2-Chlorophenol → Tert-butyl 4-(2-chlorophenoxy)piperidine-1-carboxylate

HRID 1093553Notes

Reaction equation

HRID 1093553 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]

Participants

5

Reactant 3

HCID 72452-ChlorophenolHCID 10796Cesium carbonateHCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidine

Product 1

HCID 16732586Tert-butyl 4-(2-chlorophenoxy)piperidine-1-carboxylateYield 50.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
65 °C

Procedure

To a stirred solution of 2-chlorophenol (20 g, 0.155 mole) in DMF (200 mL), was added cesium carbonate (101 g, 0.311 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (43.45 g, 0.155 mole). The reaction mixture was heated at 65° C. for 7 hours. The mixture was then filtered and concentrated under reduced. The resulting residue was diluted with ice cold water and the solid obtained was filtered and washed with water. The solid was dissolved in ether, washed with 2.5N aqueous NaOH solution, dried over sodium sulfate and concentrated under reduced pressure to afford 24.24 g (50%) of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 312.13 (M+1)+, 98.35%. A solution of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (24.2 g, 0.0776 mole) in dioxane.HCl (30 mL), was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 19.13 g (99.6%) of 4-(2-chloro-phenoxy)-piperidine hydrochloride. LCMS: 248.05 (M+1)+, 92.79%. 1H NMR (DMSO-d6): δ 9.3-8.9 (bs, 2H), 7.5-7.42 (d, 1H), 7.38-7.24 (m, 2H), 7.04-6.94 (t, 2H), 4.8-4.7 (m, 1H), 3.3-3.0 (bd, 4H), 2.2-2.05 (bs, 2H), 2.0-1.8 (bs, 2H).

Workup

  1. filtrationThe mixture was then filtered
  2. concentrationconcentrated
  3. additionThe resulting residue was diluted with ice cold water
  4. customthe solid obtained
  5. filtrationwas filtered
  6. washwashed with water
  7. dissolutionThe solid was dissolved in ether
  8. washwashed with 2.5N aqueous NaOH solution
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-7b0dfa6a98e3463f9139f70e02dbf04a
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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