Cesium carbonate → 1,1-Dimethylethyl 4-[[3-[[6-(trifluoromethyl)-3-pyridinyl]oxy]phenyl]methylene]-1-piperidinecarboxylate

HRID 1666433Notes

Reaction equation

HRID 1666433 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[F:30][C:29]([F:32])([F:31])[C:26]1[N:27]=[CH:28][C:23]([O:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH:5]=[C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]2)=[CH:24][CH:25]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 27611975-Bromo-2-(trifluoromethyl)pyridine2×HCID 53485958Tert-butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate

Product 1

HCID 668757901,1-Dimethylethyl 4-[[3-[[6-(trifluoromethyl)-3-pyridinyl]oxy]phenyl]methylene]-1-piperidinecarboxylateYield 47%

Reagents, catalysts & solvents 2

HCID 11068737tetrakis(acetonitrile)copper(I) hexafluorophosphateCatalystHCID 1140TolueneSolvent

Procedure

A mixture of tert-butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate (0.200 g), 5-bromo-2-(trifluoromethyl)pyridine (0.156 g, 1.00 equiv), cesium carbonate (0.450 g, 2.00 equiv), and tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.019 g, 0.074 equiv) in toluene (3 mL, 0.2 M) was heated to reflux for 12 h. Additional catalyst (0.02 g) and 5-bromo-2-(trifluoromethyl)pyridine (0.200 g) was added and the mixture was refluxed for an additional 6 h. The reaction was allowed to cool to room temperature and filtered through Celite washing with ethyl acetate. Water was added and the mixture was extracted with ethyl acetate (2×). The combined organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/dichloromethane) to give the title compound as a white solid (0.141 g, 47% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (9H, s), 2.32 (2H, t, J=5.6 Hz), 2.44 (2H, t, J=5.6 Hz), 3.41 (2H, t, J=5.8 Hz), 3.50 (2H, t, J=5.8 Hz), 6.32 (1H, s), 6.87-6.96 (2H, m), 7.06 (1H, d, J=7.6 Hz), 7.32-7.39 (2H, m), 7.62 (1H, d, J=8.6 Hz), 8.46 (1H, d, J=2.7 Hz).

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 12 h
  3. temperaturethe mixture was refluxed for an additional 6 h
  4. filtrationfiltered through Celite
  5. washwashing with ethyl acetate
  6. additionWater was added
  7. extractionthe mixture was extracted with ethyl acetate (2×)
  8. extractionThe combined organic extract
  9. washwas washed with brine
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe residue was purified by silica gel chromatography (10% ethyl acetate/dichloromethane)

Sources & evidence

ORD record
ord-3a14bf4a10c54e588ea966e849cdbf51
Source dataset
uspto-grants-2011_10
Patent number
US08044052B2

Reaction notes

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