2-(4-bromo-2-chlorophenyl)acetonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 2-(4-bromo-2-chlorophenyl)acetonitrile (1.11 g, 4.82 mmol) in anhydrous DMF (7.6 mL) is added methyl iodide (0.63 mL, 10.1 mmol). The solution is cooled to 0° C. and sodium hydride (60% susp. in oil, 0.63 g, 15.7 mmol) is added in 5 portions over 1 h. The reaction mixture is then left stirring to slowly warm up to room temperature for 18 h. The solution turned to a thick and brown orange paste. Water (20 mL) is then slowly added and the solution extracted with a 3:1 solution of hexane/Et2O (3×25 mL). The organic layer is washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hex/EtOAc 9:1 to 8:2) to provide the expected product 2-(4-bromo-2-chlorophenyl)-2-methylpropanenitrile (0.79 g, 63%). 1H NMR (300 MHz, CHLOROFORM-D): δ 7.61 (1H, d, J=2.1 Hz), 7.43 (1H, dd, J=8.5, 2.1 Hz), 7.34 (1H, d, J=8.6 Hz), 1.85 (6H, s). The reaction mixture is then left to slowly warm up to room temperature for 18 h the solution extracted with a 3:1 solution of hexane/Et2O (3×25 mL) The organic layer is washed with brine dried over MgSO4 filtered concentrated under reduced pressure The crude product is purified by flash chromatography (eluent: Hex/EtOAc 9:1 to 8:2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-1-(bromomethyl)-2-chlorobenzene (7.19 g, 25.3 mmol) in dichloromethane (60 mL) and water (60 mL) is added tetrabutylammonium bromide (0.82 g, 2.53 mmol). Potassium cyanide (4.94 g, 75.8 mmol) in water (60 mL) is then added. The resulting solution is stirred 4 h at room temperature and quickly turned orange. A saturated solution of NaHCO3 aq. is then added and the mixture extracted with CH2Cl2 (3×100 mL). The combined organic layer is washed with brine, dried over anhydrous MgSO4 and filtered on a silica gel pad. The pad is rinsed with CH2Cl2 and the filtrate concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-chlorophenyl)acetonitrile (5.38 g, 92%) contaminated with bromoform. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.60 (1H, d, J=1.9 Hz), 7.47 (1H, dd, J=8.3, 1.9 Hz), 7.39 (1H, d, J=8.3 Hz), 3.79 (2H, s). the mixture extracted with CH2Cl2 (3×100 mL) The combined organic layer is washed with brine dried over anhydrous MgSO4 filtered on a silica gel pad The pad is rinsed with CH2Cl2 the filtrate concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-bromo-1-bromomethyl-2-chlorobenzene (16, 62.5 g, 0.22 mol) in dichloroethane (522 mL) and water (480 mL) was added tetrabutylammonium chloride (5.05 g), followed by a solution of potassium cyanide (43.2 g, 75.8 mmol) in water (523 mL). and the solution was stirred for 4 h at room temperature. The layers were separated and the aqueous layer was extracted with dichloroethane (100 mL). The combined organic layers were washed with water (100 mL), dried over sodium sulfate filtered and evaporated. The crude product (52 g) was distilled under reduced pressure (1 mmHg), affording (4-bromo-2-chlorophenyl)-acetonitrile (45.5 g, 0.220 mol, 90%). The layers were separated the aqueous layer was extracted with dichloroethane (100 mL) The combined organic layers were washed with water (100 mL) dried over sodium sulfate filtered evaporated The crude product (52 g) was distilled under reduced pressure (1 mmHg)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (4-Bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 8.6 mmoles) was dissolved into MeOH (50 mL) and water (5 mL), and the resulting homogeneous mixture was chilled to 0° C. To this stirring (cold) mixture was slowly (carefully) added concentrated HCl (25 mL). After the addition was complete the mixture was refluxed for 16 hours. After this period the reaction mixture was combined with ice and the resulting heterogeneous mixture was extracted with diethyl ether (3×50 mL). The combined ethereal layer was washed with brine, dried over anhydrous MgSO4, and evaporated in vacuo to yield clean (4-bromo-2-chloro-phenyl)-acetic acid methyl ester (2.3 g, 80%). 1H-NMR (CDCl3): δ 7.56 (d, J=2.0 Hz, 1H), 7.37 (dd, J′=8.3 Hz, J″=2.0 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 3.73 (s, 2H), 3.72 (s, 3H). After the addition was refluxed for 16 hours After this period the reaction mixture was combined with ice the resulting heterogeneous mixture was extracted with diethyl ether (3×50 mL) The combined ethereal layer was washed with brine dried over anhydrous MgSO4 evaporated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-1-bromomethyl-2-chloro-benzene (3.04 g, 10.7 mmoles) was dissolved into anhydrous CH3CN. To this mixture (under N2 at ambient temp) was added TMSCN (2.1 mL, 15.7 mmoles) followed by 1.0M TBAF (15.7 mL, 15.7 mmoles, soln in THF). The resulting mixture was stirred at ambient temperature for 15 min after which time it was evaporated in vacuo to yield crude residue. The crude residue was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield (4-bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 80%) as an off-white solid. 1H-NMR (CDCl3): δ 7.60 (d, J=2.0 Hz, 1H), 7.47 (dd, J′=8.1 Hz, J″=1.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.79 (s, 2H). was evaporated in vacuo to yield crude residue The crude residue was purified

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-1-bromomethyl-2-chloro-benzene (3.04 g, 10.7 mmoles) was dissolved into anhydrous CH3CN. To this mixture (under N2 at ambient temp) was added TMSCN (2.1 mL, 15.7 mmoles) followed by 1.0M TBAF (15.7 mL, 15.7 mmoles, soln in THF). The resulting mixture was stirred at ambient temperature for 15 min after which time it was evaporated in vacuo to yield crude residue. The crude residue was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield (4-bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 80%) as an off-white solid. 1H-NMR (CDCl3): δ 7.60 (d, J=2.0 Hz, 1H), 7.47 (dd, J′=8.1 Hz, J″=1.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.79 (s, 2H). was evaporated in vacuo to yield crude residue The crude residue was purified