1-Bromo-2-fluorobenzene → tert-Butyl 4-(2-fluorophenyl)-4-hydroxypiperidine-1-carboxylate

HRID 1913875Notes

Reaction equation

HRID 1913875 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])([OH:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]

Participants

5

Reactant 3

HCID 612591-Bromo-2-fluorobenzeneHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 23566966tert-Butyl 4-(2-fluorophenyl)-4-hydroxypiperidine-1-carboxylateYield 65.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirring solution of 1-bromo-2-fluorobenzene (2 g, 11.4 mmol) in tetrahydrofuran (30 mL) at −70° C. under nitrogen was added a solution of n-butyllithium (5.0 mL, 12.6 mmol, 2.5 M in hexane). After 30 minutes, 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.97 g, 14.9 mmol) was added in one portion. After 30 minutes, the reaction was quenched with water (2 mL) and was allowed to warm to ambient temperature. After one hour at ambient temperature, the reaction mixture was poured into water (75 mL) and the mixture was extracted with ethyl acetate (2×75 mL). The organic layers were combined, washed with saturated aqueous sodium chloride and concentrated at reduced pressure. The resulting crude product was triturated with hexane (35 mL) for 2 hours, filtered and dried to give the product as a white solid (2.22 g, 65%). 1H NMR (CDCl3) δ 7.45 (m, 1H,), 7.24 (m, 1H), 7.19-7.01 (m, 2H), 4.03 (br s, 2H), 3.23 (m, 2H), 18 (m, 3H), 1.81 (m, 2H), 1.45 (m, 9H). MS (ES+)=296 (MH)+.

Workup

  1. waitAfter 30 minutes
  2. customthe reaction was quenched with water (2 mL)
  3. waitAfter one hour at ambient temperature
  4. additionthe reaction mixture was poured into water (75 mL)
  5. extractionthe mixture was extracted with ethyl acetate (2×75 mL)
  6. washwashed with saturated aqueous sodium chloride
  7. concentrationconcentrated at reduced pressure
  8. customThe resulting crude product was triturated with hexane (35 mL) for 2 hours
  9. filtrationfiltered
  10. customdried

Sources & evidence

ORD record
ord-53542e0a3393413f911f524761ce0b7d
Source dataset
uspto-grants-2013_12
Patent number
US08609849B1

Reaction notes

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