3-chloro-5-(hydroxymethyl)benzonitrile

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

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

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Chloro-5-(hydroxymethyl)benzonitrile (25 g, 145 mmol) was dissolved in THF (200 mL). The resulting yellow solution was cooled to 10° C. in an ice bath and treated dropwise with phosgene in toluene (152 mL, 289 mmol). The reaction mixture was stirred at ambient temperature for 16 hrs. The mixture was concentrated under reduced pressure and the crude material was diluted with toluene (200 ml) and re-concentrated under reduced pressure. The residue was purified by chromatography on silica (Redisep 340 g column on a Biotage system), eluting with EtOAc/iso-hexane to give 3-chloro-5-cyanobenzyl carbonochloridate as an oil. The mixture was concentrated under reduced pressure the crude material was diluted with toluene (200 ml) re-concentrated under reduced pressure The residue was purified by chromatography on silica (Redisep 340 g column on a Biotage system), eluting with EtOAc/iso-hexane

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

Procedure: (Step 3) Triphenylphosphine (0.94 g) was suspended in acetonitrile (20 ml), bromine (0.19 ml) was added, and the mixture was stirred for 30 min. A solution (10 ml) of 3-chloro-5-(hydroxymethyl)benzonitrile (0.60 g) obtained in Step 2 in acetonitrile was added to the reaction mixture, and the mixture was stirred at 80° C. for 4 hr. The reaction solution was quenched with water, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:2) to give 3-(bromomethyl)-5-chlorobenzonitrile (0.31 g) as a white solid. the mixture was stirred at 80° C. for 4 hr The reaction solution was quenched with water the mixture was extracted with ethyl acetate The extract was washed with aqueous sodium hydrogen carbonate solution with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:2)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Step 2) To a mixed solution of 3-chloro-5-cyanobenzoate (1.13 g) obtained in Step 1 in tetrahydrofuran:ethanol=10:1 (33 ml) was added lithium tetrahydroborate (0.19 g) at 0° C. After stirring at 60° C. for 2 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=1:1) to give 3-chloro-5-(hydroxymethyl)benzonitrile (0.60 g) as a white solid. the reaction solution was quenched with ice extracted with ethyl acetate The extract was washed with 1N hydrochloric acid with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=1:1)