5-Bromo-2-fluorobenzaldehyde → 2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine

HRID 335955Notes

Reaction equation

HRID 335955 reaction equation
Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([F:14])[C:3]=1[O:15][CH2:16][O:17][CH3:18].C([Li])CCC.BrC1C=CC(F)=C(C=1)C=O>O1CCCC1>[F:14][C:4]1[C:3]([O:15][CH2:16][O:17][CH3:18])=[CH:2][CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:5]=1

Participants

5

Reactant 3

HCID 7363275-Bromo-2-fluorobenzaldehydeHCID 673828784-Bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridineHCID 178418339Butyllithium

Product 1

HCID 673830702-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridineYield 12.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

4-Bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine (1.62 g, 5.06 mmol) was dissolved in dry tetrahydrofuran (50 mL) under nitrogen and cooled in a dry ice bath. Butyllithium solution (2.5 M in hexanes, 2.2 mL, 5.50 mmol) was added and the reaction stirred for 5 min. A solution of 5-bromo-2-fluorobenzaldehyde (1.03 g, 5.06 mmol) in dry THF (10 mL) was added and the reaction stirred for 35 min then quenched by addition of saturated ammonium chloride (20 mL). Water (100 mL) and EtOAc (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave recovered starting material (0.30 g, 18%), debrominated 2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine (0.15 g, 0.61 mmol, 12.0% yield) and the desired (5-bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)methanol (0.85 g, 1.90 mmol)

Workup

  1. temperaturecooled in a dry ice bath
  2. stirringthe reaction stirred for 35 min
  3. customthen quenched by addition of saturated ammonium chloride (20 mL)
  4. additionWater (100 mL) and EtOAc (100 mL) were added
  5. additionthe phases mixed
  6. customseparated
  7. dry with materialThe organic was dried with magnesium sulfate
  8. customevaporated to dryness under reduced pressure
  9. customPurification
  10. customgave
  11. customrecovered

Sources & evidence

ORD record
ord-89505d091e214be59aeacf602664c79f
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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