Cesium carbonate → 6-Aminoquinoline

HRID 1636527Notes

Reaction equation

HRID 1636527 reaction equation
O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].BrC(C)(C)C([NH2:24])=O>O1CCOCC1.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[NH2:24][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 113746-HydroxyquinolineHCID 24758Sodium hydride2×HCID 1012352-Bromo-2-methylpropanamide

Product 1

HCID 113736-AminoquinolineYield 39.2%

Reagents, catalysts & solvents 3

HCID 13387N-methyl-2-pyrrolidoneSolventHCID 312751,4-DioxaneSolventHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent

Procedure

To a solution of 6-hydroxyquinoline (537 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was distilled by Kugelrohr to remove residual NMP and DMPU, then chromatographed on silica (200 mL, 4 cm diam. column), eluting with 70:30:1 EtOAc/hexane/NEt3 to obtain 6-aminoquinoline as a brown solid (210 mg, 1.45 mmol, 39.2% yield).: mp 111-113° C. (lit. 116° C., Sykes, W. O., Journal of the Chemical Society, 1956, 3087); 1H NMR (300 MHz, CDCl3) δ8.66 (dd, 1 H, J=4.27, 1.63 Hz), 7.93-7.87 (m, 2 H), 7.26 (dd, 1 H, J=8.24, 4.23 Hz), 7.16 (dd, 1 H, J=9.05, 2.69), 6.90 (d, 1 H, J=2.74), 3.97 (br s, 2 H, NH2); 13C NMR (75 MHz, CDCl3) δ146.8, 144.5, 143.5, 133.7, 130.6, 129.7, 121.5, 121.4, 107.4; MS (CI/NH3) 145.

Workup

  1. stirringthe resulting mixture was stirred
  2. temperatureat reflux for 16 h
  3. stirringThe resulting mixture was stirred at 150° C. for 72 h
  4. temperatureThe reaction was cooled to room temp.
  5. custompartitioned between water (50 mL) and EtOAc (100 mL)
  6. extractionThe aqueous layer was extracted with EtOAc (100 mL)
  7. washthe combined organics washed with water (2×50 mL)
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated to about 3 g of material
  10. distillationThe brown oil was distilled by Kugelrohr
  11. customto remove residual NMP and DMPU
  12. customchromatographed on silica (200 mL, 4 cm diam. column)
  13. washeluting with 70:30:1 EtOAc/hexane/NEt3

Sources & evidence

ORD record
ord-dd8b278603bc4ca88c3457fbdb61f468
Source dataset
uspto-grants-2000_03
Patent number
US06034241

Reaction notes

Loading…