Iodine → 5-Chloro-4-(dimethoxymethyl)-2-(3-methoxypropyl)pyridine

HRID 561826Notes

Reaction equation

HRID 561826 reaction equation
II.Br[CH2:4][CH2:5][CH2:6][O:7][CH3:8].Br[C:10]1[CH:15]=[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C:13]([Cl:21])=[CH:12][N:11]=1.CCOC(C)=O>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:13]1[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[CH:15][C:10]([CH2:4][CH2:5][CH2:6][O:7][CH3:8])=[N:11][CH:12]=1

Participants

7

Reactant 4

HCID 807IodineHCID 8857Ethyl AcetateHCID 5245511-Bromo-3-methoxypropane2×HCID 575173382-Bromo-5-chloro-4-(dimethoxymethyl)pyridine

Product 1

HCID 667628875-Chloro-4-(dimethoxymethyl)-2-(3-methoxypropyl)pyridineYield 62%

Reagents, catalysts & solvents 2

HCID 178418745HCID 178418745, compoundCatalystHCID 8028TetrahydrofuranSolvent3×

Procedure

To a suspension of Mg (911 mg, 37.5 mmol) and of iodine (one crystal) in dry THF (30 mL) was added dropwise 5% of the total amount of 1-bromo-3-methoxypropane (4.59 g, 30.0 mmol). The mixture was heated to reflux with the help of a heat gun until the Grignard formation had started. The rest of the 1-bromo-3-methoxypropane was added slowly, while an exothermic reaction proceeded. After the end of the addition, the reaction mixture was stirred under reflux for 20 min, and was allowed to cool to rt. This Grignard sol. (1M in THF, 23.5 mL, 23.5 mmol) was added dropwise to a mixture of 2-bromo-5-chloro-4-dimethoxymethyl-pyridine (2.50 g, 9.38 mmol) and Ni(dppp)Cl2 (495 mg, 0.938 mmol) in THF (50 mL) at 0° C. The reaction mixture was stirred at rt for 30 min, and was then heated to reflux for 2 h. The mixture was allowed to cool to rt, and was dissolved with EtOAc. This mixture was washed with aq. sat. NaHCO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 1:1) yielded the title compound (1.51 g, 62%). LC-MS: tR=0.80 min; ES+: 260.15.

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux with the help of a heat gun until the Grignard formation
  3. additionAfter the end of the addition
  4. temperatureunder reflux for 20 min
  5. stirringThe reaction mixture was stirred at rt for 30 min
  6. temperaturewas then heated
  7. temperatureto reflux for 2 h
  8. temperatureto cool to rt
  9. washThis mixture was washed with aq. sat. NaHCO3
  10. dry with materiallayer was dried over MgSO4
  11. filtrationfiltered
  12. customthe solvents were removed under reduced pressure
  13. customPurification of the residue by FC (heptane→EtOAc/heptane 1:1)

Sources & evidence

ORD record
ord-ebf6875abcd84712b92771eabb7c6072
Source dataset
uspto-grants-2011_11
Patent number
US08063105B2

Reaction notes

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