2-bromo-6-fluorobenzonitrile

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

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

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

Procedure: To a solution of adamantanethiol (1.01 g) in N,N-dimethylacetamide (20 mL) at room temperature was added NaH (0.24 g, 60% in mineral oil) and the reaction was stirred for 10 minutes. 2-Fluoro-6-bromobenzonitrile (1 g) was added and the mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled and diluted with ether (400 mL), and the mixture was washed three times with 1M NaOH solution and once with brine, then dried over sodium sulfate, filtered and concentrated to yield the crude product which was taken on to the next step without purification. The reaction mixture was cooled the mixture was washed three times with 1M NaOH solution once with brine, then dried over sodium sulfate filtered concentrated

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

Procedure: 1-Adamantanethiol (278 mg) was dissolved in dimethyl sulfoxide (10 mL). Sodium hydride (60% in mineral oil, 42 mg) was added, and the solution was stirred at room temperature for 20 minutes. 2-Bromo-6-fluorobenzonitrile (300 mg) was added and the solution was heated to 130° C. for 1 hour. The solution was cooled, added to diethyl ether, washed with 1 M aqueous HCl three times, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the title compound. the solution was heated to 130° C. for 1 hour The solution was cooled washed with 1 M aqueous HCl three times washed with brine dried over anhydrous sodium sulfate After filtration the solvent was removed under vacuum

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

Procedure: A suspension of acetylhydroxamic acid (2.46 g, 32.8 mmol) and potassium tert-butoxide (3.68 g, 32.8 mmol) in DMF (40 mL) was stirred at room temperature for 30 minutes, treated with 2-bromo-6-fluorobenzonitrile (4.36 g, 21.8 mmol), stirred for three hours, poured into water, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5 to 20% ethyl acetate/hexanes to provide 2.5 g of the desired product. MS (ESI(+)) m/e 212.9, 214.9 (M+H)+. stirred for three hours extracted three times with ethyl acetate The combined extracts were washed with brine dried (MgSO4) filtered concentrated The residue was purified by flash column chromatography on silica gel with 5 to 20% ethyl acetate/hexanes

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

Procedure: 2-Amino-6-fluorobenzonitrile (18.0 g, 132 mmol) was dissolved in hot 1,4-dioxane (20 mL), 48% hydrobromic acid (200 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (10.5 g, 152 mmol) in water (20 mL) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (56.8 g, 396 mmol) in 48% hydrobromic acid (50 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (1200 mL) and extracted with ethyl acetate (2×400 mL). The combined organics were washed with 10% aqueous ammonia solution (400 mL), water (400 mL) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-6-fluorobenzonitrile (18.5 g, 70%) as a white solid: δH (400 MHz, CDCl3) 7.17-7.23 (1H, ddd, J 8, 8 and 1), 7.44-7.52 (2H, m). then poured onto The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min The mixture was cooled to ambient temperature extracted with ethyl acetate (2×400 mL) The combined organics were washed with 10% aqueous ammonia solution (400 mL), water (400 mL) and brine (500 mL) dried over anhydrous magnesium sulfate filtered evaporated to give an orange oil Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%)

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

Procedure: 2-Amino-6-fluorobenzonitrile (18.0 g, 132 mmol) was dissolved in hot 1,4-dioxane (20 mL), 48% hydrobromic acid (200 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (10.5 g, 152 mmol) in water (20 mL) over 1.5 h. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (56.8 g, 396 mmol) in 48% hydrobromic acid (50 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (1200 mL) and extracted with ethyl acetate (2×400 mL). The combined organics were washed with 10% aqueous ammonia solution (400 mL), water (400 mL) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give an orange oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%) gave 2-bromo-6-fluorobenzonitrile (18.5 g, 70%) as a white solid: δH (400 MHz, CDCl3) 7.17-7.23 (1H, ddd, J 8, 8 and 1), 7.44-7.52 (2H, m). then poured onto The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min The mixture was cooled to ambient temperature extracted with ethyl acetate (2×400 mL) The combined organics were washed with 10% aqueous ammonia solution (400 mL), water (400 mL) and brine (500 mL) dried over anhydrous magnesium sulfate filtered evaporated to give an orange oil Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (2-4%)

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

Procedure: To a solution of adamantanethiol (1.01 g) in N,N-dimethylacetamide (20 mL) at room temperature was added NaH (0.24 g, 60% in mineral oil) and the reaction was stirred for 10 minutes. 2-Fluoro-6-bromobenzonitrile (1 g) was added and the mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled and diluted with ether (400 mL), and the mixture was washed three times with 1M NaOH solution and once with brine, then dried over sodium sulfate, filtered and concentrated to yield the crude product which was taken on to the next step without purification. The reaction mixture was cooled the mixture was washed three times with 1M NaOH solution once with brine, then dried over sodium sulfate filtered concentrated

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

Procedure: 1-Adamantanethiol (278 mg) was dissolved in dimethyl sulfoxide (10 mL). Sodium hydride (60% in mineral oil, 42 mg) was added, and the solution was stirred at room temperature for 20 minutes. 2-Bromo-6-fluorobenzonitrile (300 mg) was added and the solution was heated to 130° C. for 1 hour. The solution was cooled, added to diethyl ether, washed with 1 M aqueous HCl three times, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the title compound. the solution was heated to 130° C. for 1 hour The solution was cooled washed with 1 M aqueous HCl three times washed with brine dried over anhydrous sodium sulfate After filtration the solvent was removed under vacuum

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

Procedure: A suspension of acetylhydroxamic acid (2.46 g, 32.8 mmol) and potassium tert-butoxide (3.68 g, 32.8 mmol) in DMF (40 mL) was stirred at room temperature for 30 minutes, treated with 2-bromo-6-fluorobenzonitrile (4.36 g, 21.8 mmol), stirred for three hours, poured into water, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5 to 20% ethyl acetate/hexanes to provide 2.5 g of the desired product. MS (ESI(+)) m/e 212.9, 214.9 (M+H)+. stirred for three hours extracted three times with ethyl acetate The combined extracts were washed with brine dried (MgSO4) filtered concentrated The residue was purified by flash column chromatography on silica gel with 5 to 20% ethyl acetate/hexanes

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

Procedure: To a microwave vial was added 1-(cyclopropylmethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2-1) (0.043 g, 0.12 mmol), 2-bromo-6-fluorobenzonitrile (0.035 g, 0.18 mmol), cesium carbonate (0.077 g, 0.24 mmol), palladium bis(tri-tert-butylphosphine) (0.012 g, 0.024 mmol), dioxane (1 mL), and water (0.2 mL). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 2-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]-6-fluorobenzonitrile (2-2) as a white solid. HRMS (M+H)+: observed=358.1015, calculated=358.1020 The crude reaction mixture to cool to room temperature filtered concentrated Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water)

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

Procedure: To a microwave vial was added 1-(cyclopropylmethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2-1) (0.043 g, 0.12 mmol), 2-bromo-6-fluorobenzonitrile (0.035 g, 0.18 mmol), cesium carbonate (0.077 g, 0.24 mmol), palladium bis(tri-tert-butylphosphine) (0.012 g, 0.024 mmol), dioxane (1 mL), and water (0.2 mL). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 2-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]-6-fluorobenzonitrile (2-2) as a white solid. HRMS (M+H)+: observed=358.1015, calculated=358.1020 The crude reaction mixture to cool to room temperature filtered concentrated Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water)