4-Fluorophenetole

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

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

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4-ethoxy-1-fluorobenzene (1.0 g, 7.1 mmol) in THF (8.0 mL) was added freshly distilled N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.8 mL) and 1.6 M n-butyllithium in hexane (5.13 ml, 8.2 mmol) at −78° C. After stirred at −60° C. for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. and the solution was warmed up to rt for 2 h. The reaction was quenched by acetic acid (1.5 ml) at 0° C. After 15 min, 30% hydrogen peroxide (1.2 ml) was introduced and the mixture was stirred from 0° C. to rt overnight. The mixture was extracted by EtOAc (3×30 mL). The combined organic layer was washed by brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 1.0 g colorless oil of 74A. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (t, J=6.81 Hz, 3 H) 3.96 (q, J=7.03 Hz, 2H) 5.30 (d, J=2.20 Hz, 1H) 6.28-6.43 (m, 1H) 6.55 (dd, J=7.47, 3.08 Hz, 1H) 6.90-7.01 (m, 1H). the solution was warmed up to rt for 2 h The reaction was quenched by acetic acid (1.5 ml) at 0° C After 15 min 30% hydrogen peroxide (1.2 ml) was introduced the mixture was stirred from 0° C. to rt overnight The mixture was extracted by EtOAc (3×30 mL) The combined organic layer was washed by brine dried over MgSO4 concentrated The crude product was purified by column chromatography

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4-ethoxy-1-fluorobenzene (1.0 g, 7.1 mmol) in THF (8.0 mL) was added freshly distilled N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.8 mL) and 1.6 M n-butyllithium in hexane (5.13 ml, 8.2 mmol) at −78° C. After stirred at −60° C. for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. and the solution was warmed up to rt for 2 h. The reaction was quenched by acetic acid (1.5 ml) at 0° C. After 15 min, 30% hydrogen peroxide (1.2 ml) was introduced and the mixture was stirred from 0° C. to rt overnight. The mixture was extracted by EtOAc (3×30 mL). The combined organic layer was washed by brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 1.0 g colorless oil of 74A. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (t, J=6.81 Hz, 3 H) 3.96 (q, J=7.03 Hz, 2H) 5.30 (d, J=2.20 Hz, 1H) 6.28-6.43 (m, 1H) 6.55 (dd, J=7.47, 3.08 Hz, 1H) 6.90-7.01 (m, 1H). the solution was warmed up to rt for 2 h The reaction was quenched by acetic acid (1.5 ml) at 0° C After 15 min 30% hydrogen peroxide (1.2 ml) was introduced the mixture was stirred from 0° C. to rt overnight The mixture was extracted by EtOAc (3×30 mL) The combined organic layer was washed by brine dried over MgSO4 concentrated The crude product was purified by column chromatography

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4-ethoxy-1-fluorobenzene (1.0 g, 7.1 mmol) in THF (8.0 mL) was added freshly distilled N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.8 mL) and 1.6 M n-butyllithium in hexane (5.13 ml, 8.2 mmol) at −78° C. After stirred at −60° C. for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. and the solution was warmed up to rt for 2 h. The reaction was quenched by acetic acid (1.5 ml) at 0° C. After 15 min, 30% hydrogen peroxide (1.2 ml) was introduced and the mixture was stirred from 0° C. to rt overnight. The mixture was extracted by EtOAc (3×30 mL). The combined organic layer was washed by brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 1.0 g colorless oil of 74A. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (t, J=6.81 Hz, 3 H) 3.96 (q, J=7.03 Hz, 2H) 5.30 (d, J=2.20 Hz, 1H) 6.28-6.43 (m, 1H) 6.55 (dd, J=7.47, 3.08 Hz, 1H) 6.90-7.01 (m, 1H). the solution was warmed up to rt for 2 h The reaction was quenched by acetic acid (1.5 ml) at 0° C After 15 min 30% hydrogen peroxide (1.2 ml) was introduced the mixture was stirred from 0° C. to rt overnight The mixture was extracted by EtOAc (3×30 mL) The combined organic layer was washed by brine dried over MgSO4 concentrated The crude product was purified by column chromatography

