Chlorotrimethylsilane → 1-(5-Chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine

Participants

Reaction Conditions

Reaction Steps

A dry 250 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.5 g, 10.3 mmoles) was added to the flask and dissolved in anhydrous ether (100 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge 1½ PrecisionGlide® needle. The stirring solution was cooled to −78° C. for 10 minutes, n-BuLi (1.6M in hexanes, 6.4 mL. 10.3 mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2-cyanopyridine (1.42 g, 10.3 mmoles) in anhydrous THF (10 mL) was added from a syringe. The reaction was stirred for 2 hours at −78° C. and trimethylchlorosilane (1.41 mL, 10.3 mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to −78° C., Benzylmagnesium chloride (2.0M in THF, 5.15 mL, 10.3 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 2 h. The reaction was quenched with H2O (10 mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel. The light brown solution was washed with saturated aqueous NH4Cl (3×100 mL), then with water (2×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel ISCO with 95-75% hexanes in ethylacetate to yield 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine 994 mg (24% yield). LC-MS (methanol) [M+1]=394. 1H NMR (500 MHz, CDCl3) δ ppm 8.58 (1H, d, J=2.75 Hz), 7.57-7.64 (2H, m), 7.45 (2H, d, J=8.25 Hz), 7.09 -7.24 (4H, m), 6.81 (2H, d, J=6.60 Hz), 3.93 (1H, d, J=13.20 Hz), 3.46 (1H, d, J=13.20 Hz), 1.87 (2H, broad s).

Provenance & Evidence