Tributylamine → rac. 4-[1-(6-methoxy-pyridin-3-yl)-methylidene]-3-methyl-3,4-dihydro-2H-isoquinolin-1-one

HRID 49234Notes

Reaction equation

HRID 49234 reaction equation
[CH3:1][CH:2]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I)[CH:3]=[CH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CCCC)CCCC)CCC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:12][O:11][C:8]1[N:7]=[CH:6][C:5]([CH:4]=[C:3]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:22])[NH:13][CH:2]2[CH3:1])=[CH:10][CH:9]=1

Participants

6

Reactant 2

HCID 7622TributylamineHCID 69208831HCID 69208831, compound

Product 1

HCID 69206500rac. 4-[1-(6-methoxy-pyridin-3-yl)-methylidene]-3-methyl-3,4-dihydro-2H-isoquinolin-1-one

Reagents, catalysts & solvents 3

HCID 70681Tetrabutylammonium ChlorideCatalystHCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
150 °C

Procedure

Under a N2 atmosphere, 8 g (19 mmol) of an (E/Z) mixture of rac. 2-iodo-benzoic acid-[1-methyl-3-(6-methoxy-pyridin-3-yl)-allylamide], 5.9 g (19 mmol) of tetrabutylammonium chloride and 0.12 g of palladium diacetate are dissolved in 170 ml of DMF, then 8.9 g (48 mmol) of tributylamine are added and stirred for 20 h at 150° C. The mixture is filtered and the DMF is partially evaporated on a RE. The residue is dissolved with EtOAc and water, the water phase separated, extracted twice with EtOAc and discarded. The organic phases are washed with water, extracted with 200 ml of 1N HCl and 2 portions of 200 ml 0.5 N HCl, washed with saturated Na2CO3 solution and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, hexane/EtOAc 1:1→1:2) and recrystallisation from acetonitrile yield rac. 4-[1-(6-methoxy-pyridin-3-yl)-methylidene]-3-methyl-3,4-dihydro-2H-isoquinolin-1-one (m.p. 194-195° C.; FAB-MS: (M+H)+=281; TLC(hexane/EtOAc 1:1): Rf=0.26). The acidic aqueous extracts are collected in a solution of 60 g of K2CO3 in 0.5 l of water. Upon standing, 4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methyl-2H-isoquinolin-1-one crystallises, and can be filtered off by suction, washed with water and recrystallised from boiling EtOAc/methanol (m.p. 234-236° C.; FAB-MS: (M+H)+=281; TLC(hexane/EtOAc 1:1): Rf=0.18).

Workup

  1. filtrationThe mixture is filtered
  2. customthe DMF is partially evaporated on a RE
  3. dissolutionThe residue is dissolved with EtOAc and water
  4. customthe water phase separated
  5. extractionextracted twice with EtOAc
  6. washThe organic phases are washed with water
  7. extractionextracted with 200 ml of 1N HCl and 2 portions of 200 ml 0.5 N HCl
  8. washwashed with saturated Na2CO3 solution and brine
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated by evaporation
  11. customColumn chromatography (SiO2, hexane/EtOAc 1:1→1:2) and recrystallisation from acetonitrile

Sources & evidence

ORD record
ord-46607720657741838a05f1c19a0b2ef9
Source dataset
uspto-grants-2004_03
Patent number
US06706731B2

Reaction notes

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