Water → tert-Butyl 4-(3-(5-bromopyridin-2-yloxy)benzylidene)piperidine-1-carboxylate

HRID 1666372Notes

Reaction equation

HRID 1666372 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[N:6][CH:7]=1

Participants

7

Reactant 4

HCID 962WaterHCID 24758Sodium hydride2×HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 86623897Diethyl 3-(5-bromopyridin-2-yloxy)benzylphosphonate

Product 1

HCID 66876348tert-Butyl 4-(3-(5-bromopyridin-2-yloxy)benzylidene)piperidine-1-carboxylateYield 62%

Reagents, catalysts & solvents 2

HCID 3633615-Crown-5CatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Diethyl 3-(5-bromopyridin-2-yloxy)benzylphosphonate (2.00 g, 5.00 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.025 mL, 0.13 mmol) were combined in THF (7 mL). The mixture was cooled to 0° C. and sodium hydride (210 mg, 60% dispersion in mineral oil, 5.25 mmol) was added. The reaction was warmed to room temperature, stirred for 30 min and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 5.25 mmol) in THF (4 mL) was added and the reaction was warmed to room temperature. After 16 h, an additional amount of sodium hydride (spatula tip) was added and the mixture was stirred an additional 6 h. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to a yellow oil. This material was crystallized from hot isopropyl ether/heptane. The supernatant was decanted and the solid was washed with heptane and dried in vacuo to afford the title compound (1.37 g, 62% yield) as an off-white solid. MS (APCI) M−100=345.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 2.30-2.37 (m, 2H) 2.44-2.50 (m, 2H) 3.38-3.44 (m, 2H) 3.48-3.54 (m, 2H) 6.35 (s, 1H) 6.85 (dd, J=8.77, 0.58 Hz, 1H) 6.94-7.00 (m, 2H) 7.03-7.07 (m, 1H) 7.35 (t, J=7.80 Hz, 1H) 7.78 (dd, J=8.67, 2.63 Hz, 1H) 8.23 (dd, J=2.53, 0.58 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 h
  5. stirringthe mixture was stirred an additional 6 h
  6. extractionthe mixture was extracted twice with ethyl acetate
  7. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated to a yellow oil
  10. customThis material was crystallized from hot isopropyl ether/heptane
  11. customThe supernatant was decanted
  12. washthe solid was washed with heptane
  13. customdried in vacuo

Sources & evidence

ORD record
ord-e6ba253229784cdab2721d88616f2cd2
Source dataset
uspto-grants-2011_10
Patent number
US08044052B2

Reaction notes

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