2',5'-Dimethoxyacetophenone → 2-(3,4-Difluoro-5-methoxyphenyl)-1-(2,5-dimethoxyphenyl)ethanone

HRID 1522875Notes

Reaction equation

HRID 1522875 reaction equation
C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].Br[C:54]1[CH:55]=[C:56]([O:62][CH3:63])[C:57]([F:61])=[C:58]([F:60])[CH:59]=1.[CH3:64][O:65][C:66]1[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][C:67]=1[C:74](=[O:76])[CH3:75]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:60][C:58]1[CH:59]=[C:54]([CH2:75][C:74]([C:67]2[CH:68]=[C:69]([O:72][CH3:73])[CH:70]=[CH:71][C:66]=2[O:65][CH3:64])=[O:76])[CH:55]=[C:56]([O:62][CH3:63])[C:57]=1[F:61]

Participants

8

Reactant 4

HCID 709912',5'-DimethoxyacetophenoneHCID 634876Binap, (A+-)-HCID 27732885-Bromo-1,2-difluoro-3-methoxybenzeneHCID 23676156Sodium t-butoxide

Product 1

HCID 866828992-(3,4-Difluoro-5-methoxyphenyl)-1-(2,5-dimethoxyphenyl)ethanoneYield 24.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

A 100-mL round-bottom flask charged with Pd2dba3 (69 mg, 0.075 mmol), BINAP (112 mg, 0.18 mmol), and NaOt-Bu (650 mg, 6.5 mmol) was degassed and filled with N2. THF (20 mL) was added, followed by a solution 5-bromo-1,2-difluoro-3-methoxybenzene (1.1 g, 5 mmol) and 1-(2,5-dimethoxyphenyl)ethanone (1.08 g, 6 mmol) in THF (10 mL). The resulting mixture was heated at 70° C. for 16 h. Water (30 mL) was added, and the mixture was extracted with ether (3×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=80/1-40/1) to give 2-(3,4-difluoro-5-methoxyphenyl)-1-(2,5-dimethoxyphenyl)ethanone (0.4 g) as a light yellow solid. 1H NMR (CDCl3): δ 7.24 (d, 1H), 7.04 (dd, 1H), 6.92 (d, 1H), 6.68-6.61 (m, 2H), 4.23 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H); LCMS: 323 (M+H)+.

Workup

  1. customwas degassed
  2. additionfilled with N2
  3. additionTHF (20 mL) was added
  4. extractionthe mixture was extracted with ether (3×50 mL)
  5. dry with materialThe combined organics were dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give the crude product, which
  9. customwas purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=80/1-40/1)

Sources & evidence

ORD record
ord-d9a7ad084b31441a8461b036e592f77e
Source dataset
uspto-grants-2015_07
Patent number
US09078871B2

Reaction notes

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