Cesium carbonate → 8-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one

HRID 1045926Notes

Reaction equation

HRID 1045926 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[C:12](I)[C:11]([Cl:15])=[CH:10][N:9]=1.[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[C:25](=[O:27])[N:24]([CH3:28])[CH2:23][CH2:22]2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[C:12]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[C:25](=[O:27])[N:24]([CH3:28])[CH2:23][CH2:22]3)[C:11]([Cl:15])=[CH:10][N:9]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 162026268-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-oneHCID 534009652,5-Dichloro-4-iodopyridine

Product 1

HCID 866551378-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-oneYield 72%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Palladium(II) acetate (0.093 g, 0.41 mmol) was added to 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.360 g, 0.62 mmol), cesium carbonate (6.76 g, 20.74 mmol), 2,5-dichloro-4-iodopyridine (2.84 g, 10.37 mmol) and 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (1.827 g, 10.37 mmol) in dioxane (100 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 18 hours then allowed to cool to room temperature. The mixture was filtered and then evaporated. The residue was dissolved in EtOAc (100 mL), and washed sequentially with a saturated solution of NaHCO3 (50 mL), water (50 mL), and finally with a saturated solution of NaCl (50 mL). The organic layer was separated, dried over MgSO4, and then evaporated. The residue was triturated with Et2O to leave a solid. The solid was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (2.398 g, 72% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.97 (2H, t), 3.05 (3H, s), 3.57 (2H, t), 7.00 (1H, m), 7.34 (1H, s), 7.44-7.51 (2H, m), 8.31 (1H, s), 11.63 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=322.29 and 324.28 and 326.29.

Workup

  1. temperatureto cool to room temperature
  2. filtrationThe mixture was filtered
  3. customevaporated
  4. dissolutionThe residue was dissolved in EtOAc (100 mL)
  5. washwashed sequentially with a saturated solution of NaHCO3 (50 mL), water (50 mL)
  6. customThe organic layer was separated
  7. dry with materialdried over MgSO4
  8. customevaporated
  9. customThe residue was triturated with Et2O
  10. customto leave a solid
  11. customThe solid was purified by chromatography on silica
  12. washeluting with a gradient of 0-5% MeOH in CH2Cl2
  13. additionFractions containing product
  14. customevaporated

Sources & evidence

ORD record
ord-dc12d310f918479fb5af65eedb0e3455
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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