4-bromo-2-hydroxybenzonitrile

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

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), ethylene carbonate (467 mg, 5.30 mmol) and potassium carbonate (348 mg, 2.52 mmol) were suspended in DMF (2.00 mL) and heated to 125° C. for 4.5 h. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to give the title compound (686 mg, 56%). 1H NMR (300 MHz, d4-MeOD): 3.92 (2H, t, J=4.7 Hz), 4.21 (2H, t, J=4.7 Hz), 7.26 (1H, dd, J=8.2, 1.7 Hz), 7.44 (1H, d, J=1.6 Hz), 7.53 (1H, d, J=8.2 Hz). The mixture was partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo The residue was purified by FCC

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), ethylene carbonate (467 mg, 5.30 mmol) and potassium carbonate (348 mg, 2.52 mmol) were suspended in DMF (2.00 mL) and heated to 125° C. for 4.5 h. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to give the title compound (686 mg, 56%). 1H NMR (300 MHz, d4-MeOD): 3.92 (2H, t, J=4.7 Hz), 4.21 (2H, t, J=4.7 Hz), 7.26 (1H, dd, J=8.2, 1.7 Hz), 7.44 (1H, d, J=1.6 Hz), 7.53 (1H, d, J=8.2 Hz). The mixture was partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo The residue was purified by FCC

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), ethylene carbonate (467 mg, 5.30 mmol) and potassium carbonate (348 mg, 2.52 mmol) were suspended in DMF (2.00 mL) and heated to 125° C. for 4.5 h. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to give the title compound (686 mg, 56%). 1H NMR (300 MHz, d4-MeOD): 3.92 (2H, t, J=4.7 Hz), 4.21 (2H, t, J=4.7 Hz), 7.26 (1H, dd, J=8.2, 1.7 Hz), 7.44 (1H, d, J=1.6 Hz), 7.53 (1H, d, J=8.2 Hz). The mixture was partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo The residue was purified by FCC

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

Procedure: To a stirred solution of 4-bromo-2-methoxy-benzonitrile (4.60 g, 21.7 mmol) in methylene chloride (20 mL) was added aluminum chloride (14.5 g, 108 mmol). After stirring under an argon atmosphere for 10 min, more methylene chloride (30 mL) was added, and the mixture left to reflux under argon overnight. The reaction was then diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure, providing (4.09 g, 95.2%) of 4-bromo-2-hydroxy-benzonitrile as a slightly gray-colored product. 1H-NMR (CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 7.19 (d, J=1.4 Hz, 1H), 7.14 (dd, J=8.4, 1.4 Hz, 1H), 6.15 (s, 1H); TLC Rf=0.78 (50% ethyl acetate—hexane). the mixture left to reflux under argon overnight washed with water, brine dried over magnesium sulfate The solvent was removed at reduced pressure

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), ethylene carbonate (467 mg, 5.30 mmol) and potassium carbonate (348 mg, 2.52 mmol) were suspended in DMF (2.00 mL) and heated to 125° C. for 4.5 h. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to give the title compound (686 mg, 56%). 1H NMR (300 MHz, d4-MeOD): 3.92 (2H, t, J=4.7 Hz), 4.21 (2H, t, J=4.7 Hz), 7.26 (1H, dd, J=8.2, 1.7 Hz), 7.44 (1H, d, J=1.6 Hz), 7.53 (1H, d, J=8.2 Hz). The mixture was partitioned between EtOAc and water The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo The residue was purified by FCC

