تفاعل #363384

معادلة التفاعل

(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester

trimethylsilyl chloride

3,4-difluoro-iodobenzene

ammonium chloride

triphenylphosphine

1,2-dibromoethane

→

(E)-3-cyclohexyl 2-(3,4-difluoro-phenyl)-acrylic acid methyl ester

المردود 95.0%

المذيبات

tetrahydrofuran

tetrahydrofuran

tetrahydrofuran

tetrahydrofuran

tetrahydrofuran

ظروف التفاعل

المعالجة

1. 1
   درجة الحرارةto cool
2. 2
   درجة الحرارةheated again
3. 3
   workup.ADDITIONDuring the addition
4. 4
   أخرىrose to 45° C
5. 5
   workup.STIRRINGThe reaction mixture was then stirred at 40-45° C. for 1 h
6. 6
   workup.STIRRINGstirred overnight at 25° C
7. 7
   أخرى(˜2 h)
8. 8
   workup.STIRRINGwas stirred at 25° C. under argon for 10 min
9. 9
   درجة الحرارةThe resulting brick red solution was heated at 25° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture
10. 10
    استخلاصthe organic compound was extracted into diethyl ether (2×50 mL)
11. 11
    غسيلThe combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL)
12. 12
    تجفيفdried over anhydrous magnesium sulfate
13. 13
    ترشيحfiltered
14. 14
    تركيزconcentrated in vacuo

الإجراء التجريبي

A mixture of zinc dust (980 mg, 15 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.37 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (82 mg, 0.75 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (prepared in Example 4, 1.47 g, 5 mmol) in dry tetrahydrofuran (1.5 mL) over 3 min. During the addition, the temperature rose to 45° C. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (5 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 3,4-difluoro-iodobenzene (960 mg, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 25° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (50 mL), and the organic compound was extracted into diethyl ether (2×50 mL), The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 5/1 hexanes/diethyl ether) afforded (E)-3-cyclohexyl 2-(3,4-difluoro-phenyl)-acrylic acid methyl ester (1.06 g, 95%) as an oil: EI-HRMS m/e calcd for C16H18F2O2 (M+) 280.1275, found 280.1275.

المصدر