Potassium Hydroxide → (3S)-1-(6-methoxypyridin-2-yl)pyrrolidin-3-ol

HRID 338553Notes

Reaction equation

HRID 338553 reaction equation
Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1.[OH-].[K+]>O1CCCC1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)C>[CH3:9][O:8][C:4]1[N:3]=[C:2]([N:10]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]2)[CH:7]=[CH:6][CH:5]=1

Participants

7

Reactant 3

HCID 14797Potassium HydroxideHCID 870092-Chloro-6-methoxypyridineHCID 2733874(3S)-pyrrolidin-3-ol

Product 1

HCID 86698868(3S)-1-(6-methoxypyridin-2-yl)pyrrolidin-3-olYield 226.5%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 11547931BippyPhosCatalystHCID 21899815MeOH tetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 2-chloro-6-methoxypyridine (1.966 g, 3.750 mmol) and commercially available (3S)-pyrrolidin-3-ol (1.437 g, 16.50 mmol) in tetrahydrofuran/methanol (137 mL/6.7 mL), was added Pd2(dba)3 (62.2 mg, 0.0688 mmol), BippyPhos (139.2 mg, 0.2750 mmol) and potassium hydroxide (1.16 g, 20.6 mmol, 88% pellets). The reaction was then was purged with nitrogen for 2 minutes and stirred at 70° C. for 18 hours. The reaction was filtered, quenched with saturated ammonium chloride solution, adjusted to pH=7˜8 with 1N hydrochloric acid and extracted with dichloromethane (100 mL*2) and ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine, dried over sodium sulfate and evaporated in vacuo. The residue was then purified by silica gel chromatography with ethyl acetate/petroleum ether, 0-25% to give the title compound (1.65 g, 62%) as a yellow gum that was used without further purification.

Workup

  1. customThe reaction was then was purged with nitrogen for 2 minutes
  2. filtrationThe reaction was filtered
  3. customquenched with saturated ammonium chloride solution
  4. extractionextracted with dichloromethane (100 mL*2) and ethyl acetate (100 mL*3)
  5. washThe combined organic phase was washed with saturated brine
  6. dry with materialdried over sodium sulfate
  7. customevaporated in vacuo
  8. customThe residue was then purified by silica gel chromatography with ethyl acetate/petroleum ether, 0-25%

Sources & evidence

ORD record
ord-72e6bcacd29247ffb74c40060173fe7c
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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