid (2 M, 45 mL) was partitioned The aqueous layer was extracted with diethyl ether (2×50 mL) The combined organic layers were dried over magnesium sulfate filtered concentrated The resulting residue was purified by flash column chromatography

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

Procedure: To a solution of 1-bromo-3-(bromomethyl)benzene (10.0 g, 40.0 mmol) in tetrahydrofuran (50 mL), under an inert atmosphere was added allylmagnesium bromide (1.0 M in diethyl ether, 40.0 mL, 40.0 mmol). The reaction was allowed to reflux overnight. The reaction was quenched with sulfuric acid (2 M, 45 mL). The resulting biphasic solution was solution was partitioned. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 100% hexanes as eluent providing the title compound as a clear liquid (7.51 g, 71%, ˜80% pure): 1H NMR (400 MHz, DMSO-d6) δ 7.42 (ddd, J=2.1, 1.4, 0.7 Hz, 1H), 7.37 (dt, J=7.1, 2.1 Hz, 1H), 7.28-7.18 (m, 2H), 5.81 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.09-4.90 (m, 2H), 2.67 (dd, J=8.6, 6.8 Hz, 2H), 2.32 (tdt, J=7.7, 6.5, 1.5 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 144.35, 137.61, 131.05, 130.28, 128.62, 127.44, 121.53, 115.37, 34.59, 33.91; EIMS m/z 210 ([M]+). to reflux overnight The reaction was quenched with sulfuric acid (2 M, 45 mL) was partitioned The aqueous layer was extracted with diethyl ether (2×50 mL) The combined organic layers were dried over magnesium sulfate filtered concentrated The resulting residue was purified by flash column chromatography

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

Procedure: To a mixture of 1-bromo-3-(but-3-en-1-yl)benzene (0.5 g, 2.369 mmol) in tetrahydrofuran (10 mL) at −78° C. was added BuLi (1.137 mL, 2.84 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.208 g, 2.84 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 3-(but-3-en-1-yl)benzaldehyde (0.3 g, 79%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.77-7.72 (m, 2H), 7.51-7.46 (m, 2H), 5.86 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.10-5.00 (m, 2H), 2.86-2.79 (m, 2H), 2.48-2.39 (m, 2H). The reaction mixture was stirred at −78° C. for 30 min rt for 3 h It was then quenched with NH4Cl extracted with ether The organic layer was dried over MgSO4 filtered concentrated

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

Procedure: A mixture of 1-bromo-3-(bromomethyl)benzene (1 g, 4.00 mmol) in THF (15 mL) was added allylmagnesium bromide (4.80 mL, 4.80 mmol) and stirred at rt for 1 h, then refluxed for 2 h. It was then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil. It was then purified by 5% EtOAc/hexane to isolate 1-bromo-3-(but-3-en-1-yl)benzene (0.7 g, 3.32 mmol, 83% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.31 (m, 2H), 7.21-7.12 (m, 2H), 5.85 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.14-4.94 (m, 2H), 2.75-2.64 (m, 2H), 2.45-2.31 (m, 2H). refluxed for 2 h It was then quenched with NH4Cl extracted with EtOAc The organic layer was dried over MgSO4 filtered concentrated to obtain an oil It was then purified by 5% EtOAc/hexane

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

Procedure: A mixture of 1-bromo-3-(bromomethyl)benzene (1 g, 4.00 mmol) in THF (15 mL) was added allylmagnesium bromide (4.80 mL, 4.80 mmol) and stirred at rt for 1 h, then refluxed for 2 h. It was then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil. It was then purified by 5% EtOAc/hexane to isolate 1-bromo-3-(but-3-en-1-yl)benzene (0.7 g, 3.32 mmol, 83% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.31 (m, 2H), 7.21-7.12 (m, 2H), 5.85 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.14-4.94 (m, 2H), 2.75-2.64 (m, 2H), 2.45-2.31 (m, 2H). refluxed for 2 h It was then quenched with NH4Cl extracted with EtOAc The organic layer was dried over MgSO4 filtered concentrated to obtain an oil It was then purified by 5% EtOAc/hexane

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

Procedure: To a solution of 1-bromo-3-(but-3-en-1-yl)benzene (CA46) (7.51 g, 35.6 mmol) in hexanes (80 mL) was added (1S,5S)-9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 74.7 mL, 37.4 mmol). The reaction was allowed to stir at room temperature overnight. To the resulting clear solution sodium hydroxide (6.0 M, 5.93 mL, 35.6 mmol) was added dropwise. The reaction was placed in an ice water bath and hydrogen peroxide (13.8 mL, 135 mmol) was added. The resulting mixture was then heated to an internal temperature of 50° C. for overnight. The reaction mixture was cooled to room temperature. The biphasic solution was partitioned, and the organic layer was washed with sodium bisulfite, and brine solution. The combined aqueous layers were made basic with saturated sodium carbonate, and extracted with diethyl ether (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The liquid was loaded on to silica and purified by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent providing the title compound as a clear liquid (7.50 g, 90%): 1H NMR (400 MHz, DMSO-d6) δ 7.40 (t, J=1.9 Hz, 1H), 7.37 (dt, J=7.6, 1.8 Hz, 1H), 7.28-7.17 (m, 2H), 4.39 (t, J=5.2 Hz, 1H), 3.40 (td, J=6.5, 5.2 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.65-1.51 (m, 2H), 1.49-1.35 (m, 2H); EIMS m/z 228 ([M]+). The reaction was placed in an ice water bath The resulting mixture was then heated to an internal temperature of 50° C. for overnight The reaction mixture was cooled to room temperature The biphasic solution was partitioned the organic layer was washed with sodium bisulfite, and brine solution extracted with diethyl ether (2×100 mL) The combined organics were dried over magnesium sulfate filtered concentrated purified by flash column chromatography

