2-bromo-5-hydroxybenzonitrile

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

Procedure: 2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0, found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run). filtered over celite the filtrate was washed with water (3×50 mL) and brine (50 mL) dried over MgSO4 evaporated purified by column chromatography (5-45% EtOAc/hexanes)

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

Procedure: 2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0, found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run). filtered over celite the filtrate was washed with water (3×50 mL) and brine (50 mL) dried over MgSO4 evaporated purified by column chromatography (5-45% EtOAc/hexanes)

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

Procedure: 2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0, found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run). filtered over celite the filtrate was washed with water (3×50 mL) and brine (50 mL) dried over MgSO4 evaporated purified by column chromatography (5-45% EtOAc/hexanes)

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

Procedure: 2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0. found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run). filtered over celite the filtrate was washed with water (3×50 mL) and brine (50 mL) dried over MgSO4 evaporated purified by column chromatography (5-45% EtOAc/hexanes)

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

Procedure: 4-bromo-3-cyanophenol (1 g, 5.05 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.40 g, 10.10 mmol) and benzyl bromide (0.66 ml, 5.56 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 289 (M+H)+. extracted with EtOAc (2×10 mL) washed with brine (saturated, 1×8 mL) dried over MgSO4 filtered the volatiles removed in vacuo The residue was purified by chromatography on silica gel Biotage 25M

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 2.50 g (13 mmol) 2-bromo-5-hydroxy-benzonitrile in 100 mL DMF are added 5.23 g (38 mmol) K2CO3 and 3.05 g (25 mmol) cyclopropylbromide. The reaction mixture is stirred for 16 h at 120° C. Afterwards the reaction is quenched by the addition of ice water and extracted with EtOAc. The org. layers are combined, washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc). Afterwards the reaction is quenched by the addition of ice water extracted with EtOAc washed with sat. aq. NaCl solution dried over Na2SO4 filtered the solvent is removed in vacuo The crude product is purified by column chromatography (silica gel, PE/EtOAc)

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

Procedure: 4-bromo-3-cyanophenol (1 g, 5.05 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.40 g, 10.10 mmol) and benzyl bromide (0.66 ml, 5.56 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 289 (M+H)+. extracted with EtOAc (2×10 mL) washed with brine (saturated, 1×8 mL) dried over MgSO4 filtered the volatiles removed in vacuo The residue was purified by chromatography on silica gel Biotage 25M

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

Procedure: To a stirred solution of 2-bromo-5-hydroxy-benzonitrile (1.4 g, 7.1 mmol), ethyl acrylate (2.12 g, 21.2 mmol), palladium(II) acetate (0.159 g, 7.0 mmol), diisopropylethylamine (0.82 g, 14.1 mmol), and tri-ortho-tolylphosphine (0.430 g, 14.1 mmol) was added propionitrile (50 mL). The reaction was stirred overnight at 80° C. under a stream of N2. The mixture was cooled, filtered, and concentrated. The crude material (3.0 g) was purified by radial chromatography (10-70% EtOAc/hexanes) to give the title compound as a white solid (1.1 g). MS [EI] m/z 216 (M+H)+. The mixture was cooled filtered concentrated The crude material (3.0 g) was purified by radial chromatography (10-70% EtOAc/hexanes)

Conditions: temp:19.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-cyanophenol (2.00 g, 18.0 mmol) in anhydrous acetonitrile (20 mL) under N2 at −30° C. was added dropwise 54% HBF4.Et2O (2.48 mL, 18.0 mmol). The temperature was maintained below −20° C. during addition. To this stirred solution was added NBS (3.27 g, 18.0 mmol) portion wise keeping the temperature below −10° C. After the addition was complete, the solution was allowed to warm to 19° C. The reaction mixture was diluted with 38% NaHSO3 (10 mL) and extracted with MTBE (2×25 mL). The organic layer was washed with H2O (2×25 mL) and brine (25 mL), dried (MgSO4), filtered, and concentrated to give a white solid (3.15 g). Purification of a portion of this product (1.0 g) by radial chromatography (30% EtOAc/hexane) gave 0.51 g of the title compound as a white solid. mp 183-184° C. Anal. Calculated for C7H4BrNO: C, 42.46; H, 2.04; N, 7.07. Found: C, 42.44; H, 1.93; N, 6.90. The temperature was maintained below −20° C. during addition the temperature below −10° C After the addition extracted with MTBE (2×25 mL) The organic layer was washed with H2O (2×25 mL) and brine (25 mL) dried (MgSO4) filtered concentrated