Allyl iodide → (4r,7s)-1-Allyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

HRID 1438001Notes

Reaction equation

HRID 1438001 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](I)[CH:24]=[CH2:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:25]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:24]=[CH2:23]

Participants

5

Reactant 2

HCID 11166Allyl iodideHCID 57941350(4r,7s)-2-(2,4-Difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one2×

Product 1

HCID 57941430(4r,7s)-1-Allyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-oneYield 30%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 989 mg, 3.25 mmol), tetrabutylammonium iodide (600 mg, 1.63 mmol) and allyl iodide (1.05 mL, 9.75 mmol) in dimethylformamide (5.7 mL) was heated in an oil-bath at 100° C. overnight. The solvent was evaporated and dichloromethane (400 mL) was added. The solution was washed with aqueous sodium thiosulfate (2×100 mL) and the combined aqueous washes were back-extracted with dichloromethane (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), filtered, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated successively with methanol, ether, and petroleum ether. The residue was triturated with hexane and the solid was dried under high vacuum at 70° C. overnight and then at 85° C. for 1 h to give (4R,7S)-1-allyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (334 mg, 30%) as an off-white solid. APCI(+)-MS (M+H) 345.

Workup

  1. customThe solvent was evaporated
  2. additiondichloromethane (400 mL) was added
  3. washThe solution was washed with aqueous sodium thiosulfate (2×100 mL)
  4. extractionthe combined aqueous washes were back-extracted with dichloromethane (2×100 mL)
  5. washThe combined organic layers were washed with water (100 mL) and brine (100 mL)
  6. dry with materialdried (magnesium sulfate)
  7. filtrationfiltered
  8. custompurified
  9. washeluting with 20-50% ethyl acetate/hexanes
  10. customFractions homogeneous for the product were evaporated
  11. customThe residue was triturated with hexane
  12. customthe solid was dried under high vacuum at 70° C. overnight

Sources & evidence

ORD record
ord-025383bebc934e54a01626a0c020d9d3
Source dataset
uspto-grants-2009_11
Patent number
US07622492B2

Reaction notes

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