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

Participants

Reaction Conditions

Reaction Steps

A dry 200 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 (972 mg, 4 mmoles) was added to the flask and dissolved in anhydrous ether (75 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, 2.25 mL. 3.6 mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2-cyanopyridine (552 mg, 4 mmoles) in anhydrous THF (5 mL) was added from a syringe. The reaction was stirred for 2 hours at −78° C. and trimethylchlorosilane (550 μL, 4 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., Benzylzinc chloride (0.5M in THF, 9.6 mL, 4.8 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 3 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 on SCX column (10 g, high load, 0.65 mmole/g) to yield 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine 890 mg (56% yield). LC-MS (methanol) [M+1]=394.

Provenance & Evidence