Oxygen → 2,6-Diethoxy-4'-fluoro-biphenyl-4-carbaldehyde

HRID 913316Notes

Reaction equation

HRID 913316 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1I)[CH:7]=[O:8])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)[CH3:2]

Participants

9

Reactant 5

HCID 977OxygenHCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2856454-Fluorophenylboronic acidHCID 226368083,5-Diethoxy-4-iodobenzaldehyde

Product 1

HCID 593831002,6-Diethoxy-4'-fluoro-biphenyl-4-carbaldehydeYield 83%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

3,5-Diethoxy-4-iodo-benzaldehyde (14.05 g, 43.89 mmol, 1.0 equiv; prepared as described in WO 01/326 33 A1 (F. Hoffmann-La Roche AG); [CAS RN 338454-05-0]) was dissolved under Ar in toluene (180 mL) and water (20 mL) and treated successively with 4-fluorophenyl boronic acid (12.28 g, 87.78 mmol, 2.0 equiv), K3PO4 (50.12 g, 236.12 mmol, 5.38 equiv), tricyclohexylphosphine (2.80 g, 9.66 mmol, 0.22 equiv) and palladium(II) acetate (1.08 g, 4.83 mmol, 0.11 equiv). The reaction mixture was heated to 100° C. for 18 h under scrupulous exclusion of oxygen, when GC indicated the absence of starting iodo-compound. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of hexane/ethyl acetate (9:1). Recrystallization from hexane/ethyl acetate provided 10.44 g (83%) of the title compound as white crystals. MS (EI): 288.2 [M]+.

Workup

  1. additionThe reaction mixture was poured
  2. extractionextracted with ethyl acetate (2×200 mL)
  3. washthe combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL)
  4. dry with materialThe organic phase was dried over Na2SO4
  5. concentrationconcentrated by evaporation under reduced pressure
  6. customthe crude material purified by silica column chromatography
  7. washeluting with a mixture of hexane/ethyl acetate (9:1)
  8. customRecrystallization from hexane/ethyl acetate

Sources & evidence

ORD record
ord-6f552bc36b0a4fb6b07ebf63a4bc8ce8
Source dataset
uspto-grants-2011_09
Patent number
US08026365B2

Reaction notes

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