4-Methoxybenzyl alcohol → 3-Bromo-2-[(4-methoxyphenyl)methoxy]pyridine

HRID 632821Notes

Reaction equation

HRID 632821 reaction equation
[H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=1>C1COCC1>[Br:13][C:14]1[C:15]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[N:16][CH:17]=[CH:18][CH:19]=1

Participants

5

Reactant 3

HCID 77384-Methoxybenzyl alcoholHCID 24758Sodium hydrideHCID 6933243-Bromo-2-chloropyridine

Product 1

HCID 613744983-Bromo-2-[(4-methoxyphenyl)methoxy]pyridineYield 92%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

3-bromo-2-(4-methoxybenzyloxy)pyridine was prepared by the procedure described in J. Med. Chem., 2008, 51, 3065. A pressure vessel was charged with anhydrous THF (25 ml) and sodium hydride (1.44 g, 36.18 mmol, 60% dispersion). To this stirred mixture was added portionwise a solution of 4-methoxybenzyl alcohol (5.0 g, 36.18 mmol) in anhydrous THF (15 ml). After addition was complete, the mixture was stirred at room temperature for 30 minutes and a solution of 3-bromo-2-chloropyridine (4.64 g, 24.08 mmol) in anhydrous THF (15 ml) was added. The vessel was sealed and the reaction mixture was heated at 75° C. for 6 hours. Upon cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water, sat'd NaCl(aq.), dried over MgSO4, filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes: EtOAc) gave the title compound as a clear oil (6.51 g, 92%).

Workup

  1. custom3-bromo-2-(4-methoxybenzyloxy)pyridine was prepared by the procedure
  2. additionAfter addition
  3. customThe vessel was sealed
  4. temperaturethe reaction mixture was heated at 75° C. for 6 hours
  5. temperatureUpon cooling to room temperature
  6. customthe reaction mixture was partitioned between ethyl acetate and water
  7. washThe separated organic layer was washed with water, sat'd NaCl(aq.)
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. washElution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes: EtOAc)

Sources & evidence

ORD record
ord-24121bfa9c7540cd98af7339d3f14f4c
Source dataset
uspto-grants-2016_04
Patent number
US09321766B1

Reaction notes

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