1-(4-bromophenoxy)-2-methylpropan-2-ol

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

Procedure: A solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) was added to oil-free sodium hydride (132 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes and then cooled to -78° C. 1.6M Butyl lithium in hexane (6.9 ml) was added over 5 minutes and the solution was stirred at -78° C. for 30 minutes. Trimethylborate (1.14 g) was added over 1 minute and the mixture was stirred at -78° C. for 1 hour. Saturated ammonium chloride solution (25 ml) was added and the mixture was allowed to warm to room temperature. Water (25 ml) was added and the mixture was extracted with ether (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg), 1H NMR (d6 -DMSO): 1.2 (s, 6 H), 3.7 (s, 2 H), 4.5 (br s, 1 H), 6.85 (d, 2 H), 7.6-7.8 (m, 4 H). the solution was stirred at -78° C. for 30 minutes the mixture was stirred at -78° C. for 1 hour to warm to room temperature the mixture was extracted with ether (2×25 ml) The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) dried (MgSO4) Volatile material was removed by evaporation the residue was purified by flash chromatography eluting with ethyl acetate/hexane (7:3 v/v)

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

Procedure: A solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) was added to oil-free sodium hydride (132 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes and then cooled to -78° C. 1.6M Butyl lithium in hexane (6.9 ml) was added over 5 minutes and the solution was stirred at -78° C. for 30 minutes. Trimethylborate (1.14 g) was added over 1 minute and the mixture was stirred at -78° C. for 1 hour. Saturated ammonium chloride solution (25 ml) was added and the mixture was allowed to warm to room temperature. Water (25 ml) was added and the mixture was extracted with ether (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg), 1H NMR (d6 -DMSO): 1.2 (s, 6H), 3.7 (s, 2H), 4.5 (br s, 1H), 6.85 (d, 2H), 7.6-7.8 (m, 4H the solution was stirred at -78° C. for 30 minutes the mixture was stirred at -78° C. for 1 hour to warm to room temperature the mixture was extracted with ether (2×25 ml) The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) dried (MgSO4) Volatile material was removed by evaporation the residue was purified by flash chromatography eluting with ethyl acetate/hexane (7:3 v/v)

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

Procedure: A solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) was added to oil-free sodium hydride (132 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes and then cooled to -78° C. 1.6M Butyl lithium in hexane (6.9 ml) was added over 5 minutes and the solution was stirred at -78° C. for 30 minutes. Trimethylborate (1.14 g) was added over 1 minute and the mixture was stirred at -78° C. for 1 hour. Saturated ammonium chloride solution (25 ml) was added and the mixture was allowed to warm to room temperature. Water (25 ml) was added and the mixture was extracted with ether (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg), 1H NMR (d6 -DMSO): 1.2 (s, 6H), 3.7 (s, 2H), 4.5 (br s, 1H), 6.85 (d, 2H), 7.6-7.8 (m, 4H the solution was stirred at -78° C. for 30 minutes the mixture was stirred at -78° C. for 1 hour to warm to room temperature the mixture was extracted with ether (2×25 ml) The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) dried (MgSO4) Volatile material was removed by evaporation the residue was purified by flash chromatography eluting with ethyl acetate/hexane (7:3 v/v)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (25 mg, 0.100 mmol), K3PO4 (63.5 mg, 0.299 mmol), copper (1) iodide (18.99 mg, 0.100 mmol), 1-(4-bromophenoxy)-2-methylpropan-2-ol and N,N′-dimethylethylenediamine (0.032 mL, 0.299 mmol) in dioxane (1.0 mL) was stirred at 110° C. for 60 min. After removal of the precipitate by filtration, the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (CH2Cl2 to 10% MeOH/CH2Cl2) to elute 3-(4-chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one (31.82 mg, 0.073 mmol, 73.1% yield) as white solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.32 (2H, d), 7.23-7.29 (4 H, m), 7.02 (2H, d), 6.84 (2H, s), 4.51 (2H, t, J=7.29 Hz), 3.83 (2H, s), 3.13 (2H, t, J=7.15 Hz), 1.36 (6H, s). After removal of the precipitate by filtration the filtrate was concentrated The crude product was purified by silica gel chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (25 mg, 0.100 mmol), K3PO4 (63.5 mg, 0.299 mmol), copper (1) iodide (18.99 mg, 0.100 mmol), 1-(4-bromophenoxy)-2-methylpropan-2-ol and N,N′-dimethylethylenediamine (0.032 mL, 0.299 mmol) in dioxane (1.0 mL) was stirred at 110° C. for 60 min. After removal of the precipitate by filtration, the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (CH2Cl2 to 10% MeOH/CH2Cl2) to elute 3-(4-chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one (31.82 mg, 0.073 mmol, 73.1% yield) as white solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.32 (2H, d), 7.23-7.29 (4 H, m), 7.02 (2H, d), 6.84 (2H, s), 4.51 (2H, t, J=7.29 Hz), 3.83 (2H, s), 3.13 (2H, t, J=7.15 Hz), 1.36 (6H, s). After removal of the precipitate by filtration the filtrate was concentrated The crude product was purified by silica gel chromatography

