Cycloheptanone → 4-[(4-Bromophenyl)(cycloheptylidene)methyl]-2-fluorophenol

HRID 229219Notes

Reaction equation

HRID 229219 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 3

HCID 10400CycloheptanoneHCID 11430Potassium CarbonateHCID 18434174(4-Bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone

Product 1

HCID 686542804-[(4-Bromophenyl)(cycloheptylidene)methyl]-2-fluorophenolYield 79%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 24193Titanium TetrachlorideCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20 mL) was slowly added TiCl4 (0.45 mL, 4.07 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02 mmol) and cycloheptanone (0.35 g, 3.05 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 20:1) to give 0.30 g (79%) of compound 133 as a yellow solid. mp 102-104° C. 1H NMR (400 MHz, CDCl3): δ 1.56 (br s, 8H), 2.20-2.35 (m, 4H), 4.96 (br s, 1H), 6.75-6.86 (m, 2H), 6.90 (t, J=8.6 Hz, 1H), 7.00 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H). LCMS (ES): m/z 373 (M−H)−.

Workup

  1. customat room temperature
  2. temperatureThe mixture was heated
  3. temperatureat reflux for 2 h
  4. temperatureThe reaction mixture was heated
  5. temperatureat reflux
  6. filtrationThe reaction mixture was filtered through a pad of Celite
  7. washthe pad was washed with EtOAc (100 mL)
  8. customThe filtrate was transferred to a separatory funnel
  9. customthe layers were separated
  10. extractionThe aqueous layer was further extracted with EtOAc (25 mL)
  11. washThe combined organic phase was washed with brine
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. concentrationthe filtrate was concentrated
  15. customto give the crude product as brown oil
  16. customThe crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 20:1)

Sources & evidence

ORD record
ord-b921be90bd534303b55a1fd547bb10bf
Source dataset
uspto-grants-2009_07
Patent number
US07560589B2

Reaction notes

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