Diisopropylamine → Lithium diisopropylamide

HRID 2380053Notes

Reaction equation

HRID 2380053 reaction equation
C([Li:5])CCC.[CH:6]([NH:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([O:22]CC)=O)[CH:14]=1.[F:25][C:26]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:27]=1C(OC)=O>CCCCCC.O1CCCC1.Cl>[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Li+:5].[F:25][C:26]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:27]=1[C:20](=[O:22])[CH2:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1

Participants

9

Reactant 4

HCID 7912DiisopropylamineHCID 96490Ethyl 3-pyridylacetateHCID 2782897Methyl 2,4-DifluorobenzoateHCID 178418339Butyllithium

Product 2

HCID 2724682Lithium diisopropylamideHCID 189565241-(2,4-Difluorophenyl)-2-(3-pyridinyl)-ethanone

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Procedure

A solution of lithium diisopropylamide was prepared using n-butyllithium (66 ml of a 1.6M solution in hexane) and diisopropylamine (10.8 g) in dry tetrahydrofuran (200 ml) under an atmosphere of dry nitrogen as described in Example 1(i). Ethyl 3-pyridylacetate was added dropwise to this solution at -70°. The thick mixture was stirred at -70° for 0.25 hour and then a solution of methyl 2,4-diflourobenzoate (18.36 g) in dry tetrahydrofuran (100 ml) was added over 0.05 hour. The cooling bath was removed and the mixture was stirred at room temperature for 5 hours. Acetic acid (12 ml) was added and the mixture was diluted with water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and evaporated to give an oil which was heated under reflux in concentrated hydrochloric acid (40 ml) for 5 hours. The solution was evaporated, the residue was dissolved in water and concentrated ammonia solution was added to ca. pH7. The mixture was extracted twice with ethyl acetate and the combined extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethyl acetate (70:30) gave the title compound as an oil (6.98 g) which was used directly in the next stage.

Workup

  1. customThe cooling bath was removed
  2. stirringthe mixture was stirred at room temperature for 5 hours
  3. additionAcetic acid (12 ml) was added
  4. additionthe mixture was diluted with water and ethyl acetate
  5. customThe organic layer was separated
  6. dry with materialdried (Na2SO4)
  7. customevaporated
  8. customto give an oil which
  9. temperaturewas heated
  10. customThe solution was evaporated
  11. dissolutionthe residue was dissolved in water
  12. additionconcentrated ammonia solution was added to ca. pH7
  13. extractionThe mixture was extracted twice with ethyl acetate
  14. washthe combined extracts were washed with brine
  15. dry with materialdried (Na2SO4)
  16. customEvaporation of the solvent
  17. customgave an oil which
  18. customwas chromatographed on silica gel
  19. washElution with dichloromethane/ethyl acetate (70:30)

Sources & evidence

ORD record
ord-b448ee70148f4e41b086267cf65002f6
Source dataset
uspto-grants-1994_11
Patent number
US05364938

Reaction notes

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