1-chloro-3-fluoro-2-methoxybenzene

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

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

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

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

Procedure: Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg, 6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml). The organic phase was extracted and further washed with water (2×20 ml) then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless liquid in 94% yield, 1.03 g. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml) The organic phase was extracted further washed with water (2×20 ml) then dried over sodium sulphate concentrated in vacuo

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

Procedure: 2-Chloro-6-fluoro anisole (5 g, 31.13 mmol) was dissolved in DCM (300 mL) and cooled to about −78° C. To the solution was added BBr3 (7.35 mL, 77.8 mmol) in one portion. The reaction was warmed to r.t, stirred for about 16 hours and poured over ice to quench remaining BBr3. The material was partitioned between water and DCM (500 mL each). The aqueous layer was back extracted with DCM (200 mL), and the combined organics were dried (NaSO4), filtered and concentrated to give the product (4.60 g) as a dark oil. The reaction was warmed poured over ice to quench The material was partitioned between water and DCM (500 mL each) The aqueous layer was back extracted with DCM (200 mL) the combined organics were dried (NaSO4) filtered concentrated

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

Procedure: Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg, 6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml). The organic phase was extracted and further washed with water (2×20 ml) then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless liquid in 94% yield, 1.03 g. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml) The organic phase was extracted further washed with water (2×20 ml) then dried over sodium sulphate concentrated in vacuo

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

Procedure: Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg, 6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml). The organic phase was extracted and further washed with water (2×20 ml) then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless liquid in 94% yield, 1.03 g. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml) The organic phase was extracted further washed with water (2×20 ml) then dried over sodium sulphate concentrated in vacuo

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

Procedure: Aluminum chloride (1.16 g, 8.72 mmol) was added to a stirred mixture of 1-chloro-3-fluoro-2-methoxybenzene (1.00 mL, 8.72 mmol) and hexanoyl chloride (1.47 mL, 10.46 mmol) at room temperature. The mixture warmed and HCl evolution occurred. The resulting mixture was stirred at room temperature for 67 hours and then partitioned between EtOAc (40 mL) and ice cold water (40 mL). The EtOAc layer was washed with brine (30 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield crude 1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone as an oil. The mixture warmed partitioned between EtOAc (40 mL) and ice cold water (40 mL) The EtOAc layer was washed with brine (30 mL) dried over MgSO4 filtered evaporated under vacuum

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

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

Procedure: Aluminum chloride (1.16 g, 8.72 mmol) was added to a stirred mixture of 1-chloro-3-fluoro-2-methoxybenzene (1.00 mL, 8.72 mmol) and hexanoyl chloride (1.47 mL, 10.46 mmol) at room temperature. The mixture warmed and HCl evolution occurred. The resulting mixture was stirred at room temperature for 67 hours and then partitioned between EtOAc (40 mL) and ice cold water (40 mL). The EtOAc layer was washed with brine (30 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield crude 1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone as an oil. The mixture warmed partitioned between EtOAc (40 mL) and ice cold water (40 mL) The EtOAc layer was washed with brine (30 mL) dried over MgSO4 filtered evaporated under vacuum

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

Procedure: Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.

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

Procedure: Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.