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

Procedure: A mixture of 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (25 mg, 0.100 mmol), K3PO4. (63.5 mg, 0.299 mmol), copper (1) iodide (18.99 mg, 0.100 mmol), 1-(4-bromophenoxy)-2-methylpropan-2-ol and N,N′-dimethylethylenediamine (0.032 mL, 0.299 mmol) in dioxane (1.0 mL) was stirred at 110° C. for 60 min. After removal of the precipitate by filtration, the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (CH2Cl2 to 10% MeOH/CH2Cl2) to elute 3-(4-chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one (31.82 mg, 0.073 mmol, 73.1% yield) as white solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.32 (2H, d), 7.23-7.29 (4 H, m), 7.02 (2H, d), 6.84 (2H, s), 4.51 (2H, t, J=7.29 Hz), 3.83 (2H, s), 3.13 (2H, t, J=7.15 Hz), 1.36 (6H, s). After removal of the precipitate by filtration the filtrate was concentrated The crude product was purified by silica gel chromatography

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

Procedure: A solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) was added to oil-free sodium hydride (132 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes and then cooled to -78° C. 1.6M Butyl lithium in hexane (6.9 ml) was added over 5 minutes and the solution was stirred at -78° C. for 30 minutes. Trimethylborate (1.14 g) was added over 1 minute and the mixture was stirred at -78° C. for 1 hour. Saturated ammonium chloride solution (25 ml) was added and the mixture was allowed to warm to room temperature. Water (25 ml) was added and the mixture was extracted with ether (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg), 1H NMR (d6 -DMSO): 1.2 (s, 6 H), 3.7 (s, 2 H), 4.5 (br s, 1 H), 6.85 (d, 2 H), 7.6-7.8 (m, 4 H). the solution was stirred at -78° C. for 30 minutes the mixture was stirred at -78° C. for 1 hour to warm to room temperature the mixture was extracted with ether (2×25 ml) The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) dried (MgSO4) Volatile material was removed by evaporation the residue was purified by flash chromatography eluting with ethyl acetate/hexane (7:3 v/v)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-chloro-2-methylpropan-2-ol (434.4 mg, 4 mmol) in DMF (10 mL) was added K2CO3 (552 mg, 4 mmol) and 4-bromophenol (346 mg, 2 mmol), the reaction was stirred at 140° C. for 48 hours. About of 10% 4-bromophenol was remained and the reaction was poured into 30 mL of water, extracted with EA (20 mL×3), washed with 30 mL of water and brine, concentrated and purified on TLC (EA:PE=1:3) to give yellow solid. MS (m/z): 196 (M−50)+ extracted with EA (20 mL×3) washed with 30 mL of water and brine concentrated purified on TLC (EA:PE=1:3) to give yellow solid

