Imidazole → 3-Ethyl-5-imidazol-1-yl-2-methoxy-6-methyl-pyridine

HRID 1921343Notes

Reaction equation

HRID 1921343 reaction equation
Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>[Cu](I)I>[CH2:8]([C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[C:2]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:7]=1)[CH3:9]

Participants

6

Reactant 4

HCID 795ImidazoleHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 116586693-Bromo-5-ethyl-6-methoxy-2-methylpyridine

Product 1

HCID 674923193-Ethyl-5-imidazol-1-yl-2-methoxy-6-methyl-pyridineYield 28.1%

Reagents, catalysts & solvents 1

HCID 83717Copper iodideCatalyst

Conditions

Temperature
185 °C

Procedure

Into each of 2 microwave vials is added 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (200 mg, 0.869 mmol), potassium carbonate (180 mg, 1.30 mmol), copper iodide (16 mg, 0.084 mmol), sodium hydroxide (84 mg, 2.10 mmol) and imidazole (59 mg, 0.869 mmol). The vials are flushed with N2 before anhydrous dimethylformamide (5.5 mL) is added and then sealed. Each reaction is heated in the CEM Discover microwave at 185° C. for 1 hr. The 2 reactions are combined diluted with water and extracted with 3 portions of dichloromethane. The combined dichloromethane layers are washed with 2 portions of 1 M aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1). Fractions containing the product are combined. The solvent evaporated, and the residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1, increasing to 2:1). Clean fractions containing the product are combined and evaporated to give 3-ethyl-5-(imidazol-1-yl)-2-methoxy-6-methyl-pyridine (53 mg, 14% yield) as a yellow oil. MS: m/e=218 (M+H); 1H NMR (300 MHz, CDCl3, δ ppm): 7.54 (1H, s) 7.22 (1H, s), 7.21 (1H, s), 7.00 (1H, s), 3.98 (3H, s), 2.59 (2H, q), 2.25 (3H, s), 1.10 (3H, t).

Workup

  1. customThe vials are flushed with N2 before anhydrous dimethylformamide (5.5 mL)
  2. additionis added
  3. customsealed
  4. additionThe 2 reactions are combined diluted with water
  5. extractionextracted with 3 portions of dichloromethane
  6. washThe combined dichloromethane layers are washed with 2 portions of 1 M aqueous sodium hydroxide
  7. dry with materialdried over magnesium sulfate
  8. customevaporated
  9. customto give a dark oil
  10. customThe crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1)
  11. additionFractions containing the product
  12. customThe solvent evaporated
  13. customthe residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1, increasing to 2:1)
  14. additionClean fractions containing the product
  15. customevaporated

Sources & evidence

ORD record
ord-b53e918b7d6a46f88535313e40c55e4d
Source dataset
uspto-grants-2012_05
Patent number
US08173682B2

Reaction notes

Loading…