3-bromo-5-(bromomethyl)benzonitrile

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

Procedure: A suspension of 3-bromo-5-(bromomethyl)benzonitrile (12.5 g, 45.5 mmol), potassium phthalate (7.16 g, 38.6 mmol), and in DMF (100 mL) was stirred under reflux for 4 h. After cooling to room temperature, the solvent was remove under reduced pressure and the residue was dissolved in CHCl3 (200 mL). The organic layer was washed with water (50 mL×2), dried over Na2SO4, and concentrated in vacuum to obtain 15.2 g of the crude product. The product, 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 23%) was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.81-7.80 (m, 1H), 7.77-7.75 (m, 2H), 7.71-7.70 (m, 1H), 7.66-7.65 (m, 1H), 4.83 (s, 2H). under reflux for 4 h the solvent was remove under reduced pressure the residue was dissolved in CHCl3 (200 mL) The organic layer was washed with water (50 mL×2) dried over Na2SO4 concentrated in vacuum

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

Procedure: A suspension of 3-bromo-5-(bromomethyl)benzonitrile (12.5 g, 45.5 mmol), potassium phthalate (7.16 g, 38.6 mmol), and in DMF (100 mL) was stirred under reflux for 4 h. After cooling to room temperature, the solvent was remove under reduced pressure and the residue was dissolved in CHCl3 (200 mL). The organic layer was washed with water (50 mL×2), dried over Na2SO4, and concentrated in vacuum to obtain 15.2 g of the crude product. The product, 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 23%) was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.81-7.80 (m, 1H), 7.77-7.75 (m, 2H), 7.71-7.70 (m, 1H), 7.66-7.65 (m, 1H), 4.83 (s, 2H). under reflux for 4 h the solvent was remove under reduced pressure the residue was dissolved in CHCl3 (200 mL) The organic layer was washed with water (50 mL×2) dried over Na2SO4 concentrated in vacuum

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

Procedure: A mixture of 3-bromo-5-methylbenzonitrile (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile. was heated for 10 h at reflux filtered the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL) The combined organic phases were dried over Na2SO4 concentrated in vacuum

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

Procedure: A suspension of 3-bromo-5-(bromomethyl)benzonitrile (12.5 g, 45.5 mmol), potassium phthalate (7.16 g, 38.6 mmol), and in DMF (100 mL) was stirred under reflux for 4 h. After cooling to room temperature, the solvent was remove under reduced pressure and the residue was dissolved in CHCl3 (200 mL). The organic layer was washed with water (50 mL×2), dried over Na2SO4, and concentrated in vacuum to obtain 15.2 g of the crude product. The product, 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 23%) was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.81-7.80 (m, 1H), 7.77-7.75 (m, 2H), 7.71-7.70 (m, 1H), 7.66-7.65 (m, 1H), 4.83 (s, 2H). under reflux for 4 h the solvent was remove under reduced pressure the residue was dissolved in CHCl3 (200 mL) The organic layer was washed with water (50 mL×2) dried over Na2SO4 concentrated in vacuum

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

Procedure: A mixture of 3-bromo-5-methylbenzonitrile (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile. was heated for 10 h at reflux filtered the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL) The combined organic phases were dried over Na2SO4 concentrated in vacuum

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

Procedure: A suspension of 3-bromo-5-(bromomethyl)benzonitrile (12.5 g, 45.5 mmol), potassium phthalate (7.16 g, 38.6 mmol), and in DMF (100 mL) was stirred under reflux for 4 h. After cooled to room temperature, the solvent was remove under reduced pressure and the residue was dissolved in CHCl3 (200 mL). The organic layer was washed with water (50 mL×2), dried over Na2SO4, and concentrated in vacuum to obtain 15.2 g of the crude product. The product, 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 23%) was purified by flash column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.90-7.87 (m, 2 H), 7.81-7.80 (m, 1 H), 7.77-7.75 (m, 2 H), 7.71-7.70 (m, 1 H), 7.66-7.65 (m, 1 H), 4.83 (s, 2 H). under reflux for 4 h the solvent was remove under reduced pressure the residue was dissolved in CHCl3 (200 mL) The organic layer was washed with water (50 mL×2) dried over Na2SO4 concentrated in vacuum

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

Procedure: A mixture of 3-bromo-5-methylbenzonitrile (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile. was heated for 10 h at reflux filtered the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL) The combined organic phases were dried over Na2SO4 concentrated in vacuum

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

Procedure: MeOH (0.088 mL, 2.18 mmol) was added to a slurry of NaH (45 mg, 1.13 mmol) in DMF (2 mL). When gas evolution ceased, a solution of 3-bromo-5-(bromomethyl)benzonitrile (see WO2009/100169; 240 mg, 0.87 mmol) in DMF (1 mL) was added. The reaction was quenched by adding aq. sat NH4Cl solution. The mixture was partitioned between toluene (5 mL) and water (3 mL). The toluene layer was collected, washed with water, dried over Na2SO4, and concentrated in vacuo. The crude product was dried at reduced pressure and used in the next step: GCMS (CI) m/z 226 [M+H]+. The reaction was quenched by adding aq. The mixture was partitioned between toluene (5 mL) and water (3 mL) The toluene layer was collected washed with water dried over Na2SO4 concentrated in vacuo The crude product was dried at reduced pressure

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

Procedure: MeOH (0.088 mL, 2.18 mmol) was added to a slurry of NaH (45 mg, 1.13 mmol) in DMF (2 mL). When gas evolution ceased, a solution of 3-bromo-5-(bromomethyl)benzonitrile (see WO2009/100169; 240 mg, 0.87 mmol) in DMF (1 mL) was added. The reaction was quenched by adding aq. sat NH4Cl solution. The mixture was partitioned between toluene (5 mL) and water (3 mL). The toluene layer was collected, washed with water, dried over Na2SO4, and concentrated in vacuo. The crude product was dried at reduced pressure and used in the next step: GCMS (CI) m/z 226 [M+H]+. The reaction was quenched by adding aq. The mixture was partitioned between toluene (5 mL) and water (3 mL) The toluene layer was collected washed with water dried over Na2SO4 concentrated in vacuo The crude product was dried at reduced pressure