Potassium Carbonate → 4-Chloro-2-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)nicotinaldehyde

HRID 1021884Notes

Reaction equation

HRID 1021884 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[C:16]1[N:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Cl:24][C:20]1[C:17]([CH:18]=[O:19])=[C:16]([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)[N:23]=[CH:22][CH:21]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 104622984,7-Dimethoxy-1,10-phenanthrolineHCID 676394086,7,8,9-Tetrahydropyridazino[4,5-b]indolizin-1(2H)-oneHCID 866839142-Bromo-4-chloropyridine-3-carbaldehyde

Product 1

HCID 866843544-Chloro-2-(1-oxo-6,7,8,9-tetrahydropyridazino[4,5-b]indolizin-2(1H)-yl)nicotinaldehydeYield 43.3%

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 reflux condenser was charged with 1,4-dioxane (40 mL), 193e (800 mg, 3.6 mmol), 2-bromo-4-chloronicotinaldehyde (2.8 g, 12.6 mmol), and potassium carbonate (1.2 g, 8.4 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, copper(I) iodide (800 mg, 4.2 mmol) and 4,7-dimethoxy-1,10-phenanthroline (1.0 g, 4.2 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 (60 mL) and water (40 mL). The aqueous layer was separated and extracted with methylene chloride (3×40 mL). The combined organic layer was washed with brine (30 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 1:1 ethyl acetate/petroleum ether to afford 193f as a brown solid (513 mg, yield 37%). MS-ESI: [M+H]+ 329.1.

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a reflux condenser
  2. customAfter bubbling nitrogen through the resulting mixture for 30 minutes
  3. temperatureAfter this time the reaction was cooled to room temperature
  4. filtrationfiltered
  5. customThe filtrate was partitioned between methylene chloride (60 mL) and water (40 mL)
  6. customThe aqueous layer was separated
  7. extractionextracted with methylene chloride (3×40 mL)
  8. washThe combined organic layer was washed with brine (30 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 1:1 ethyl acetate/petroleum ether

Sources & evidence

ORD record
ord-a49d8aa7f3264fc7ad579ccb99e20981
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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