Iodine → HCID 59383064, compound

HRID 2266239Notes

Reaction equation

HRID 2266239 reaction equation
[Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[O:19])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C@:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:21]2)([OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH2:12][CH2:13]1

Participants

6

Reactant 4

HCID 807IodineHCID 873631-Chloro-4-methoxybutaneHCID 5462224Magnesium2×HCID 59382885HCID 59382885, compound

Product 1

HCID 59383064HCID 59383064, compoundYield 91.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

A flame dried 50 mL three-necked flask was charged with magnesium turnings (380 mg, 15.8 mmol) and a small crystal of iodine in THF (5 mL). The flask was evacuated and refilled with N2. Then a solution of 1-chloro-4-methoxybutane (1.6 g, 13.2 mmol) in THF (10 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of the magnesium was consumed. The resulting Grignard reagent was used as follows. To another 100 mL three-necked flask was added (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (0.5 g, 1.32 mmol) and THF (10 mL). The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with sat'd aq NH4Cl (10 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4 Evaporation of the solvent and purification by flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (560 mg, 91%). 1H NMR (400 MHz, CDCl3): 0.35 (m, 2H), 0.63 (m, 2H), 1.05 (m, 1H), 1.43 (s, 9H), 1.55-1.20 (m, 9H), 1.85 (m, 1H), 2.55 (m, 1H), 2.67 (m, 1H), 3.27 (s, 3H), 3.33 (m, 2H), 3.85 (m, 1H), 4.05 (m, 2H), 4.25 (m, 1H), 6.97 (m, 3H). MS (E/Z): 466 (M+H+).

Workup

  1. customA flame dried 50 mL three-necked flask
  2. customThe flask was evacuated
  3. additionrefilled with N2
  4. customwas consumed
  5. customThe flask was evacuated
  6. additionrefilled with N2
  7. temperatureThe mixture was cooled with a dry ice-acetone bath
  8. additionthe Grignard reagent (250 mL) was added
  9. stirringwhile stirring overnight
  10. customThe mixture was quenched with sat'd aq NH4Cl (10 mL)
  11. extractionextracted with EtOAc (3×)
  12. dry with materialthe combined organic layers were dried over Na2SO4 Evaporation of the solvent and purification by flash column chromatography
  13. washeluting with 10% EtOAc/PE

Sources & evidence

ORD record
ord-9c0506fb8ff6435b8b27330ba8af5e2a
Source dataset
uspto-grants-2010_12
Patent number
US07858624B2

Reaction notes

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