4-bromo-2-ethyl-1-fluorobenzene

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl iodide (0.14 ml, 1.8 mmol) was added to a solution of (5-bromo-2-fluorophenyl)(iodo)zinc (0.5M in tetrahydrofuran) (5.4 ml, 2.7 mmol) in HMPA (10 ml). The reaction mixture was heated to 100° C. for 48 hrs. After which time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo. The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes:ethyl acetate, to afford the title compound as a yellow oil (0.4 g). After which time the reaction mixture was cooled to room temperature partitioned between ethyl acetate (100 ml) and water (100 ml) The organic layer was separated dried over anhydrous sodium sulfate filtered the solvent was removed in vacuo The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-bromo-2-ethyl-1-fluoro-benzene (2.4 g, 11.82 mmol) in N,N-dimethylformamide (100 mL), trimethylsilyl acetylene (2.0 mL, 14.19 mmol), PdCl2(PPh3)2 (500 mg, 0.72 mmol), LiCl (1 g, 23.64 mmol), CuI (25 mg, 0.1 mmol) and triethylamine (3 mL) were added and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (hexanes) to give a brown oil. 1.58 g, 61%. extracted with diethyl ether The extract was dried (Na2SO4) concentrated The residue was chromatographed on silica gel (hexanes) to give a brown oil

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-bromo-2-ethyl-1-fluoro-benzene (2.4 g, 11.82 mmol) in N,N-dimethylformamide (100 mL), trimethylsilyl acetylene (2.0 mL, 14.19 mmol), PdCl2(PPh3)2 (500 mg, 0.72 mmol), LiCl (1 g, 23.64 mmol), CuI (25 mg, 0.1 mmol) and triethylamine (3 mL) were added and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel (hexanes) to give a brown oil. 1.58 g, 61%. extracted with diethyl ether The extract was dried (Na2SO4) concentrated The residue was chromatographed on silica gel (hexanes) to give a brown oil

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

Procedure: The yellow oil from step A (2.8 g, 10 mmol) was dissolved in Ethyl acetate (200 mL). Palladium-on-carbon (10%, 250 mg) was added and the mixture was hydrogenated under 1 atmosphere until TLC showed complete reaction. The mixture was filtered and the filtrate was concentrated to give an oil. 2.4 g, 87%. reaction The mixture was filtered the filtrate was concentrated to give an oil

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

Procedure: To a solution of 95A (290 mg, 1.43 mmol) in THF (5 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.86 mL, 2.15 mmol). The mixture was stirred at −78° C. for 30 min before trimethyl borate (0.32 mL, 2.86 mmol) was added. The reaction was left stirring from −78° C. to rt over 3 h. It was quenched with 1.0 N HCl (2 mL), extracted with EtOAc, washed with Na2S2O3, brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was purified by silica gel column chromatography eluting with gradient CH2Cl2 in hexanes (0-15%) to give 95B (170 mg, 71% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.09 (t, J=7.47 Hz, 3H) 2.54 (q, J=7.47 Hz, 2H) 6.81-6.88 (m, 1H) 7.42-7.47 (m, 1H) 7.51 (d, J=9.23 Hz, 1H). was added The reaction was left It was quenched with 1.0 N HCl (2 mL) extracted with EtOAc washed with Na2S2O3, brine dried over Na2SO4 After evaporation of the solvent the crude solid product was purified by silica gel column chromatography eluting with gradient CH2Cl2 in hexanes (0-15%)

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

Procedure: 4-Bromo-1-fluoro-2-vinylbenzene (470 mg) was hydrogenated in EtOAc with 10% Pd/C (100 mg) with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration. The filtrate was condensed to give 95A (290 mg, 62% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (t, J=6.81 Hz, 3H) 2.63 (d, J=7.03 Hz, 2H) 6.88 (t, J=8.57 Hz, 1H) 7.25 (s, 1H) 7.32 (d, J=4.39 Hz, 1H). The Pd/C was removed by filtration condensed

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl iodide (0.14 ml, 1.8 mmol) was added to a solution of (5-bromo-2-fluorophenyl)(iodo)zinc (0.5M in tetrahydrofuran) (5.4 ml, 2.7 mmol) in HMPA (10 ml). The reaction mixture was heated to 100° C. for 48 hrs. After which time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo. The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes:ethyl acetate, to afford the title compound as a yellow oil (0.4 g). After which time the reaction mixture was cooled to room temperature partitioned between ethyl acetate (100 ml) and water (100 ml) The organic layer was separated dried over anhydrous sodium sulfate filtered the solvent was removed in vacuo The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl iodide (0.14 ml, 1.8 mmol) was added to a solution of (5-bromo-2-fluorophenyl)(iodo)zinc (0.5M in tetrahydrofuran) (5.4 ml, 2.7 mmol) in HMPA (10 ml). The reaction mixture was heated to 100° C. for 48 hrs. After which time the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo. The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes:ethyl acetate, to afford the title compound as a yellow oil (0.4 g). After which time the reaction mixture was cooled to room temperature partitioned between ethyl acetate (100 ml) and water (100 ml) The organic layer was separated dried over anhydrous sodium sulfate filtered the solvent was removed in vacuo The crude oil was purified by column chromatography on silica gel eluting with 80:20 hexanes