Benzophenone imine → (R)-3-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-3-methyl-[1,4]oxazepan-5-one

HRID 1186185Notes

Reaction equation

HRID 1186185 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]2([CH3:16])[NH:14][C:13](=[O:15])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:54](=[NH:67])([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[C:54](=[N:67][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]2([CH3:16])[NH:14][C:13](=[O:15])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1)([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1

Participants

7

Reactant 4

HCID 136809Benzophenone imineHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 23676156Sodium t-butoxideHCID 58562938(R)-3-(5-bromo-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one

Product 1

HCID 58563044(R)-3-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-3-methyl-[1,4]oxazepan-5-one

Reagents, catalysts & solvents 2

HCID 11029508Palladium, tris[mu-[(1,2-eta:4,5-eta)-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one]]di-, compd. with trichloromethane (1:1)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

Under an argon atmosphere a mixture of the crude (R)-3-(5-bromo-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one (626 mg, 1.2 mmol), sodium tert-butoxide (356 mg, 3.59 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (52.4 mg, 0.12 mmol), tris(dibenzylideneacetone)-dipalladium(0) chloroform adduct (38.3 mg, 0.036 mmol), and benzophenonimine (447 mg, 2.4 mmol) in toluene (15 ml) was heated at 105° C. for 16 hours in a sealed vial. For the workup, the reaction mixture was cooled to room temperature, evaporated at reduced pressure, and purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 10/20 as the eluent. (R)-3-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-3-methyl-[1,4]oxazepan-5-one (intermediate C12A) was obtained as a light yellow foam (348 mg, 69% of theory). MS (ISP): m/z=403.3 [M+H]+.

Workup

  1. temperatureFor the workup, the reaction mixture was cooled to room temperature
  2. customevaporated at reduced pressure
  3. custompurified by chromatography on Silicycle-Si-amine column

Sources & evidence

ORD record
ord-324040da4b7345159e3e64a0893d390a
Source dataset
uspto-grants-2014_03
Patent number
US08673894B2

Reaction notes

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