4-Fluorophenol → Tert-butyl 4-(4-fluorophenoxy)piperidine-1-carboxylate

HRID 1714386Notes

Reaction equation

HRID 1714386 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.[C:40]([N:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1.O>[C:43]([O:42][C:40]([N:47]1[CH2:52][CH2:51][CH:50]([O:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH2:49][CH2:48]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]

Participants

7

Reactant 4

HCID 97324-FluorophenolHCID 11776TriphenylphosphineHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 5462977Diethyl azodicarboxylate

Product 1

HCID 50999114Tert-butyl 4-(4-fluorophenoxy)piperidine-1-carboxylateYield 60.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of triphenyl phosphine (7.7 g, 29 mmol), in tetrahydrofuran (40 mL), diethylazodicarboxylate (5.12 g, 29 mmol) was added and the solution was stirred for 20 minutes. 4-Fluorophenol (3 g, 27 mmol) was added and the mixture was stirred for another 20 minutes at 0° C. N—Boc-4-hydroxypiperidine (5.9 g, 29 mmol) was added dissolved in tetrahydrofuran (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with hexane:ethyl acetate (1:0 to 1:1) to give 4.8 g (60%) of the product as a white solid. MS (m/e): 296.3 (M−H+).

Workup

  1. stirringthe mixture was stirred for another 20 minutes at 0° C
  2. stirringthe mixture was stirred at room temperature overnight
  3. extractionthe solution was extracted three times with dichloromethane
  4. washThe combined organic layers were washed with water and brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customThe crude product was purified by flash-chromatography on silica gel with hexane:ethyl acetate (1:0 to 1:1)

Sources & evidence

ORD record
ord-7bc44d3ee3e64e8fb05055f8c62444ec
Source dataset
uspto-grants-2010_09
Patent number
US07795437B2

Reaction notes

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