Water → tert-Butyl 4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxylate

HRID 1666319Notes

Reaction equation

HRID 1666319 reaction equation
C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH:11]=1)(=O)OCC)C.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH:17]([O:16][CH:12]([CH3:11])[CH3:13])([CH3:22])[CH3:29].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)[CH:11]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]

Participants

8

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 86623890Diethyl (3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)phosphonate

Product 2

HCID 7914Diisopropyl EtherHCID 66875665tert-Butyl 4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxylateYield 144.2%

Reagents, catalysts & solvents 2

HCID 3633615-Crown-5CatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (2.3 g, 6.0 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.03 mL, 0.15 mmol) were combined in THF (10 mL). The mixture was cooled to 0° C. and sodium hydride (240 mg, 60% dispersion in mineral oil, 6.0 mmol) was added. The reaction was warmed to room temperature, stirred for 30 minutes and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.0 mmol) in THF (6 mL) was added and the reaction was warmed to room temperature. After 16 hours, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a thick oil. Treatment of the oil with hot isopropyl ether (45 mL) provided the title compound as a white solid (1.88 g). 1H NMR (400 MHz, CD3OD) δ ppm 1.46 (s, 9H) 2.34 (td, J=5.85, 1.18 Hz, 2H) 2.46 (td, J=5.87, 1.07 Hz, 2H) 3.37-3.44 (m, 2H) 3.45-3.57 (m, 2H) 6.41 (s, 1H) 6.92-7.04 (m, 2H) 7.06-7.17 (m, 2H) 7.31-7.54 (m, 1H) 8.08 (ddd, J=8.74, 2.59, 0.56 Hz, 1H) 8.42 (td, J=1.73, 0.90 Hz, 1H).

Workup

  1. temperatureThe reaction was warmed to room temperature
  2. temperaturecooled back to 0° C
  3. temperaturethe reaction was warmed to room temperature
  4. waitAfter 16 hours
  5. customthe layers were separated
  6. extractionThe aqueous layer was extracted with EtOAc (2×200 mL)
  7. dry with materialthe combined organic layer was dried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated to a thick oil

Sources & evidence

ORD record
ord-8b78f39efa4a4607941a1eddc0456b35
Source dataset
uspto-grants-2011_10
Patent number
US08044052B2

Reaction notes

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