2,4-Dibromo-1-fluorobenzene → (+/-)-(3aR*,7aS*)-7a-(5-bromo-2-fluorophenyl)-hexahydropyrano[3,4-c]isoxazole

HRID 217998Notes

Reaction equation

HRID 217998 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](Br)[CH:3]=1.C([Li])CCC.[N:15]1[O:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]=12>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C@:19]23[CH2:20][O:21][CH2:22][CH2:23][C@H:18]2[CH2:17][O:16][NH:15]3)[CH:3]=1

Participants

5

Reactant 3

HCID 150342,4-Dibromo-1-fluorobenzeneHCID 574756753,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazoleHCID 178418339Butyllithium

Product 1

HCID 59281218(+/-)-(3aR*,7aS*)-7a-(5-bromo-2-fluorophenyl)-hexahydropyrano[3,4-c]isoxazole

Reagents, catalysts & solvents 1

HCID 22635083Tetrahydrofuran tolueneSolvent2×

Conditions

Temperature
-78 °C

Procedure

1,3-Dibromo-4-fluorobenzene (837 mg) was dissolved in a toluene-THF (10:1) mixture (15 ml). The mixture was cooled to −78° C. and n-butyllithium (2.64 M, 1.19 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (200 mg) in toluene-THF (10:1) (5.0 ml) and a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time. After stirring at the same temperature for three hours, the reaction was terminated with an ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (365 mg).

Workup

  1. additiona boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time
  2. stirringAfter stirring at the same temperature for three hours
  3. customthe reaction was terminated with an ammonium chloride solution
  4. extractionThe aqueous layer was extracted with ethyl acetate
  5. washthe organic layer was washed with water and brine
  6. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  7. customthe solvent was evaporated under reduced pressure
  8. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-1d6841f74bc844ed9f0bc8cc83fddfb0
Source dataset
uspto-grants-2012_06
Patent number
US08198269B2

Reaction notes

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