2-(4-bromo-2-methylphenyl)acetonitrile

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

Procedure: To a stirred solution of 2-(4-bromo-2-methylphenyl)acetonitrile (3.93 g, 18.8 mmol) in anhydrous DMF (35 mL) is added methyl iodide (2.45 mL, 39.4 mmol). The solution is cooled to 0° C. and sodium hydride (60% susp. in oil, 1.47 g, 61.1 mmol) is added in 3 equal portions over 20 min. The reaction mixture is then left stirring and slowly warmed up to room temperature for 18 h. The solution turned to a thick brown-orange paste. At 0° C., water (50 mL) is then slowly added and the solution is extracted with a 2:1 solution of hexane/Et2O (3×50 mL). The organic layer is washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The crude is purified by flash-chromatography, eluting with hexane/EtOAc (9:1) to provide the expected product 2-(4-bromo-2-methylphenyl)-2-methylpropanenitrile (3.1 g, 66%) as a clear yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.30 (2H, m), 7.16 (2H, d, J=8.5 Hz), 2.63 (3H, s), 1.77 (6H, s). The reaction mixture is then left slowly warmed up to room temperature for 18 h the solution is extracted with a 2:1 solution of hexane/Et2O (3×50 mL) The organic layer is washed with brine dried with MgSO4 filtered concentrated under reduced pressure The crude is purified by flash-chromatography eluting with hexane/EtOAc (9:1)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-4-(bromomethyl)-3-methylbenzene (13.2 g, 50.1 mmol) is dissolved in DMF (65 mL). The reaction mixture is cooled to 0-5° C. and NaCN (3.66 g, 74.6 mmol) is added follow by water (8 mL). The reaction is stirred overnight at room temperature and water (170 mL) is added followed by NaHCO3 sat. (130 mL) and hexane/Et2O (2:1) (150 mL). The organic phase is separated and the aqueous phase extracted with hexane/Et2O (2:1) (3×150 mL). The combined organic phases are washed with water (170 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-methylphenyl)acetonitrile (9.76 g, 93%) as an orange oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.32 (2H, m), 7.23 (2H, d, J=8.2 Hz), 3.61 (2H, s), 2.32 (3H, s). The organic phase is separated the aqueous phase extracted with hexane/Et2O (2:1) (3×150 mL) The combined organic phases are washed with water (170 mL) dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of (4-bromo-2-methyl-phenyl)-acetonitrile (1.26 g, 6 mmol) from step 3 above in DMF (15 mL) cooled to −10° C. was added a potassium t-butoxide (1.62 g, 14.4 mmol). The reaction was stirred for 15 minutes, iodomethane (0.86 mL, 13.8 mmol) was added slowly. The reaction was stirred for 2 hours then quenched with HOAc (0.51 mL, 9 mmol). The reaction mixture stirred for 20 minutes and mixed with IPE (250 mL) and water (200 mL). The layers were separated, and the aqueous layer was extracted with 3×100 mL IPE. The combined organics were washed with 200 mL water, and then dried over MgSO4. After filtering off the solids, the mother liquor was concentrated to the crude product by rotary evaporation. The residue was purified by flash column chromatography (0% to 75% EtOAc in Hexane) to give the desired product. Yield: 1.28 g, 89%. 1H NMR (400 MHz, CDCl3): δ 1.77 (6 H, s) 2.62 (3 H, s) 7.16 (1 H, d, J=8.59 Hz) 7.31–7.40 (2 H, m). The reaction was stirred for 2 hours The reaction mixture stirred for 20 minutes The layers were separated the aqueous layer was extracted with 3×100 mL IPE The combined organics were washed with 200 mL water dried over MgSO4 After filtering off the solids the mother liquor was concentrated to the crude product by rotary evaporation The residue was purified by flash column chromatography (0% to 75% EtOAc in Hexane)

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

Procedure: To a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (3.96 g, 15 mmol) dissolved in DMF (16 mL) were added sodium cyanide (0.85 g, 17.25 mmol) and water (1.8 mL). The reaction was stirred for overnight at room temperature. To the reaction was added 100 mL water; 80 mL saturated NaHCO3, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3×100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7% yield). 1H NMR (400 MHz, CDCl3): δ 2.32 (2 H, s), 3.62 (1 H, s), 7.20–7.27 (1 H, m), 7.32–7.41 (1 H, m). The layers were separated the aqueous layer was extracted with 3×100 mL EtOAc The combined organics were washed with 100 mL water dried over Na2SO4 After filtering off the solids the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7% yield)

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

Procedure: To a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (3.96 g, 15 mmol) dissolved in DMF (16 mL) were added sodium cyanide (0.85 g, 17.25 mmol) and water (1.8 mL). The reaction was stirred for overnight at room temperature. To the reaction was added 100 mL water; 80 mL saturated NaHCO3, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3×100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7% yield). 1H NMR (400 MHz, CDCl3): δ 2.32 (2 H, s), 3.62 (1 H, s), 7.20–7.27 (1 H, m), 7.32–7.41 (1 H, m). The layers were separated the aqueous layer was extracted with 3×100 mL EtOAc The combined organics were washed with 100 mL water dried over Na2SO4 After filtering off the solids the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7% yield)

