5-chloro-2-methylbenzonitrile

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

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

Procedure: A solution of LAH (1 M in ether, 40 mL) was added to a stirred solution of 5-chloro-2-methylbenzonitrile (3.03 g, 20.0 mmol) in Et2O (10 mL) at 0° C. and the resulting solution was warmed to ambient temperature. After 30 min the solution was cooled to 0° C. and water (1.52 mL), 15% NaOH (1.52 mL) and water (4.56 mL) were added successively. The solids were removed by filtration and the filtrate was evaporated in vacuo to give 5-chloro-2-methylbenzylamine (3.11 g) as an oil. After 30 min the solution was cooled to 0° C. The solids were removed by filtration the filtrate was evaporated in vacuo

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

Procedure: A solution of LAH (1 M in ether, 40 mL) was added to a stirred solution of 5-chloro-2-methylbenzonitrile (3.03 g, 20.0 mmol) in Et2O (10 mL) at 0° C. and the resulting solution was warmed to ambient temperature. After 30 min the solution was cooled to 0° C. and water (1.52 mL), 15% NaOH (1.52 mL) and water (4.56 mL) were added successively. The solids were removed by filtration and the filtrate was evaporated in vacuo to give 5-chloro-2-methylbenzylamine (3.11 g) as an oil. After 30 min the solution was cooled to 0° C. The solids were removed by filtration the filtrate was evaporated in vacuo

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

Procedure: A solution of 5-chloro-2-methylbenzonitrile (1.5 g, 9.89 mmol), hydroxylamine hydrochloride (1.38 g, 19.79 mmol) and sodium bicarbonate (3.33 g, 39.6 mmol) in methanol (100 mL) was heated to 70° C. for 6 h. The mixture was cooled to room temperature and diluted with methanol (100 mL). The mixture was filtered, and the filtrate was concentrated, diluted with water and extracted with EtOAc (100 mL, 3×). The EtOAc extract was dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude 5-chloro-N′-hydroxy-2-methylbenzimidamide (1.8 g, 99% crude yield). LC/MS: m/e 185.0 (M+H)+. 1H NMR (400 MHz, CD3OD) δ ppm 7.30-7.29 (2 H, m), 7.23 (1 H, d), 2.36 (3H, s). The mixture was filtered the filtrate was concentrated diluted with water extracted with EtOAc (100 mL, 3×) The EtOAc extract was dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: A 500-mL, three-necked, round-bottomed flask equipped with a dry ice-acetone cooled reflux condenser, addition funnel, and a gas inlet was charged with liquid ammonia (150 mL). Iron (III) nitrate nonahydrate (spatula end) was added in one portion as a solid, and then potassium metal (5.16 g, 132.0 mmol) was added cautiously in small portions. A solution of 5-chloro-2-methylbenzonitrile (10.00 g, 65.96 mmol) in THF (30 mL) was added dropwise over 5 minutes, the reaction mixture was stirred for 5 minutes, a solution of 1-cyanonaphthalene (15.16 g, 98.97 mmol) in THF was added dropwise over 5 minutes, and the reaction mixture was allowed to stir overnight as the liquid ammonia gradually evaporated. The crude reaction mixture was cautiously poured into saturated aqueous NH4Cl, and the aqueous phase was extracted with methylene chloride. The combined organic extracts were dried and concentrated. The residue was purified by flash chromatography with 2:1 hexane-ethyl acetate, and the crude product was recrystallized from 2:1 hexane-ethyl acetate to afford the title compound (2.88 g, 9.45 mmol, 14% yield) as yellow crystals: mp 180°-181°; IR(CHCl3) 3513, 3409 cm-1 ; MS m/e 305 (M+ +H NMR(CDCl3) δ 8.00-8.17(m,1H), 7.83-8.00(m,2H), 7.80(s,1H), 7.33-7.79(m,6H), 7.25(s,1H), 5.35(s,2H). Anal. Calcd for C19H13ClN2 : C,74.88; H,4.30; Cl,11.83; N,9.19. Found: C,74.77; H,4.09; Cl,11.87; N,8.81. cooled reflux condenser, addition funnel, and a gas inlet gradually evaporated The crude reaction mixture the aqueous phase was extracted with methylene chloride The combined organic extracts were dried concentrated The residue was purified by flash chromatography with 2:1 hexane-ethyl acetate the crude product was recrystallized from 2:1 hexane-ethyl acetate

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

Procedure: A solution of 2-methyl-5-chlorobenzonitrile (2 g, 13.2 mmol), in THF (30 mL) was cooled to −15° C. and treated with 1 M lithium aluminum hydride in THF (13.4 mL). The reaction mixture was allowed to warm gradually to 0° C. over 2 h and was then stirred at room temperature for 1.5 h. It was then cooled to 0° C. and quenched sequentially with EtOAc (1 mL), water (0,5 mL), 15% NaOH (0.5 mL), and water (1.5 mL). After stirring for 1 h, the solids were removed via filtration. The filtrate was concentrated and the resulting residue purified by flash chromatography (98:2 methylene chloride/methanol) to give the product as an oil: 1H NMR (CDCl3) δ7.33 (d, J=2.0 Hz, 1H), 7.08 (m, 2H),, 3.83 (s, 2H),, 2.28 (s, 3H), 1.42 (br s, 2H). It was then cooled to 0° C. quenched sequentially with EtOAc (1 mL), water (0,5 mL), 15% NaOH (0.5 mL), and water (1.5 mL) After stirring for 1 h the solids were removed via filtration The filtrate was concentrated the resulting residue purified by flash chromatography (98:2 methylene chloride/methanol)

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

Procedure: A solution of LAH (1 M in ether, 40 mL) was added to a stirred solution of 5-chloro-2-methylbenzonitrile (3.03 g, 20.0 mmol) in Et2O (10 mL) at 0° C. and the resulting solution was warmed to ambient temperature. After 30 min the solution was cooled to 0° C. and water (1.52 mL), 15% NaOH (1.52 mL) and water (4.56 mL) were added successively. The solids were removed by filtration and the filtrate was evaporated in vacuo to give 5-chloro-2-methylbenzylamine (3.11 g) as an oil. After 30 min the solution was cooled to 0° C. The solids were removed by filtration the filtrate was evaporated in vacuo

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

Procedure: A solution of 5-chloro-2-methylbenzonitrile (1.5 g, 9.89 mmol), hydroxylamine hydrochloride (1.38 g, 19.79 mmol) and sodium bicarbonate (3.33 g, 39.6 mmol) in methanol (100 mL) was heated to 70° C. for 6 h. The mixture was cooled to room temperature and diluted with methanol (100 mL). The mixture was filtered, and the filtrate was concentrated, diluted with water and extracted with EtOAc (100 mL, 3×). The EtOAc extract was dried over MgSO4, filtered and concentrated under reduced pressure to obtain crude 5-chloro-N′-hydroxy-2-methylbenzimidamide (1.8 g, 99% crude yield). LC/MS: m/e 185.0 (M+H)+. 1H NMR (400 MHz, CD3OD) δ ppm 7.30-7.29 (2 H, m), 7.23 (1 H, d), 2.36 (3H, s). The mixture was filtered the filtrate was concentrated diluted with water extracted with EtOAc (100 mL, 3×) The EtOAc extract was dried over MgSO4 filtered concentrated under reduced pressure