1,5-Dibromo-2,4-difluorobenzene → (+/-)-1-(5-Bromo-2,4-difluorophenyl)-2-(but-3-en-2-yloxy)ethanone

HRID 68381Notes

Reaction equation

HRID 68381 reaction equation
Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[CH3:16][CH:17]([O:20][CH2:21][C:22](N(OC)C)=[O:23])[CH:18]=[CH2:19]>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([C:22](=[O:23])[CH2:21][O:20][CH:17]([CH:18]=[CH2:19])[CH3:16])[CH:7]=1

Participants

5

Reactant 3

HCID 105645111,5-Dibromo-2,4-difluorobenzeneHCID 867078202-but-3-en-2-yloxy-N-methoxy-N-methylacetamideHCID 178418339Butyllithium2×

Product 1

HCID 68296192(+/-)-1-(5-Bromo-2,4-difluorophenyl)-2-(but-3-en-2-yloxy)ethanoneYield 230%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-78 °C

Procedure

1,5-Dibromo-2,4-difluorobenzene (1.16 g, 4.28 mmol) was dissolved in Et2O (2 mL) and the solution was cooled to −78° C. nBuLi (1.26 mL 2.5M solution in hexanes) was added dropwise, maintaining the internal temperature below −70° C. Immediately after addition of nBuLi is complete, a solution of (±)-2-(but-3-en-2-yloxy)-N-methoxy-N-methylacetamide (0.5 g, 2.85 mmol) in Et2O (2 mL) was added dropwise, keeping the internal temperature below −70° C. The reaction was stirred at −78° C. for 15 minutes before quenching with saturated NH4Cl. The mixture was extracted with DCM (×3), dried (MgSO4) and concentrated in vacuo. The reaction was repeated a further 5 times on the same scale. The residues from all six reactions were combined and purified by column chromatography (Biotage SNAP 25 g 0-10% EtOAc in hexane) to leave the desired compound as a yellow oil (2 g). 1H NMR (400 MHz, CDCl3) δ ppm: 8.20 (t, J=7.46 Hz, 1H), 6.98 (dd, J=7.95, 10.15 Hz, 1H), 5.76 (ddd, J=7.70, 10.09, 17.42 Hz, 1H), 5.16-5.26 (m, 2H), 4.51-4.69 (m, 2H), 3.93-4.04 (m, 1H), 1.34-1.40 (m, 3H)

Workup

  1. additionwas added dropwise
  2. temperaturemaintaining the internal temperature below −70° C
  3. customthe internal temperature below −70° C
  4. custombefore quenching with saturated NH4Cl
  5. extractionThe mixture was extracted with DCM (×3)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. custompurified by column chromatography (Biotage SNAP 25 g 0-10% EtOAc in hexane)

Sources & evidence

ORD record
ord-f6d3e0553af94a90bdeb2a86f9465e49
Source dataset
uspto-grants-2014_09
Patent number
US08822455B2

Reaction notes

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