Boron trifluoride etherate → (3S,3aS,6aS)-rel-3-(2-fluoro-phenyl)-3-methyl-hexahydro-furo[3,4-d]isoxazole

HRID 2178193Notes

Reaction equation

HRID 2178193 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH3:14][C:15]1[C@H:19]2[CH2:20][O:21][CH2:22][C@H:18]2[O:17][N:16]=1.B(F)(F)F.CCOCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C.O>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C@:15]1([CH3:14])[C@H:19]2[CH2:20][O:21][CH2:22][C@H:18]2[O:17][NH:16]1

Participants

10

Reactant 5

HCID 8000Boron trifluoride etherateHCID 25517Ammonium ChlorideHCID 612591-Bromo-2-fluorobenzeneHCID 68159032(3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazoleHCID 178418339Butyllithium

Product 1

HCID 68158180(3S,3aS,6aS)-rel-3-(2-fluoro-phenyl)-3-methyl-hexahydro-furo[3,4-d]isoxazoleYield 85.7%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-100 °C

Procedure

A solution of 1-bromo-2-fluorobenzene (31.1 g, 178 mmol) in a mixture of toluene (750 ml) and tetrahydrofuran (75 ml) was cooled to −100° C. Within 10 minutes a solution of n-butyllithium (1.6 M in hexane; 100 ml, 160 mmol) was added dropwise at a rate so that temperature could be maintained between −95 and −102° C. After 10 minutes stirring at −100° C. a mixture of (3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (11.3 g, 88.9 mmol) and boron trifluoride diethyl etherate (25.2 g, 178 mmol) in a mixture of toluene (75 ml) and tetrahydrofuran (14 ml) was added within 3-5 minutes keeping the temperature below −94° C. The reaction mixture was stirred additional 10 minutes at −95 to −102° C. For the workup, a saturated solution of ammonium chloride (60 ml), water (100 ml) and ethyl acetate (200 ml) were added and the reaction mixture was left to warm to 0° C. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by chromatography using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The (3S,3aS,6aS)-rel-3-(2-fluoro-phenyl)-3-methyl-hexahydro-furo[3,4-d]isoxazole (17 g, 81% yield) was obtained as an off-white solid. MS (ISP): m/z=224.1 [M+H]+.

Workup

  1. temperaturecould be maintained between −95 and −102° C
  2. additionwas added within 3-5 minutes
  3. customthe temperature below −94° C
  4. stirringThe reaction mixture was stirred additional 10 minutes at −95 to −102° C
  5. waitthe reaction mixture was left
  6. temperatureto warm to 0° C
  7. customThe layers were separated
  8. extractionthe aqueous layer was extracted once more with ethyl acetate
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over sodium sulphate
  11. customevaporated at reduced pressure
  12. customThe crude product was purified by chromatography

Sources & evidence

ORD record
ord-c7f3d4e4a846476ea07ee6fa529b5032
Source dataset
uspto-grants-2015_06
Patent number
US09067924B2

Reaction notes

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