4-(benzyloxy)-2-chloro-3-(trifluoroMethyl)pyridine synthesis

Yield: 50%

Reaction Conditions:

Stage #1:benzyl alcohol with sodium hydride in N,N-dimethyl-formamide;mineral oil at 0; for 0.5 h;Inert atmosphere;
Stage #2:2,4-dichloro-3-(trifluoromethyl)pyridine in N,N-dimethyl-formamide;mineral oil at 0; for 1 h;Inert atmosphere;regioselective reaction;

Steps:

6.2.1. 4-(Benzyloxy)-2-chloro-3-(trifluoromethyl)pyridine
A solution of benzyl alcohol (commercially available, 1.201 mL, 11.55 mmol) was added to a mixture of 60% sodium hydride dispersion in mineral oil (0.484 g, 12.10 mmol) and DMF (30 mL) in an ice bath at 0 °C. The mixture was allowed to stir at 0 °C for 30 min, then a solution of 2,4-dichloro-3-(trifluoromethyl)pyridine³⁰ (2.376 g, 11 mmol) in DMF (3 mL) was quickly added. The resulting mixture was stirred at 0 °C for 1 h, then quenched by the addition of water. The aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (5:1 hexanes/ethyl acetate) to afford 4-(benzyloxy)-2-chloro-3-(trifluoromethyl)pyridine (1.59 g, 50% yield) as a white solid. ¹H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 5.9 Hz, 1H), 7.47-7.37 (m, 6H), 6.95 (d, J = 5.6 Hz, 1H), 5.28 (s, 2H); LC-MS (M+H)⁺ 288.1.

References:

Higgins, Mendi A.;Marcin, Lawrence R.;Christopher Zusi;Gentles, Robert;Ding, Min;Pearce, Bradley C.;Easton, Amy;Kostich, Walter A.;Seager, Matthew A.;Bourin, Clotilde;Bristow, Linda J.;Johnson, Kim A.;Miller, Regina;Hogan, John;Whiterock, Valerie;Gulianello, Michael;Ferrante, Meredith;Huang, Yanling;Hendricson, Adam;Alt, Andrew;Macor, John E.;Bronson, Joanne J. [Bioorganic and Medicinal Chemistry,2017,vol. 25,# 2,p. 496 - 513]