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

HRID 1690790Notes

Reaction equation

HRID 1690790 reaction equation
O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:13]1CCCC1.C(O[CH:21]=[CH:22][C:23](=O)[C:24]([F:27])([F:26])[F:25])C.C([O-])(=O)C.[NH4+]>O1CCOCC1.O.C1(C)C=CC=CC=1>[F:25][C:24]([F:27])([F:26])[C:23]1[CH:22]=[CH:21][C:3]2[CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=2[N:13]=1

Participants

8

Reactant 4

HCID 31268PyrrolidineHCID 317638Ethyl 4-oxocyclohexanecarboxylateHCID 517165Ammonium AcetateHCID 27803954-Ethoxy-1,1,1-trifluoro-3-buten-2-one

Product 1

HCID 58118622Ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-6-carboxylateYield 27.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent2×

Procedure

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)+.

Workup

  1. temperaturewas heated
  2. concentrationthe cooled mixture was concentrated
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto afford crude enamine as an oil (3.97 g)
  7. additionwas added dropwise over 10 min to the yellow suspension, which
  8. temperaturethe mixture heated
  9. temperatureto reflux for 2.5 h
  10. concentrationThe mixture was concentrated to an oil

Sources & evidence

ORD record
ord-2c8c96c2e2834739b26ca07ad83a33c1
Source dataset
uspto-grants-2012_04
Patent number
US08153651B2

Reaction notes

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