2,2,2-Trifluoro-N-methoxy-N-methylacetamide → 2,2,2-Trifluoro-1-(2-fluoro-5-((4-fluorophenyl)(hydroxy)methyl)phenyl)ethanone

HRID 928768Notes

Reaction equation

HRID 928768 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1I.C(=O)=O.CC(C)=O.C([Mg]Cl)(C)C.[F:32][C:33]([F:41])([F:40])[C:34](N(OC)C)=[O:35]>C1COCC1>[F:32][C:33]([F:41])([F:40])[C:34]([C:12]1[CH:13]=[C:14]([CH:15]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:16])[CH:17]=[CH:18][C:11]=1[F:10])=[O:35]

Participants

7

Reactant 5

HCID 27823822,2,2-Trifluoro-N-methoxy-N-methylacetamideHCID 103080734-Fluoro-3-iodobenzaldehydeHCID 18522661Acetone cardiceHCID 178418676HCID 178418676, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 867156112,2,2-Trifluoro-1-(2-fluoro-5-((4-fluorophenyl)(hydroxy)methyl)phenyl)ethanone

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 4-fluorophenylmagnesium bromide (3.64 mL, 1.1 M in THF, 4.0 mmol) in THF (3.6 mL) was stirred on a dry ice/acetone bath under argon while a solution of 4-fluoro-3-iodobenzaldehyde (1.00 g, 4.00 mmol, Intermediate 35: step a) in THF (6.4 mL) was added rapidly dropwise over 1.5 minutes, and the reaction was then immediately transferred to a room temperature water bath and stirred for 5 minutes. The clear, ˜colorless reaction was then cooled in the dry ice/acetone bath and treated with iPrMgCl (2.04 mL, 2.06 M in THF, 4.20 mmol) rapidly dropwise over 2.5 minutes. The yellow reaction was stirred for 30 minutes, and was then treated with 2,2,2-trifluoro-N-methoxy-N-methylacetamide dropwise over ˜30 seconds. The homogeneous yellow reaction was then immediately removed from the cold bath and allowed to warm to room temperature with stirring. After 2.5 hours, the dark yellow homogeneous reaction was chilled in a dry ice/acetone bath and quenched with 1 M aqueous NaH2PO4 (10 mL) in one portion. The reaction was warmed to room temperature and extracted with MTBE (1×10 mL, 1×5 mL), and the combined organic layers were washed with 5 M NaCl (1×3 mL), dried (Na2SO4), filtered, and concentrated twice from DCM to provide the crude title compound as a clear yellow oil.

Workup

  1. customwas then immediately transferred to a room temperature
  2. customThe clear, ˜colorless reaction
  3. customThe yellow reaction
  4. stirringwas stirred for 30 minutes
  5. customThe homogeneous yellow reaction
  6. customwas then immediately removed from the cold bath
  7. stirringwith stirring
  8. waitAfter 2.5 hours
  9. customthe dark yellow homogeneous reaction
  10. temperaturewas chilled in a dry ice/acetone bath
  11. customquenched with 1 M aqueous NaH2PO4 (10 mL) in one portion
  12. temperatureThe reaction was warmed to room temperature
  13. extractionextracted with MTBE (1×10 mL, 1×5 mL)
  14. washthe combined organic layers were washed with 5 M NaCl (1×3 mL)
  15. dry with materialdried (Na2SO4)
  16. filtrationfiltered
  17. concentrationconcentrated twice from DCM

Sources & evidence

ORD record
ord-64da4fd4d59f4dea8f6cfa078e68bf12
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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