Iodine → (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate

HRID 1254285Notes

Reaction equation

HRID 1254285 reaction equation
[Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C@:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]2)([OH:32])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:30]=[CH:29][CH:28]=1

Participants

6

Reactant 4

HCID 807IodineHCID 873631-Chloro-4-methoxybutaneHCID 5462224Magnesium2×HCID 46831638(R)-Tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate

Product 1

HCID 59382922(R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylateYield 73%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

A 250 mL three-necked flask was charged with magnesium turnings (2.88 g, 0.12 mol) and a small crystal of iodine in THF (20 mL). The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (40 mL) was added dropwise to the above mixture. After heating under reflux for 1 h, most of magnesium was consumed, the reaction mixture cooled to rt. Another 250 mL three-necked flask was charged with (R)-3-(3-chloro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 10 mmol) and THF (50 mL), which was evacuated and refilled with N2. The mixture was cooled with dry ice-acetone bath and the Grignard reagent derived from 1-chloro-4-methoxybutane (20 mL) was added dropwise. After addition, the mixture was allowed to warm slowly to rt and stirred for 2 h. The mixture was quenched with sat'd aq NH4Cl (100 mL), extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE 10:90) to give (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (3.0 g, 73%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.52-1.58 (m, 3H), 1.75 (m, 1H), 1.92 (m, 2H), 2.52 (m, 2H), 3.25 (s, 3H), 3.27 (m, 2H), 3.95 (m, 1H), 4.35 (m, 1H), 7.20-7.26 (m, 3H), 7.36 (m, 1H). MS (E/Z): 412 (M+H+).

Workup

  1. customThe flask was evacuated
  2. additionrefilled with N2
  3. temperatureAfter heating
  4. customwas consumed
  5. customwas evacuated
  6. additionrefilled with N2
  7. temperatureThe mixture was cooled with dry ice-acetone bath
  8. additionwas added dropwise
  9. additionAfter addition
  10. temperatureto warm slowly to rt
  11. customThe mixture was quenched with sat'd aq NH4Cl (100 mL)
  12. extractionextracted with EtOAc (3×80 mL)
  13. washThe combined organic layers were washed with brine
  14. dry with materialdried over Na2SO4
  15. concentrationconcentrated in vacuo
  16. customThe residue was purified by flash column chromatography (EA/PE 10:90)

Sources & evidence

ORD record
ord-5f2c7c18fa0f443aab86e336a25b5775
Source dataset
uspto-grants-2013_06
Patent number
US08455521B2

Reaction notes

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