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

Procedure: To a stirred solution of 2-(4-bromo-2-methylphenyl)acetonitrile (3.93 g, 18.8 mmol) in anhydrous DMF (35 mL) is added methyl iodide (2.45 mL, 39.4 mmol). The solution is cooled to 0° C. and sodium hydride (60% susp. in oil, 1.47 g, 61.1 mmol) is added in 3 equal portions over 20 min. The reaction mixture is then left stirring and slowly warmed up to room temperature for 18 h. The solution turned to a thick brown-orange paste. At 0° C., water (50 mL) is then slowly added and the solution is extracted with a 2:1 solution of hexane/Et2O (3×50 mL). The organic layer is washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The crude is purified by flash-chromatography, eluting with hexane/EtOAc (9:1) to provide the expected product 2-(4-bromo-2-methylphenyl)-2-methylpropanenitrile (3.1 g, 66%) as a clear yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.30 (2H, m), 7.16 (2H, d, J=8.5 Hz), 2.63 (3H, s), 1.77 (6H, s). The reaction mixture is then left slowly warmed up to room temperature for 18 h the solution is extracted with a 2:1 solution of hexane/Et2O (3×50 mL) The organic layer is washed with brine dried with MgSO4 filtered concentrated under reduced pressure The crude is purified by flash-chromatography eluting with hexane/EtOAc (9:1)

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

Procedure: To a stirred solution of 2-(4-bromo-2-methylphenyl)acetonitrile (3.93 g, 18.8 mmol) in anhydrous DMF (35 mL) is added methyl iodide (2.45 mL, 39.4 mmol). The solution is cooled to 0° C. and sodium hydride (60% susp. in oil, 1.47 g, 61.1 mmol) is added in 3 equal portions over 20 min. The reaction mixture is then left stirring and slowly warmed up to room temperature for 18 h. The solution turned to a thick brown-orange paste. At 0° C., water (50 mL) is then slowly added and the solution is extracted with a 2:1 solution of hexane/Et2O (3×50 mL). The organic layer is washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. The crude is purified by flash-chromatography, eluting with hexane/EtOAc (9:1) to provide the expected product 2-(4-bromo-2-methylphenyl)-2-methylpropanenitrile (3.1 g, 66%) as a clear yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.30 (2H, m), 7.16 (2H, d, J=8.5 Hz), 2.63 (3H, s), 1.77 (6H, s). The reaction mixture is then left slowly warmed up to room temperature for 18 h the solution is extracted with a 2:1 solution of hexane/Et2O (3×50 mL) The organic layer is washed with brine dried with MgSO4 filtered concentrated under reduced pressure The crude is purified by flash-chromatography eluting with hexane/EtOAc (9:1)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-4-(bromomethyl)-3-methylbenzene (13.2 g, 50.1 mmol) is dissolved in DMF (65 mL). The reaction mixture is cooled to 0-5° C. and NaCN (3.66 g, 74.6 mmol) is added follow by water (8 mL). The reaction is stirred overnight at room temperature and water (170 mL) is added followed by NaHCO3 sat. (130 mL) and hexane/Et2O (2:1) (150 mL). The organic phase is separated and the aqueous phase extracted with hexane/Et2O (2:1) (3×150 mL). The combined organic phases are washed with water (170 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-methylphenyl)acetonitrile (9.76 g, 93%) as an orange oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.32 (2H, m), 7.23 (2H, d, J=8.2 Hz), 3.61 (2H, s), 2.32 (3H, s). The organic phase is separated the aqueous phase extracted with hexane/Et2O (2:1) (3×150 mL) The combined organic phases are washed with water (170 mL) dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: 4-Bromo-1-chloromethyl-2-methyl-benzene (63 g, 287 mmol) was dissolved in DMF (180 mL). NaCN (15.5 g, 316 mmol, 1.1 eq.) was added in 1 portion, and the reaction was stirred at room temperature overnight under a N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was taken into a mixture of sat. aq. NH4Cl (300 mL) and EtOAc (300 mL). The bi-phase solution was diluted with H2O (200 mL). The EtOAc layer was separated, and the aqueous layer was re-extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (3×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure, yielding the title compound (58.8 g, 280 mmol, 98%) with acceptable purity as a brown oil, which solidified to a brown solid on standing. 1H-NMR (CDCl3, 300 MHz) δ ppm 2.34 (s, 3H); 3.63 (s, 2H); 7.26 (t, 1H); 7.38 (d, 2H). The mixture was concentrated under reduced pressure the residue was taken into a mixture of sat. aq. NH4Cl (300 mL) and EtOAc (300 mL) The bi-phase solution was diluted with H2O (200 mL) The EtOAc layer was separated the aqueous layer was re-extracted with EtOAc (2×200 mL) The combined organic layers were washed with brine (3×300 mL) dried (Na2SO4) filtered concentrated under reduced pressure