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

Procedure: To a solution of 1-bromo-3-(but-3-en-1-yl)benzene (CA46) (7.51 g, 35.6 mmol) in hexanes (80 mL) was added (1S,5S)-9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 74.7 mL, 37.4 mmol). The reaction was allowed to stir at room temperature overnight. To the resulting clear solution sodium hydroxide (6.0 M, 5.93 mL, 35.6 mmol) was added dropwise. The reaction was placed in an ice water bath and hydrogen peroxide (13.8 mL, 135 mmol) was added. The resulting mixture was then heated to an internal temperature of 50° C. for overnight. The reaction mixture was cooled to room temperature. The biphasic solution was partitioned, and the organic layer was washed with sodium bisulfite, and brine solution. The combined aqueous layers were made basic with saturated sodium carbonate, and extracted with diethyl ether (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The liquid was loaded on to silica and purified by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent providing the title compound as a clear liquid (7.50 g, 90%): 1H NMR (400 MHz, DMSO-d6) δ 7.40 (t, J=1.9 Hz, 1H), 7.37 (dt, J=7.6, 1.8 Hz, 1H), 7.28-7.17 (m, 2H), 4.39 (t, J=5.2 Hz, 1H), 3.40 (td, J=6.5, 5.2 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.65-1.51 (m, 2H), 1.49-1.35 (m, 2H); EIMS m/z 228 ([M]+). The reaction was placed in an ice water bath The resulting mixture was then heated to an internal temperature of 50° C. for overnight The reaction mixture was cooled to room temperature The biphasic solution was partitioned the organic layer was washed with sodium bisulfite, and brine solution extracted with diethyl ether (2×100 mL) The combined organics were dried over magnesium sulfate filtered concentrated purified by flash column chromatography

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

Procedure: To a solution of 1-bromo-3-(bromomethyl)benzene (10.0 g, 40.0 mmol) in tetrahydrofuran (50 mL), under an inert atmosphere was added allylmagnesium bromide (1.0 M in diethyl ether, 40.0 mL, 40.0 mmol). The reaction was allowed to reflux overnight. The reaction was quenched with sulfuric acid (2 M, 45 mL). The resulting biphasic solution was solution was partitioned. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 100% hexanes as eluent providing the title compound as a clear liquid (7.51 g, 71%, ˜80% pure): 1H NMR (400 MHz, DMSO-d6) δ 7.42 (ddd, J=2.1, 1.4, 0.7 Hz, 1H), 7.37 (dt, J=7.1, 2.1 Hz, 1H), 7.28-7.18 (m, 2H), 5.81 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.09-4.90 (m, 2H), 2.67 (dd, J=8.6, 6.8 Hz, 2H), 2.32 (tdt, J=7.7, 6.5, 1.5 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 144.35, 137.61, 131.05, 130.28, 128.62, 127.44, 121.53, 115.37, 34.59, 33.91; EIMS m/z 210 ([M]+). to reflux overnight The reaction was quenched with sulfuric acid (2 M, 45 mL) was partitioned The aqueous layer was extracted with diethyl ether (2×50 mL) The combined organic layers were dried over magnesium sulfate filtered concentrated The resulting residue was purified by flash column chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.245 gm (1.16 mmol) of 1-bromo-3-but-3-enylbenzene in CH2Cl2 at 0° C. was treated with 0.39 gm (1.74 mmol) of N-iodosuccinimide and 1.05 gm (1.74 mmol) of 50% wt/wt tetrabutylammoniumdihydrogen trifluoride in CH2Cl2, stirred at 0° C. for 2 h, warmed to room temperature over a 1 h period and poured into CH2Cl2. The resultant organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes afforded 1-bromo-3-(3-fluoro-4-iodo-butyl)-benzene as an oil, 0.40 gm (50% yield); 1H NMR (400 MHz, CDCl3) δ: 2.03 (m, 2H), 2.74 (m, 2H), 3.29 (dd, 2H, J=5.4, 19.1 Hz), 4.47 (m, 1H), 7.12 (m, 2H), 7.32 (m, 2H). warmed to room temperature over a 1 h period The resultant organic phase was washed sequentially with water and brine dried over Na2SO4 concentrated under reduced pressure Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1.34 gm (3.77 mmol) of methyltriphenylphosphonium bromide in THF at 0° C. was treated dropwise with 2.3 mL of 1.6 M n-BuLi in hexanes (3.77 mmol), stirred at 0° C. for 0.25 h, cooled to −78° C., treated dropwise with a solution of 3-(3-bromophenyl)propionaldehyde (0.7 gm, 3.28 mmol) in THF, stirred at −78° C. for 1 h, allowed to warm to room temperature, quenched with aqueous NH4Cl and concentrated under reduced pressure. The resultant residue was taken up in EtOAc, washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of this concentrate on silica gel with a gradient of 0.5% EtOAc-hexanes to 2.0% EtOAc-hexanes gave 1-bromo-3-but-3-enylbenzene as an oil, 0.35 gm (50% yield); 1H NMR (400 MHz, CDCl3) δ: 2.33 (m, 2H), 2.66 (t, 2H, J=7.4 Hz), 4.98 (m, 2H), 5.79 (m, 1H), 7.12 (m, 2H), 7.30 (m, 2H). cooled to −78° C. stirred at −78° C. for 1 h to warm to room temperature quenched with aqueous NH4Cl concentrated under reduced pressure washed sequentially with water and brine dried over Na2SO4 concentrated under reduced pressure Chromatography of this concentrate on silica gel with a gradient of 0.5% EtOAc-hexanes to 2.0% EtOAc-hexanes