Hexane → HCID 21993302, compound

HRID 1977560Notes

Reaction equation

HRID 1977560 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[O:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:21][CH2:22][CH2:23]CCC.C([Li])CCC.[F:32][C:33]1[CH:34]=[C:35](Br)[CH:36]=[CH:37][C:38]=1[Cl:39]>C1COCC1.[Cl-].[Zn+2].[Cl-].O>[CH2:21]([CH:18]1[CH2:17][O:16][CH:15]([CH:12]2[CH2:13][CH2:14][CH:9]([C:4]3[CH:5]=[C:6]([F:8])[C:7]([C:35]4[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([F:32])[CH:34]=4)=[C:2]([F:1])[CH:3]=3)[CH2:10][CH2:11]2)[O:20][CH2:19]1)[CH2:22][CH3:23]

Participants

8

Reactant 4

HCID 8058HexaneHCID 27246904-Bromo-1-chloro-2-fluorobenzeneHCID 85794970HCID 85794970, compoundHCID 178418339Butyllithium

Product 1

HCID 21993302HCID 21993302, compoundYield 95%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-65 °C

Procedure

The above 5-propyl-2-(4-(3,5-difluorophenyl)cyclohexyl-1,3-dioxane 1.3 g (4.0 mmol) was dissolved in THF 10 ml, and cooled to −65° C. under a nitrogen atmosphere. To this solution, 1.68 M hexane solution 3.0 ml (5.0 mmol) of n-butyllithium was added dropwise keeping the liquid temperature below −55° C., and the mixture was stirred for one hour at the same temperature. Then, to the reactant, 0.5 M THF solution 10 ml (5.0 mmol) of zinc chloride was added dropwise keeping the liquid temperature below −50° C., and the mixture was heated to room temperature and stirred for 30 minutes. Tetrakistriphenylphosphin paradium 0.5 g and 3-fluoro-4-chlorobromobenzene 1.1 g (5.3 mmol) were added to the solution, and the mixture was refluxed with heating for 3 hours. Water 30 ml was added to the resulting reactant, and the product was extracted with toluene. The extract was washed with 3N-hydrochloric acid, a saturated bicarbonate aqueous solution and then a saturated sodium chloride aqueous solution, and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene), and recrystallized twice from a mixed solvent of heptane/ethyl acetate=1/1 to obtain 5-propyl-2-(4-(4-(3-fluoro-4-chlorophenyl)-3,5-difluorophenyl) cyclohexyl)-1,3-dioxane 1.7 g (3.8 mmol). The yield was 95.0% from 5-propyl-2-(4-(3,5-difluorophenyl)ethyl)-1,3-dioxane.

Workup

  1. customthe liquid temperature below −55° C.
  2. customthe liquid temperature below −50° C.
  3. temperaturethe mixture was heated to room temperature
  4. stirringstirred for 30 minutes
  5. temperaturethe mixture was refluxed
  6. temperaturewith heating for 3 hours
  7. extractionthe product was extracted with toluene
  8. washThe extract was washed with 3N-hydrochloric acid
  9. dry with materiala saturated bicarbonate aqueous solution and then a saturated sodium chloride aqueous solution, and dried over magnesium sulfate
  10. distillationthe solvent was distilled off
  11. customThe residue was purified by silica gel column chromatography (eluent: toluene)
  12. customrecrystallized twice from a mixed solvent of heptane/ethyl acetate=1/1

Sources & evidence

ORD record
ord-35e15e3842164236a7fb44454eb9c1e1
Source dataset
uspto-grants-2001_05
Patent number
US06235355B1

Reaction notes

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