4-Fluorobenzoyl chloride → (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine

Participants

Reaction Steps

N-(4-chloro-2-fluorophenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was made following general procedure G, substituting 4-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. The amine-aryl coupling was performed differently to what is described in procedure G. Therefore (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (obtained from the hydrogenation step, 200 mg, 0.6 mmol, 1 equ.) was dissolved in ethylene glycol dimethyl ether (1 mL) in a Schlenk tube. To this solution was added sequentially 1-bromo-4-chloro-2-fluorobenzene (105 uL, 0.84 mmol, 1.4 equ.), cesium carbonate (274 mg, 0.84 mmol, 1.4 equ.), palladium acetate (16 mg, 0.024 mmol, 0.04 equ.) and 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (23 mg, 0.048 mmol, 0.08 equ.). The reaction mixture was flushed with nitrogen and heated to 95° C. in the Schlenk tube for 48 h. Reaction mixture was concentrated to leave a residue which was partitioned between water and ethyl acetate and extracted. The aqueous layer was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a black oil. The crude product was purified by silica gel chromatography (methylene chloride/methanol: 100/0 to 99/1 gradient) to provide (2S,4R)-N-(4-chloro-2-fluorophenyl)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (60 mg, 24%).

Provenance & Evidence