4-(Bromoacetyl)benzonitrile → HCID 13102050, compound

Participants

Reaction Steps

Following the procedure of Corey et al. (Angew. Chem. Int. Ed., 37:1986-2012 (1998)), a solution of 4-(2-bromoacetyl)benzonitrile (10.00 g, 44.6 mmol) in THF (50 mL) was cooled to 0° C. and treated with (S)-methyl oxazaborolidine (1.0 M in toluene) (8.93 mL, 8.93 mmol) followed by borane-methyl sulfide complex (2.0 M in THF) (13.01 mL, 26.0 mmol) over 10 minutes. The reaction was stirred for 1.5 hours and then quenched by adding MeOH. The reaction was concentrated on a rotary evaporator and then extracted from 1 M HCl using DCM×3 followed by drying over MgSO4, and filtering. The crude material was concentrated in vacuo and purified on a 220 g SiO2 cartridge using 20-80% EtOAc/hexanes gradient over 10 column volumes. The product eluted in fractions 46-60 to afford 9.8 g of 4-(2-bromo-1-hydroxyethyl)-benzonitrile as a clear oil. Chiral HPLC conditions showed 80% e.e. favoring the (S) stereoisomer based on the Corey precedent. The minor (R) stereoisomer was removed by chiral HPLC using multiple runs on a Thar 350 Preparative SFC instrument equipped with a CHIRALPAK® AD-H (25×5 cm, 5 μM). Temp: 35° C.; Flow rate: 280 mL/min; Mobile phase: CO2/iPrOH in 88:12 ratio; Runtime 7.7 min; Retention time=5.1 min to give (S)-4-(2-bromo-1-hydroxyethyl)-benzonitrile in 99.8% d.e. 1H NMR (400 MHz, CDCl3) δ ppm 7.76 (2H, d), 7.56 (2H, d), 5.02 (1H, dd), 3.68 (1H, dd), 3.55 (1H, dd), 3.53 (1H, s).

Provenance & Evidence