Water → 2-Fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)-benzonitrile

Participants

Reaction Conditions

Reaction Steps

A mixture of 4-bromo-2-fluoro-benzonitrile (2.6 g, 13 mmol), 10% palladium on carbon (300 mg), triphenylphosphine (300 mg, 1.2 mmol), CuI (108 mg, 0.57 mmol), and K2CO3 (4.55 g, 33 mmol), was prepared in 1,2-dimethoxyethane (20 mL), and H2O (20 mL). The resulting suspension was stirred under nitrogen for 30 minutes, and was then treated with 2-methyl-but-3-yn-2-ol (2.6 mL, 27 mmol). The reaction was then heated in an 80° C. oil bath. After stirring for 15 hours at 80° C., TLC analysis of the reaction mixture showed some of the starting 4-bromo-2-fluoro-benzonitrile remaining. A small amount of PdCl2 was then added in an attempt to drive the reaction to completion. After an additional 2 hr stirring at 80° C. the TLC had changed very little. The reaction mixture was allowed to cool to ambient temperature, and was filtered through a pad of Celite. The Celite pad was washed thoroughly with EtOAc, and the filtrate was diluted with EtOAc and H2O. The layers were separated and the aqueous was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark oil. The crude material was purified by flash chromatography eluting with a gradient from 10% to 40% ethyl acetate/hexane to afford 2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)-benzonitrile (2.60 g, 98% yield) as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 7.58-7.53 (1H, m), 7.30-7.22 (2H, m), 2.10 (1H, s), 1.62 (6H, s).

Provenance & Evidence