Cesium carbonate → 2-Bromo-4-fluoro-6-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)benzaldehyde

HRID 519392Notes

Reaction equation

HRID 519392 reaction equation
[C:1]1(=[O:14])[C:6]2[CH:7]=[C:8]3[N:13]([C:5]=2[CH:4]=[N:3][NH:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3.[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[C:17]=1[CH:18]=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([N:2]2[C:1](=[O:14])[C:6]3[CH:7]=[C:8]4[N:13]([C:5]=3[CH:4]=[N:3]2)[CH2:12][CH2:11][CH2:10][CH2:9]4)[C:17]=1[CH:18]=[O:19]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 104622984,7-Dimethoxy-1,10-phenanthrolineHCID 444746662,6-Dibromo-4-fluorobenzaldehydeHCID 676394086,7,8,9-Tetrahydropyridazino[4,5-b]indolizin-1(2H)-one

Product 1

HCID 866837702-Bromo-4-fluoro-6-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)benzaldehydeYield 31%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 127e (450 mg, 2.4 mmol), 2,6-dibromo-4-fluorobenzaldehyde (2.0 g, 7.2 mmol), cesium carbonate (1.6 g, 4.8 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting mixture for 10 minutes, copper(I) iodide (450 mg, 2.4 mmol) and 4,7-dimethoxy-1,10-phenanthroline (571 mg, 2.4 mmol) were added, and the reaction mixture was heated at 90° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between methylene chloride (40 mL) and water (40 mL). The aqueous layer was separated and extracted with methylene chloride (3×30 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:2 ethyl acetate/petroleum ether to afford 127f as a brown solid (251 mg, 31%). MS-ESI: (M+H)+ 390.0.

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter bubbling nitrogen through the resulting mixture for 10 minutes
  3. temperatureAfter this time the reaction was cooled to room temperature
  4. filtrationfiltered
  5. customThe filtrate was partitioned between methylene chloride (40 mL) and water (40 mL)
  6. customThe aqueous layer was separated
  7. extractionextracted with methylene chloride (3×30 mL)
  8. washThe combined organic layer was washed with brine (50 mL)
  9. dry with materialdried over sodium sulfate
  10. customThe drying agent was removed by filtration
  11. concentrationthe filtrate was concentrated under reduced pressure
  12. customThe residue was purified by silica-gel column chromatography
  13. washeluting with 1:2 ethyl acetate/petroleum ether

Sources & evidence

ORD record
ord-d33eb396637e46dca4a6b2e3a82cabd5
Source dataset
uspto-grants-2015_08
Patent number
US09115152B2

Reaction notes

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