Reaction #2139950

Reaction equation

hydrochloric acid

n-butyllithium

methyl 6-bromo-2-fluoro-3-(4-pentylcyclohexyl)benzoate

1-bromo-4-butoxy-3-fluoro-2-(2-methoxyethoxy-methoxy)benzene

→

methyl 4′-butoxy-3,3′-difluoro-2′-(2-methoxyethoxymethoxy)-4-(4-pentylcyclohexyl)-biphenyl-2-carboxylate

Yield 55.0%

Solvents

hexane

tetrahydrofuran

tetrahydrofuran

tetrahydrofuran

Conditions

Workup

1. 1
   TemperatureThe batch was refluxed for 4 hours
2. 2
   Extractionextracted with MTB ether
3. 3
   WashThe combined organic phases were washed with water
4. 4
   Dryingdried over sodium sulfate
5. 5
   Otherevaporated
6. 6
   OtherThe crude product was chromatographed over silica gel with n-pentane/MTB ether (3:1)

Procedure

16.4 g (0.046 mol) of 1-bromo-4-butoxy-3-fluoro-2-(2-methoxyethoxy-methoxy)benzene were dissolved in 20 ml of tetrahydrofuran, and 31.6 ml (0.052 mol) of a 15 percent solution of n-butyllithium in hexane were added at −70° C. After addition of a solution of 5.94 g (0.027 mol) of zinc bromide in 30 ml of tetrahydrofuran, the batch was allowed to thaw, and the resultant solution was added at the boiling point to a mixture of 18 g (0.046 mol) of methyl 6-bromo-2-fluoro-3-(4-pentylcyclohexyl)benzoate and 730 mg (1.00 mmol) of Pd(dppf)2Cl2 in 60 ml of tetrahydrofuran. The batch was refluxed for 4 hours, stirred overnight at room temperature, acidified using dilute hydrochloric acid and extracted with MTB ether. The combined organic phases were washed with water, dried over sodium sulfate and evaporated. The crude product was chromatographed over silica gel with n-pentane/MTB ether (3:1), giving 14.6 g (55%) of methyl 4′-butoxy-3,3′-difluoro-2′-(2-methoxyethoxymethoxy)-4-(4-pentylcyclohexyl)-biphenyl-2-carboxylate as a yellow oil. This was dissolved in 56 ml of tetrahydrofuran, 11 ml of conc. hydrochloric acid were added, and the mixture was stirred overnight at room temperature. The precipitated product was filtered off with suction, washed with ethyl acetate and dried, giving 7.6 g (68%) of 3-butoxy-4,7-difluoro-8-(4-pentylcyclohexyl)-benzo[c]chromen-6-one as colourless crystals.

Source