2-(4-chloro-2-fluorophenyl)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:0.00; pressure:0.00; stir:

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

Procedure: Then, 18.5 g of 4-chloro-2-fluorobenzyl chloride was dissolved in a mixed solvent consisting of 130 ml of ethanol and 30 ml of water, to which 5.3 g of sodium cyanide was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was allowed to stand for cooling to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 15.1 g of 4-chloro-2-fluorophenylacetonitrile. was added the mixture was heated under reflux for 2 hours After completion of the reaction extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried concentrated

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-2-fluorophenylacetonitrile (Matrix) (5 g, 30 mmol) and 3-chloro-2-fluorobenzaldehyde (Oakwood) (5 g, 32 mmol) in methanol (200 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (21 mL, 92 mmol). The reaction mixture was heated and stirred at 45° C. for 5 h. The mixture was cooled to room temperature and filtered. The white precipitate was washed with water, cold methanol, and then dried under reduced pressure to afford (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (8 g, 86%). The reaction mixture was heated The mixture was cooled to room temperature filtered The white precipitate was washed with water, cold methanol dried under reduced pressure

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

Procedure: To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (3.39 g, 20.0 mmol) and cyclopropyl-acetaldehyde (Aldrich) (1.68.0 g, 20.0 mmol) in iPrOH (25 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight under reduced pressure to afford (Z)-2-(4-chloro-2-fluoro-phenyl)-4-cyclopropyl-but-2-enenitrile (2.36 g, 50.0%) as a colorless oil which was used in the next step without further purification. the organic layer was separated washed with water, brine dried over Na2SO4 concentrated The residue was dried overnight under reduced pressure

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

Procedure: To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (3.39 g, 20.0 mmol) and cyclopropyl-acetaldehyde (Aldrich) (1.68.0 g, 20.0 mmol) in iPrOH (25 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight under reduced pressure to afford (Z)-2-(4-chloro-2-fluoro-phenyl)-4-cyclopropyl-but-2-enenitrile (2.36 g, 50.0%) as a colorless oil which was used in the next step without further purification. the organic layer was separated washed with water, brine dried over Na2SO4 concentrated The residue was dried overnight under reduced pressure

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

Procedure: To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (1.70 g, 10.0 mmol) and 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10.0 mmol) in iPrOH (20 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight in vacuum to give (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2.52 g, 100%) as a colorless oil which was used in the next step without further purification. the organic layer was separated washed with water, brine dried over Na2SO4 concentrated The residue was dried overnight in vacuum

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

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

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