Benzenepropanenitrile, 3-fluoro-α,α-dimethyl- synthesis

Yield:1267939-80-9 65%

Reaction Conditions:

Stage #1: Isobutyronitrilewith lithium diisopropyl amide in tetrahydrofuran at -10; for 1.5 h;
Stage #2: m-fluorobenzyl chloride in tetrahydrofuran at -10 - 0; for 3 h;

Steps:

2.2. 2,2-Dimethyl-3-(naphthalen-2-yl)propanenitrile (16c)

General procedure: A solution of anhydrous diisopropylamide (2.30 mL, 16.37 mmol) in anhydrous THF (34 mL) was cooled to-10°C. To the solution was added n-BuLi (2.5 M in hexane, 7.00 mL) dropwise over 20 min. The resulting mixture was stirred at -10°C for 55 min. To the mixture was added isobutyronitrile (1.22 mL, 13.57 mmol)dropwise over 15 min. After the mixture was stirred at -10°C for 75 min, a solution of 2-bromomethylnaphthalene (16d, 2 g, 9.05 mmol) in anhydrous THF (2 mL) was added dropwise over 10 min. The reaction mixture was stirred at -10°C for 20 min, then allowed at 0°C for additional 2.5 h. The reaction was carefully quenched by saturated NH4Cl aqueous solution. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 mL × 5). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give a brown oil, which was recrystallized from petroleum ether (10mL) to give 16c as a white solid (0.91 g, 48 %).

References:

Sun, Xiaowei;Wen, Xiaoan;Chen, Yan-Yan;Shi, Chen;Gao, Chengzhe;Wu, Yong;Wang, Li-Jun;Yang, Xiu-Hong;Sun, Hongbin [European Journal of Medicinal Chemistry,2015,vol. 103,p. 269 - 288] Location in patent:supporting information