Potassium Hydroxide → {4-Bromo-3-[2-(1-methyl-pyrrolidine-2-yl)-ethoxy]-phenyl}-acetonitrile

Participants

Reaction Steps

A suspension of KCN (16.0 g, 238.3 mmol) in DMF (100 mL) was heated at 60° C. for 30 min. The slurry was cooled to room temperature and treated with a solution of 2-bromo-5-bromomethylphenol 72 (4.16 g, 15.7 mmol) in DMF (50 mL). The resultant mixture stirred at room temperature for 23 h, and then was diluted with water and extracted with ethyl acetate (5×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to afford impure (4-bromo-3-hydroxy-phenyl)acetonitrile 73. To a solution of KOH (26.5 mg) in MEOH (1.5 mL) was added (4-bromo-3-hydroxy-phenyl)-acetonitrile 73 (100.0 mg), the resulting mixture was stirred at room temperature for 10 min then conentrated in vacuo. DMSO (3 mL) and methanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester, (prepared from 2-(1-methyl-pyrrolidin-2-yl)-ethanol, methane sulfonyl chloride in presence of triethylamine) were added. The reaction mixture was stirred at room temperature overnight. DCM (80 mL) was added and the organics washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried with MgSO4. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH, 4/1) to give 74. MS (EI) m/z (M+H+) 324.

Provenance & Evidence