Pyrrole → 3-Ethyl-2-methoxy-6-methyl-5-pyrrol-1-yl-pyridine

HRID 1921345Notes

Reaction equation

HRID 1921345 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][CH: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][CH:23]=[CH:22]2)[CH:7]=1)[CH3:9]

Participants

6

Reactant 4

HCID 8027PyrroleHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 116586693-Bromo-5-ethyl-6-methoxy-2-methylpyridine

Product 1

HCID 674922843-Ethyl-2-methoxy-6-methyl-5-pyrrol-1-yl-pyridineYield 36.2%

Reagents, catalysts & solvents 1

HCID 83717Copper iodideCatalyst2×

Conditions

Temperature
185 °C

Procedure

Into each of 2 microwave vials is added 3-bromo-5-ethyl-6-methoxy-2-methyl-pyridine (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 pyrrole (72 μL, 1.04 mmol). The vials are flushed with N2 before anhydrous dimethylformamide (5 mL) is added then sealed. The first reaction is heated in the CEM Discover microwave at 185° C. (max wattage set to 150 W) for 1 hr. LC/MS shows the reaction is incomplete. The reaction is re-microwaved at 185° C. for a further 1 hr but LC/MS shows no further apparent product formation. The second reaction is microwaved at 185° C. for 1 hr. Further copper iodide (150 mg) is added, the reaction is flushed with N2 and re-microwaved at 185° C. for a further 1 hr. LC/MS shows the reaction is largely complete. The two reactions are combined, diluted with water and extracted with three portions of dichloromethane. The combined organic layers are washed with two portions of 1 M aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to give a black oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with ethyl acetate:heptane (1:49, increasing to 1:1). Clean fractions containing the product are combined and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-pyrrol-1-yl-pyridine (68 mg, 18% yield) as a yellow-orange oil. MS: m/e=217 (M+H); 1H NMR (CDCl3, δ ppm): 7.26 (1H, s, obscured by CHCl3 in CDCl3), 6.73 (2H, m), 6.30 (2H, m), 3.98 (3H, s), 2.58 (2H, q), 2.27 (3H, s), 1.10 (3H, t).

Workup

  1. customThe vials are flushed with N2 before anhydrous dimethylformamide (5 mL)
  2. additionis added
  3. customthen sealed
  4. customThe first reaction
  5. customThe reaction is re-microwaved at 185° C. for a further 1 hr
  6. customThe second reaction
  7. customis microwaved at 185° C. for 1 hr
  8. customthe reaction is flushed with N2
  9. customre-microwaved at 185° C. for a further 1 hr
  10. additiondiluted with water
  11. extractionextracted with three portions of dichloromethane
  12. washThe combined organic layers are washed with two portions of 1 M aqueous sodium hydroxide
  13. dry with materialdried over magnesium sulfate
  14. customevaporated
  15. customto give a black oil
  16. customThe crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with ethyl acetate:heptane (1:49, increasing to 1:1)
  17. additionClean fractions containing the product
  18. customevaporated

Sources & evidence

ORD record
ord-f197e68e7aa5490886342712dadfabf7
Source dataset
uspto-grants-2012_05
Patent number
US08173682B2

Reaction notes

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