Pyrrolidine → Ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-6-carboxylate

Participants

Reaction Steps

A mixture of ethyl 4-oxocyclohexanecarboxylate (3.0 g, 17 mmol), pyrrolidine (3.6 mL, 43 mmol, 2.5 equiv.) and toluene (50 mL) was heated to reflux with azeotropic removal of water. After 17 h the reaction was judged complete, and the cooled mixture was concentrated. The residue was taken up in ether (100 mL), dried (MgSO4), filtered and concentrated to afford crude enamine as an oil (3.97 g). The crude enamine (assumed 17 mmol) was dissolved in 1,4-dioxane (50 mL), and the solution cooled to 10° C., before a solution of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (3.5 g, 21 mmol) in 1,4-dioxane (10 mL) was added dropwise over 10 min to the yellow suspension, which rapidly clarified and darkened to a deep red-brown. The mixture was allowed to warm to room temperature overnight. After 18 h ammonium acetate (2.7 g, 35 mmol, 2 equiv.) was added, and the mixture heated to reflux for 2.5 h. The mixture was concentrated to an oil. Chromatography on silica (0-20% EtOAc/hexane) afforded the desired trifluoromethylpyridine as an oil (1.27 g, 27%). 1H NMR (400 MHz, CDCl3) [δ] 7.57 (d, J=7.9 Hz, 1JH), 7.44 (d, J=7.9 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.18-2.96 (m, 4H), 2.85-2.76 (m, 1H), 2.48-2.39 (M, 1H), 2.09-1.97 (m, 1H), 1.29 (t, J=7.2 Hz, 3H); m/z=274.2 (M+H)+.

Provenance & Evidence