Phthalimide → 2-{[trans-2-(4-Fluorophenyl)cyclopropyl]methyl}isoindoline-1,3-dione

HRID 1506157Notes

Reaction equation

HRID 1506157 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11](OCC)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45](=[O:52])[NH:44]1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:44]2[C:45](=[O:52])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:43]2=[O:53])=[CH:6][CH:7]=1

Participants

8

Reactant 6

HCID 6809PhthalimideHCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 21226445Aluminium lithium hydrideHCID 66880968DIAD tolueneHCID 71263929trans-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester

Product 1

HCID 712582282-{[trans-2-(4-Fluorophenyl)cyclopropyl]methyl}isoindoline-1,3-dioneYield 87%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

trans-Ethyl 2-(4-Fluorophenyl)cyclopropane-1-carboxylate (793 mg, 4.57 mmol) in tetrahydrofuran (7 mL) was stirred with lithium aluminium hydride (173 mg, 4.57 mmol) under cooling with ice for 10 minutes. After addition of 1 M aqueous sodium hydroxide, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (10 mL), mixed with triphenylphosphine (999 mg, 3.81 mmol), isoindoline-1,3-dione (560 mg, 3.81 mmol) and azodicarboxylic acid diisopropyl ester-toluene solution (1.9 M, 2.00 mL, 3.81 mmol) under cooling with ice, and the reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a colorless solid (975 mg, yield 87% (2 steps)).

Workup

  1. temperatureunder cooling with ice for 10 minutes
  2. extractionthe reaction mixture was extracted with ethyl acetate
  3. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. dissolutionThe resulting residue was dissolved in tetrahydrofuran (10 mL)
  6. temperatureunder cooling with ice
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v))

Sources & evidence

ORD record
ord-eb05aa0e010b47099354f0f222e96e66
Source dataset
uspto-grants-2015_12
Patent number
US09216999B2

Reaction notes

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