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

Procedure: To a stirred solution of 4-bromo-2-methoxy-benzonitrile (4.60 g, 21.7 mmol) in methylene chloride (20 mL) was added aluminum chloride (14.5 g, 108 mmol). After stirring under an argon atmosphere for 10 min, more methylene chloride (30 mL) was added, and the mixture left to reflux under argon overnight. The reaction was then diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure, providing (4.09 g, 95.2%) of 4-bromo-2-hydroxy-benzonitrile as a slightly gray-colored product. 1H-NMR (CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 7.19 (d, J=1.4 Hz, 1H), 7.14 (dd, J=8.4, 1.4 Hz, 1H), 6.15 (s, 1H); TLC Rf=0.78 (50% ethyl acetate—hexane). the mixture left to reflux under argon overnight washed with water, brine dried over magnesium sulfate The solvent was removed at reduced pressure

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

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

Procedure: To a solution of 4-bromo-2-hydroxybenzonitrile (2 g, 10 mmol) in DMF (15 mL) and was added iodomethanel (2.87 g, 20.2 mmol) and potassium carbonate (2.79 g, 20.2 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-bromo-2-methoxybenzonitrile (2.08 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.0 Hz, 1H), 7.10 (dd, J=8.4, 1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 3.87 (s, 3H). extracted with ethyl acetate (10 mL*3) The combined organic layers were dried over anhydrous Na2SO4 concentrated under reduced pressure

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

Procedure: A solution of 4-bromo-2-hydroxy-benzonitrile (0.89 g, 4.45 mmol) in THF (50 mL) and 1-butanol (2.0 mL) is slowly added to NaH (0.356 g, 8.90 mmol). The mixture is stirred at room temperature for one hour and quenched with water (10 mL). The mixture is concentrated, and the residue is extracted with ethyl acetate (20 mL×2). The combined organic layers are dried over sodium sulfate and concentrated to provide 4-bromo-2-butoxy-benzonitrile (0.65 g, 57%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.34 (d, 1H), 7.11-7.08 (d, 1H), 7.08 (s, 1H), 4.04-4.01 (t, 2H), 1.80 (tt, 2H), 1.50 (tt, 2H), 0.95 (t, 3H). quenched with water (10 mL) The mixture is concentrated the residue is extracted with ethyl acetate (20 mL×2) The combined organic layers are dried over sodium sulfate concentrated

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

Procedure: A solution of 4-bromo-2-hydroxy-benzonitrile (0.89 g, 4.45 mmol) in THF (50 mL) and 1-butanol (2.0 mL) is slowly added to NaH (0.356 g, 8.90 mmol). The mixture is stirred at room temperature for one hour and quenched with water (10 mL). The mixture is concentrated, and the residue is extracted with ethyl acetate (20 mL×2). The combined organic layers are dried over sodium sulfate and concentrated to provide 4-bromo-2-butoxy-benzonitrile (0.65 g, 57%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.34 (d, 1H), 7.11-7.08 (d, 1H), 7.08 (s, 1H), 4.04-4.01 (t, 2H), 1.80 (tt, 2H), 1.50 (tt, 2H), 0.95 (t, 3H). quenched with water (10 mL) The mixture is concentrated the residue is extracted with ethyl acetate (20 mL×2) The combined organic layers are dried over sodium sulfate concentrated

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

Procedure: A mixture of 2-fluoro-5-bromobenzonitrile (30 g, 152.3 mmole), potassium acetate (222.4 g, 228.5 mmole), and 18-crown-6 ether (60.4 g, 288.5 mmole) in MeCN (400 mL) was heated at reflux in 36 h. The mixture was cooled, added 2.5 N NaOH (200 mL), stirred at RT overnight. The mixture was extracted with ether (discarded). The aqueous layer was acidified with 6N HCl, extracted with EtOAc, dried over MgSO4, concentrated, purified by flash column chromatography (40% EtOAc/Hex) to give a light yellow foam (24.45 g, 81%). 1H-NMR (300 MHz, DMSO-d6): δ7.13 (dd, J=1.7, 8.3 Hz, 1H), 7.17 (d, J=1.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H). was heated at reflux in 36 h The mixture was cooled The mixture was extracted with ether (discarded) extracted with EtOAc dried over MgSO4 concentrated purified by flash column chromatography (40% EtOAc/Hex)