Reaction #1596951

Reaction equation

4-(4-ethylcyclohexyl)-2-fluorobenzeneboronic acid

hydrazine hydroxide

5-((4-bromo-2,6-difluorophenyl)difluoromethoxy)-1,3-difluoro-2-(trifluoromethyl)benzene

sodium metaborate

→

4-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-4′-(4-ethylcyclohexyl)-3,5,2′-trifluorobiphenyl

Solvents

water

THF

Conditions

Workup

1. 1
   Otherat room temperature
2. 2
   Temperaturethe mixture is heated at the boil for 18 h
3. 3
   TemperatureAfter cooling
4. 4
   Extractionthe batch is extracted with MTBE
5. 5
   ExtractionThe aqueous phase is extracted with MTBE
6. 6
   Washthe combined organic phases are washed with water and saturated sodium chloride solution
7. 7
   OtherThe solution is dried
8. 8
   Concentrationconcentrated to dryness
9. 9
   OtherThe crude product is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=9:1)
10. 10
    OtherThe further purification
11. 11
    Otheris carried out by recrystallisation from ethanol and n-heptane

Procedure

0.11 ml (2.33 mmol) of hydrazine hydroxide is added to a mixture of 9.70 g (22.1 mmol) of 5-((4-bromo-2,6-difluorophenyl)difluoromethoxy)-1,3-difluoro-2-(trifluoromethyl)benzene, 12 ml (18 mmol) of 1.5 N aqueous sodium metaborate soln. and 0.62 g (0.88 mmol) of bis(triphenylphosphine)palladium(II) chloride in 150 ml of THF at room temperature. 6.1 g (24.3 mmol) of 4-(4-ethylcyclohexyl)-2-fluorobenzeneboronic acid are added, and the mixture is heated at the boil for 18 h. After cooling, water is added, and the batch is extracted with MTBE. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 4-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-4′-(4-ethylcyclohexyl)-3,5,2′-trifluorobiphenyl as a colourless solid having an m.p. of 77° C.

Source