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-chloro-2-methylpropan-2-ol (434.4 mg, 4 mmol) in DMF (10 mL) was added K2CO3 (552 mg, 4 mmol) and 4-bromophenol (346 mg, 2 mmol), the reaction was stirred at 140° C. for 48 hours. About of 10% 4-bromophenol was remained and the reaction was poured into 30 mL of water, extracted with EA (20 mL×3), washed with 30 mL of water and brine, concentrated and purified on TLC (EA:PE=1:3) to give yellow solid. MS (m/z): 196 (M−50)+ extracted with EA (20 mL×3) washed with 30 mL of water and brine concentrated purified on TLC (EA:PE=1:3) to give yellow solid

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

Procedure: A solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) was added to oil-free sodium hydride (132 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes and then cooled to −78° C. 1.6M Butyl lithium in hexane (6.9 ml) was added over 5 minutes and the solution was stirred at −78° C. for 30 minutes. Trimethylborate (1.14 g) was added over 1 minute and the mixture was stirred at −78° C. for 1 hour. Saturated ammonium chloride solution (25 ml) was added and the mixture was allowed to warm to room temperature. Water (25 ml) was added and the mixture was extracted with ether (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg), 1H NMR (d6-DMSO): 1.2 (s, 6H), 3.7 (s, 2H), 4.5 (br s, 1H), 6.85 (d, 2H), 7.6-7.8 (m, 4H). the solution was stirred at −78° C. for 30 minutes the mixture was stirred at −78° C. for 1 hour to warm to room temperature the mixture was extracted with ether (2×25 ml) The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) dried (MgSO4) Volatile material was removed by evaporation the residue was purified by flash chromatography eluting with ethyl acetate/hexane (7:3 v/v)

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

Procedure: A solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) was added to oil-free sodium hydride (132 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes and then cooled to -78° C. 1.6M Butyl lithium in hexane (6.9 ml) was added over 5 minutes and the solution was stirred at -78° C. for 30 minutes. Trimethylborate (1.14 g) was added over 1 minute and the mixture was stirred at -78° C. for 1 hour. Saturated ammonium chloride solution (25 ml) was added and the mixture was allowed to warm to room temperature. Water (25 ml) was added and the mixture was extracted with ether (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg), 1H NMR (d6 -DMSO): 1.2 (s, 6H), 3.7 (s, 2H), 4.5 (br s, 1H), 6.85 (d, 2H), 7.6-7.8 (m, 4H the solution was stirred at -78° C. for 30 minutes the mixture was stirred at -78° C. for 1 hour to warm to room temperature the mixture was extracted with ether (2×25 ml) The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) dried (MgSO4) Volatile material was removed by evaporation the residue was purified by flash chromatography eluting with ethyl acetate/hexane (7:3 v/v)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (25 mg, 0.100 mmol), K3PO4 (63.5 mg, 0.299 mmol), copper (1) iodide (18.99 mg, 0.100 mmol), 1-(4-bromophenoxy)-2-methylpropan-2-ol and N,N′-dimethylethylenediamine (0.032 mL, 0.299 mmol) in dioxane (1.0 mL) was stirred at 110° C. for 60 min. After removal of the precipitate by filtration, the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (CH2Cl2 to 10% MeOH/CH2Cl2) to elute 3-(4-chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one (31.82 mg, 0.073 mmol, 73.1% yield) as white solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.32 (2H, d), 7.23-7.29 (4 H, m), 7.02 (2H, d), 6.84 (2H, s), 4.51 (2H, t, J=7.29 Hz), 3.83 (2H, s), 3.13 (2H, t, J=7.15 Hz), 1.36 (6H, s). After removal of the precipitate by filtration the filtrate was concentrated The crude product was purified by silica gel chromatography