Hydrochloric Acid → 3,3'-Dichloro-5'-fluoropropiophenone

HRID 1819666Notes

Reaction equation

HRID 1819666 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].Cl>[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Cl:11][CH2:12][CH2:13][C:14]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:15]

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 693643-Chloropropionyl chlorideHCID 178505832HCID 178505832, compound

Product 1

HCID 685287683,3'-Dichloro-5'-fluoropropiophenoneYield 50.1%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalyst2×HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A reaction flask (500 mL) containing zinc chloride (6.98 g, 51.2 mmol) was dried by heating using a heat gun under vacuum. After cooling to room temperature, a solution of 3-chloro-5-fluorophenylmagnesium bromide (0.5 M in dry tetrahydrofuran, 100 mL, 50.0 mmol) was added to the reaction flask via a cannula, and the mixture was stirred until all zinc chloride solid was dissolved and the formation of a sluggish bright yellow solution (˜1 h). A warm bath (40° C) may be applied to complete this process. Anhydrous tetrahydrofuran (100 mL) was added, followed by tetrakis(triphenylphosphine)palladium (2.89 g, 2.50 mmol, 0.05 equiv.). After cooling to 0° C., 3-chloropropionyl chloride (5.05 mL, 52.5 mmol, 1.05 equiv.) was added dropwise and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was acidified with an aqueous hydrochloric acid solution (3 N), then extracted with diethyl ether (2×250 mL). The combined ether extracts were washed with a saturated aqueous sodium bicarbonate solution, brine, dried (anhydrous sodium sulfate), and concentrated. The crude oil was purified by Isco CombiFlash Companion column chromatography (silica gel, 0-15% ethyl acetate/hexane) and the resulting white solid was recrystallized (minimal diethyl ether/hexane/−25° C.) to give pure 3-chloro-1-(3-chloro-5-fluorophenyl)propan-1-one as a white powder (5.54 g, 50%).

Workup

  1. customwas dried
  2. temperatureby heating
  3. dissolutionwas dissolved
  4. customthe formation of a sluggish bright yellow solution (˜1 h)
  5. customA warm bath (40° C) may be applied
  6. temperatureAfter cooling to 0° C.
  7. extractionextracted with diethyl ether (2×250 mL)
  8. washThe combined ether extracts were washed with a saturated aqueous sodium bicarbonate solution, brine
  9. dry with materialdried (anhydrous sodium sulfate)
  10. concentrationconcentrated
  11. customThe crude oil was purified by Isco CombiFlash Companion column chromatography (silica gel, 0-15% ethyl acetate/hexane)
  12. customthe resulting white solid was recrystallized (minimal diethyl ether/hexane/−25° C.)

Sources & evidence

ORD record
ord-2435a42cf172444e84b685c67a648394
Source dataset
uspto-grants-2009_10
Patent number
US07601744B2

Reaction notes

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