Cesium carbonate → 2-((2S)-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-yl)isoindoline-1,3-dione

HRID 870903Notes

Reaction equation

HRID 870903 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1.[OH:17][CH2:18][C@@H:19]([N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34])[CH2:20][CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][CH:21]([CH3:23])[CH2:20][C@H:19]([N:24]1[C:25](=[O:34])[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]1=[O:33])[CH2:18][O:17][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 713789222-[(2S)-1-Hydroxy-4-methylpentan-2-yl]-1H-isoindole-1,3(2H)-dioneHCID 866958978-bromo-5-methyl-5H-chromeno[3,4-c]pyridine

Product 1

HCID 866958962-((2S)-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-yl)isoindoline-1,3-dioneYield 64%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 8-bromo-5-methyl-5H-chromeno[3,4-c]pyridine (200 mg, 0.724 mmol) in toluene (4 mL), were added (S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (537 mg, 2.173 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (185 mg, 0.435 mmol), cesium carbonate (354 mg, 1.086 mmol) and palladium (II) acetate (48.8 mg, 0.217 mmol). Nitrogen was bubbled through the reaction mixture for 10 min and the mixture was heated at 80° C. 12 h. The reaction mixture was cooled to room temperature and filtered through celite and residue rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified via prep TLC (60% ethyl acetate in pet ether) to afford 2-((2S)-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-yl)isoindoline-1,3-dione (205 mg, 0.463 mmol, 64% yield). LCMS (ESI) m/e 443.2 [(M+H)+, calcd for C27H27N2O4 443.2]; LC/MS retention time (Method C): tR=2.27 min.

Workup

  1. customNitrogen was bubbled through the reaction mixture for 10 min
  2. custom12 h
  3. temperatureThe reaction mixture was cooled to room temperature
  4. filtrationfiltered through celite and residue
  5. washrinsed with ethyl acetate
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. custompurified via prep TLC (60% ethyl acetate in pet ether)

Sources & evidence

ORD record
ord-350e0e34f4e54b4dba955127c82e9d75
Source dataset
uspto-grants-2015_03
Patent number
US08969564B2

Reaction notes

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