2-(bromomethyl)-4-chlorobenzonitrile

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

Procedure: To a stirred solution 4-Chloro-2-methyl-benzonitrile 1(5.0 g, 33.0 mmol) in carbon tetrachloride (150 mL) was added N-bromosuccinamide (7.6 g, 42.9 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield a white solid (40%). 1H NMR (400 MHz, CDCl3) δ7.61 (d, J=8.3 Hz, 1 H, Ar), 7.57 (d, J=2.2 Hz, 1 H, Ar), 7.41 (dd, J=8.3, 2.0 Hz, 1 H, Ar), 4.59 (s, 2 H, CH2). The reaction mixture was refluxed 6 hrs filtered concentrated partitioned between ether and water The ether layer was dried concentrated purified by silica gel chromatography (10% ether/hexanes)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 2-bromomethyl-4-chloro-benzonitrile (0.116 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-chloro-2-(1-oxo-1,3-dihydroisoindol-2-ylmethyl)benzonitrile (0.057 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.48 (s, 2H), 5.08 (s, 2H), 7.42-7.65 (m, 611), 7.92 (d, 1H). GC-MS: m/z 282 (M)+.

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

Procedure: To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-4-chlorobenzonitrile (0.31 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-4:1). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (2 mg). The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-4:1) 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature the obtained precipitate was recrystallized from methanol-ethyl acetate

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

Procedure: To a stirred solution 4-Chloro-2-methyl-benzonitrile 1(5.0 g, 33.0 mmol) in carbon tetrachloride (150 mL) was added N-bromosuccinamide (7.6 g, 42.9 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield a white solid (40%). 1H NMR (400 MHz, CDCl3) δ7.61 (d, J=8.3 Hz, 1 H, Ar), 7.57 (d, J=2.2 Hz, 1 H, Ar), 7.41 (dd, J=8.3, 2.0 Hz, 1 H, Ar), 4.59 (s, 2 H, CH2). The reaction mixture was refluxed 6 hrs filtered concentrated partitioned between ether and water The ether layer was dried concentrated purified by silica gel chromatography (10% ether/hexanes)