tert-Butyl isocyanate → 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide

Participants

Reaction Conditions

Reaction Steps

To a solution of 2-(3-bromo-5-fluorophenyl)-2-methylpropanenitrile (30 g, 124 mmol, 1.0 equiv.) in 180 mL THF was added lithium diisopropylamide (82.6 ml of 1.8 M, 149 mmol, 1.2 equiv.) dropwise at −75° C. The reaction mixture was stirred at −76° C. for 2 hr. The tert-butylisocyanate (18.4 g, 21.8 ml, 186 mmol, 1.5 equiv.) was added dropwise at −75° C. and stirring was continued for 2 hr. An additional 0.5 equiv. of tert-butylisocyanate was added and the reaction mixture was allowed to warm gradually to room temperature and stirred overnight. The reaction mixture was quenched with 180 mL water and the THF was then removed under reduced pressure at 60° C. IPA was added at 60° C. and the product was crystallized out from 180 mL H2O and 120 mL IPA at 60° C. The mixture was cooled to room temperature slowly overnight. The crystals were collected by filtration, washed with H2O, H2O/IPA (1/1), and heptane, and dried overnight to afford 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (34.7 g, 102 mmol, 82.1% yield) as white crystalline solid with >99% HPLC purity. 1H NMR (300 MHz, DMSO-d6) 8 ppm 1.34 (s, 9 H) 1.70 (s, 6 H) 7.47 (dd, J=10.01, 1.70 Hz, 1 H) 7.60 (s, 1 H) 8.34 (s, 1 H).

Provenance & Evidence