Cesium carbonate → Ethyl 1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylate

HRID 1021218Notes

Reaction equation

HRID 1021218 reaction equation
Br[C:2]1[C:3]([F:17])=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si](C(C)(C)C)(C)C.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.C1(C)C=CC=CC=1>[F:17][C:3]1[C:4]([CH2:5][OH:6])=[CH:14][CH:15]=[CH:16][C:2]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 70770Ethyl 4-piperidinecarboxylateHCID 634876Binap, (A+-)-HCID 86686195((3-Bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane

Product 1

HCID 68308904Ethyl 1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylateYield 57.9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (2 g) and ethyl piperidine-4-carboxylate (1.6 g) were mixed with toluene (30 ml), and Pd2(dba)3 (150 mg), BINAP (300 mg), and cesium carbonate (3.2 g) were added thereto, followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtration using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, the residue was then mixed with THF (30 ml), and a 1 M TBAF/THF solution (12 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added EtOAc and water, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylate (1.02 g).

Workup

  1. additionwere added
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfollowed by filtration
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. additionthe residue was then mixed with THF (30 ml)
  6. additiona 1 M TBAF/THF solution (12 ml) was added
  7. stirringby stirring at room temperature for 1 hour
  8. additionTo the reaction mixture were added EtOAc and water
  9. dry with materialthe organic layer was dried over Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. customThe obtained residue was purified by silica gel column chromatography (hexane/EtOAc)

Sources & evidence

ORD record
ord-2230caff0e68418180964caf535523ae
Source dataset
uspto-grants-2014_05
Patent number
US08716470B2

Reaction notes

Loading…