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

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

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-ethoxy-4-fluorobenzene (1.1 g, 7.9 mmol) and pentamethyl diethylene triamine (2 mL) in anhydrous THF (6 mL) was added BuLi dropwise (1.38 M, 5.98 mL, 8.3 mmol) at −78° C. After addition, the reaction mixture was warmed up to −40° C. and stirred for 30 min, the reaction mixture was then cooled to −78° C. and DMF (0.7 mL) was added. The solution was warmed to rt, and stirred for 1 h. The reaction mixture was then partitioned between EtOAc and sat. NH4Cl, the organic layer was dried over (Na2SO4), filtered and concentrated. The residue was subjected to chromatographic purification (0-10% EtOAc/hexanes gradient), 600 mg (55%) of Intermediate 53.1 was obtained. 1H NMR (CDCl3) δ 1.40 (t, 3H), 4.08 (q, 2H), 6.81 (m, 1H), 7.15 (m, 1H), 7.29 (m, 1H), 10.33 (s, 1H). After addition the reaction mixture was then cooled to −78° C. The solution was warmed to rt stirred for 1 h The reaction mixture was then partitioned between EtOAc and sat. NH4Cl the organic layer was dried over (Na2SO4) filtered concentrated The residue was subjected to chromatographic purification (0-10% EtOAc/hexanes gradient)

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

Procedure: To 150 ml of a THF solution containing 10.5 g of 1-ethoxy-4-fluorobenzene, 50 ml of n-butyllithium (1.58 M, hexane solution) was added dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred for 4 and a half hours, then 8.9 ml of trimethoxy boron was added thereto. Then, the temperature of the mixture was slowly allowed to rise to room temperature. The reaction mixture was stirred for 3 and a half hours, then 12.9 ml of acetic acid and 12.7 ml of a 30% hydrogen peroxide aqueous solution were added thereto at 0° C. The mixture was stirred at room temperature overnight, and then a saturated sodium sulfite aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give a crude product of 5-ethoxy-2-fluorophenol. was added dropwise at −78° C. under a nitrogen atmosphere to rise to room temperature The reaction mixture was stirred for 3 and a half hours at 0° C The mixture was stirred at room temperature overnight The mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate The desiccating agent was removed by filtration the filtrate was concentrated under reduced pressure The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4-ethoxy-1-fluorobenzene (1.0 g, 7.1 mmol) in THF (8.0 mL) was added freshly distilled N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.8 mL) and 1.6 M n-butyllithium in hexane (5.13 ml, 8.2 mmol) at −78° C. After stirred at −60° C. for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. and the solution was warmed up to rt for 2 h. The reaction was quenched by acetic acid (1.5 ml) at 0° C. After 15 min, 30% hydrogen peroxide (1.2 ml) was introduced and the mixture was stirred from 0° C. to rt overnight. The mixture was extracted by EtOAc (3×30 mL). The combined organic layer was washed by brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 1.0 g colorless oil of 74A. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (t, J=6.81 Hz, 3 H) 3.96 (q, J=7.03 Hz, 2H) 5.30 (d, J=2.20 Hz, 1H) 6.28-6.43 (m, 1H) 6.55 (dd, J=7.47, 3.08 Hz, 1H) 6.90-7.01 (m, 1H). the solution was warmed up to rt for 2 h The reaction was quenched by acetic acid (1.5 ml) at 0° C After 15 min 30% hydrogen peroxide (1.2 ml) was introduced the mixture was stirred from 0° C. to rt overnight The mixture was extracted by EtOAc (3×30 mL) The combined organic layer was washed by brine dried over MgSO4 concentrated The crude product was purified by column chromatography