Water → 1-(3,5-Bis-trifluoromethyl-benzyloxymethyl)-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

HRID 1295360Notes

Reaction equation

HRID 1295360 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][OH:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:33][C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][O:15][CH2:33][C:34]3[CH:35]=[C:36]([C:44]([F:46])([F:47])[F:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=3)([CH2:11]2)[CH:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 962WaterHCID 3251421Potassium bis(trimethylsilyl)amideHCID 69336648(1S,2S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl esterHCID 860846061-Iodomethyl-3,5-bis-trifluoromethyl-benzene

Product 1

HCID 866020451-(3,5-Bis-trifluoromethyl-benzyloxymethyl)-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl esterYield 73%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To Intermediate 19, one enantiomer being (1S,2S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.40 g, 1.4 mmol) in THF (10 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5M/toluene, 4.1 mL, 2.1 mmol) dropwise and the mixture was stirred for an additional 5 minutes. 1-Iodomethyl-3,5-bis-trifluoromethyl-benzene (0.69 g, 1.9 mmol) in THF (4 mL) was added and the reaction stirred at −78° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. Water was added cautiously and the solvent removed at reduced pressure. The residue was partitioned between H2O and EtOAc, the organics were washed with brine and dried over calcium sulfate, filtered and concentrated to an oil. The crude product was purified by flash chromatography by elution with a gradient of hexanes to 20% EtOAc/Hexanes to give the title compound (0.52 g, 73% yield).

Workup

  1. customat −78° C.
  2. stirringthe reaction stirred at −78° C. for 10 minutes
  3. stirringstirred for 2 hours
  4. customthe solvent removed at reduced pressure
  5. customThe residue was partitioned between H2O and EtOAc
  6. washthe organics were washed with brine
  7. dry with materialdried over calcium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated to an oil
  10. customThe crude product was purified by flash chromatography by elution with a gradient of hexanes to 20% EtOAc/Hexanes

Sources & evidence

ORD record
ord-2184f3a36e494913a9de0bd2fd226ae1
Source dataset
uspto-grants-2007_07
Patent number
US07241798B2

Reaction notes

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