tert-Butyl 4-oxopiperidine-1-carboxylate → tert-Butyl 4-(4-chloro-2-(hydroxymethyl)phenyl)-4-hydroxypiperidine-1-carboxylate

HRID 1016174Notes

Reaction equation

HRID 1016174 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].[Li]CCCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]2)=[C:3]([CH2:9][OH:10])[CH:4]=1

Participants

5

Reactant 3

HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 23363134(2-Bromo-5-chlorophenyl)methanolHCID 178418339Butyllithium

Product 1

HCID 57889172tert-Butyl 4-(4-chloro-2-(hydroxymethyl)phenyl)-4-hydroxypiperidine-1-carboxylateYield 61.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A solution of (2-bromo-5-chlorophenyl)methanol (1.48 g, 6.68 mmol) in anhydrous THF (30 mL) was cooled to −78° C. and treated with the dropwise addition of n-BuLi (1.6 M in hexanes) (8.77 mL, 14.03 mmol), and the mixture was stirred for 30 minutes at −78° C., during which a thick white precipitate was observed. The dianion was treated with the dropwise addition of a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.465 g, 7.35 mmol) in THF (10 mL), and the mixture was stirred for 1 hour at −78° C., during which a yellow homogeneous solution was observed, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride and the mixture was extracted 3× with ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was split into two equal fractions, and each was purified over a 40 g silica gel column via ISCO, eluting with a 10-100% EtOAc/Hexanes gradient over 15 minutes. The fractions from each run which contained the desired product were combined to yield the title compound (1.4 g, 4.10 mmol, 61.3% yield) as a colorless foam. MS (ESI+)=268, (M+H-tBuOH)+.

Workup

  1. stirringthe mixture was stirred for 1 hour at −78° C., during which a yellow homogeneous solution
  2. temperatureto warm to room temperature
  3. stirringstirred overnight
  4. customThe reaction was quenched with saturated ammonium chloride
  5. extractionthe mixture was extracted 3× with ethyl acetate
  6. washThe combined organic phases were washed with water and brine
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated in-vacuo
  9. customThe residue was split into two equal fractions
  10. customeach was purified over a 40 g silica gel column via ISCO
  11. washeluting with a 10-100% EtOAc/Hexanes
  12. waitgradient over 15 minutes

Sources & evidence

ORD record
ord-50f7394bf3dd45e9b401e99799ebe909
Source dataset
uspto-grants-2011_07
Patent number
US07985861B2

Reaction notes

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