Diisopropylamine → Lithium diisopropylamide

HRID 1196922Notes

Reaction equation

HRID 1196922 reaction equation
[CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C([Li:12])CCC.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:14].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:36])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1>CCCCCC.O1CCCC1.O.C(O)(=O)C>[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:12].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]([OH:36])([CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1

Participants

10

Reactant 4

HCID 7912DiisopropylamineHCID 108224-EthylpyridineHCID 5880801-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanoneHCID 178418339Butyllithium

Product 2

HCID 2724682Lithium diisopropylamideHCID 189565112-(2,4-Difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Procedure

A solution of lithium diisopropylamide was prepared as described in Example 1(i) from diisopropylamine (40.4 g) and n-butyllithium (160 ml of a 2.5M solution in hexane) in dry tetrahydrofuran (800 ml) under an atmosphere of dry nitrogen. To this solution at -70° was added 4-ethylpyridine (42.8 g), dropwise with stirring over 0.17 hour. The solution was stirred at -70° for 0.33 hour and then a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (89.2 g) in dry tetrahydrofuran (350 ml) was added over 0.33 hour. The solution was stirred at -70° for a further 0.75 hour and then acetic acid (40 ml) was added dropwise. The solution was allowed to reach room temperature and was diluted with water. The mixture was extracted three times with ether and the combined extracts were washed with water. The aqueous washings were extracted once with ethyl acetate and the organic extracts were combined, dried (Na2SO4) and evaporated. The residue was dissolved in boiling dichloromethane, an equal volume of ether was added and then the solution was allowed to cool. The precipitated solid was filtered off to give recovered ketone starting material (17.5 g). The filtrate was evaporated and the residue was chromatographed on silica gel. Initial elution with ethyl acetate/hexane (1:1) gave further recovered ketone starting material. Further elution with ethyl acetate gave fractions containing the title compound, diastereoisomeric pair A (not treated further). The solvent was then changed to ethyl acetate/methanol (19:1) and elution was continued until pure fractions containing the title compound, diastereoisomeric pair B, were obtained. These fractions were combined, evaporated and the residue was crystallised from dichloromethane/ether to give the title compound, diastereoisomeric pair B, (20.5 g), m.p. 155°-157° (N.M.R. [300 MHz] spectrum identical with that obtained for a sample of diastereoisomeric pair B prepared as described in Method A, part (ii)).

Workup

  1. stirringThe solution was stirred at -70° for 0.33 hour
  2. stirringThe solution was stirred at -70° for a further 0.75 hour
  3. customto reach room temperature
  4. extractionThe mixture was extracted three times with ether
  5. washthe combined extracts were washed with water
  6. extractionThe aqueous washings were extracted once with ethyl acetate
  7. dry with materialdried (Na2SO4)
  8. customevaporated
  9. dissolutionThe residue was dissolved
  10. additionan equal volume of ether was added
  11. temperatureto cool
  12. filtrationThe precipitated solid was filtered off
  13. customto give
  14. customrecovered ketone starting material (17.5 g)
  15. customThe filtrate was evaporated
  16. customthe residue was chromatographed on silica gel
  17. washInitial elution with ethyl acetate/hexane (1:1)
  18. customgave further
  19. customrecovered ketone starting material
  20. washFurther elution with ethyl acetate
  21. customgave fractions
  22. additioncontaining the title compound, diastereoisomeric pair A (not
  23. additiontreated further)
  24. washThe solvent was then changed to ethyl acetate/methanol (19:1) and elution
  25. additioncontaining the title compound, diastereoisomeric pair B
  26. customwere obtained
  27. customevaporated
  28. customthe residue was crystallised from dichloromethane/ether

Sources & evidence

ORD record
ord-a520c89e147f478383d7d04008be560e
Source dataset
uspto-grants-1992_05
Patent number
US05116844

Reaction notes

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