Lithium diisopropylamide → Racemic 1-[2-(3,5-dichlorophenyl)pyridin-3-yl]-2,2-dipyridin-3-ylethanol

HRID 1009093Notes

Reaction equation

HRID 1009093 reaction equation
[CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[N:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=[O:33])[CH:26]=[C:27]([Cl:29])[CH:28]=1>C1COCC1.C1CCCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[C:31]([CH:32]([OH:33])[CH:1]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:34][CH:35]=[CH:36][N:37]=2)[CH:26]=[C:27]([Cl:29])[CH:28]=1

Participants

6

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 147626403,3'-MethylenedipyridineHCID 771748772-(3,5-Dichlorophenyl)nicotinaldehyde

Product 1

HCID 16058687Racemic 1-[2-(3,5-dichlorophenyl)pyridin-3-yl]-2,2-dipyridin-3-ylethanol

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8078CyclohexaneSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 3,3′-methylenedipyridine (340 mg, 1.99 mmol) in THF (20 mL) at −78° C. was treated with lithium diisopropylamide (2.65 mL of a 1.5 M solution of the mono-THF complex in cyclohexane, 3.98 mmol) dropwise. After stirring at −78° C. for 30 min, 2-(3,5-dichlorophenyl)nicotinaldehyde (500 mg as a solution in 6 mL THF, 1.99 mmol) was added dropwise via syringe. The reaction mixture was stirred for 1 h at −78° C., warmed to 0° C. over 5 min, then quenched with the addition of 100 mL H2O. The mixture was extracted with EtOAc (3×60 mL) and organic extracts were pooled, dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (40 g SiO2, 0-10% MeOH/CH2Cl2 gradient elution) to provide racemic 1-[2-(3,5-dichlorophenyl)pyridin-3-yl]-2,2-dipyridin-3-ylethanol. Resolution was performed by HPLC using a chiral stationary phase (ChiralPak AD, 5 cm×50 cm, 20μ, 40-100% i-PrOH/hexanes gradient elution modified with 1 mL/L diethylamine, 80 mL/min) and provided the title compound.

Workup

  1. stirringThe reaction mixture was stirred for 1 h at −78° C.
  2. temperaturewarmed to 0° C. over 5 min
  3. customquenched with the addition of 100 mL H2O
  4. extractionThe mixture was extracted with EtOAc (3×60 mL) and organic extracts
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. custompurified by flash chromatography (40 g SiO2, 0-10% MeOH/CH2Cl2 gradient elution)

Sources & evidence

ORD record
ord-69e6d11f196c401587096de55ea42f1e
Source dataset
uspto-grants-2011_07
Patent number
US07973059B2

Reaction notes

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