Ethyl Acetoacetate → 4-Chloro-7-iodo-2,6-dimethylquinoline

HRID 2121646Notes

Reaction equation

HRID 2121646 reaction equation
[I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10](OCC)(=O)[CH2:11][C:12]([CH3:14])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:31][C:32]1[C:41]([CH3:42])=[CH:40][CH:39]=[C:38]2[C:33]=1[C:34](=O)[CH:35]=[C:36]([CH3:43])[NH:37]2.[Cl-:45].[P+]=O.[OH-].[NH4+]>C1CCCCC1.CN(C)C=O.O>[Cl:45][C:10]1[C:6]2[C:4](=[CH:3][C:2]([I:1])=[C:8]([CH3:9])[CH:7]=2)[N:5]=[C:12]([CH3:14])[CH:11]=1.[Cl:45][C:34]1[C:33]2[C:38](=[CH:39][CH:40]=[C:41]([CH3:42])[C:32]=2[I:31])[N:37]=[C:36]([CH3:43])[CH:35]=1

Participants

11

Reactant 6

HCID 8868Ethyl AcetoacetateHCID 14923Ammonium HydroxideHCID 1188893-Iodo-p-toluidineHCID 521998p-Toluenesulfonic acid monohydrateHCID 22054564HCID 22054564, compoundHCID 178527006HCID 178527006, compound

Product 2

HCID 220545734-Chloro-7-iodo-2,6-dimethylquinolineHCID 22054605HCID 22054605, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8078CyclohexaneSolvent

Conditions

Temperature
50 °C

Procedure

A suspension of 3-iodo-4-methylaniline (50.0 g, 215 mmol), ethyl acetoacetate (30.7 g, 236 mmol), and toluene-4-sulfonic acid monohydrate (430 mg, 2.15 mmol) was refluxed for 2 h in cyclohexane (100 mL), allowing the water formed to collect in a Dean-Stark trap, then after cooling insoluble material was removed by filtration and the filtrate evaporated. The residue was dissolved in Dowtherm® A (25 mL) and added dropwise to hot (ca. 250° C.) Dowtherm® A. After 15 min the reaction mixture was allowed to reach room temperature, then heptane (150 mL) was added and the precipitate collected by filtration. This material was triturated in ethyl acetate to afford a 1:1 mixture of 7-iodo-2,6-methyl-1H-quinolin-4-one and 5-iodo-2,6-dimethyl-1H-quinolin-4-one (46.4 g), which was treated with phosphorus oxide chloride (130 mL) and N,N-dimethylformamide (0.6 mL). The solution obtained was stirred at 50° C. for 20 min, then carefully poured upon ice and brought to pH 7 with 25% aq. ammonium hydroxide solution. After extraction with ethyl acetate, the organic layer was washed with brine, dried (MgSO4), and evaporated. Recrystallization of the product mixture thus produced (4-chloro-7-iodo-2,6-dimethyl-quinoline and 4-chloro-5-iodo-2,6-dimethyl-quinoline) in hexane/ethyl acetate 9:1 (150 mL) afforded the title compound (7.55 g, 11%). Light brown solid, ISP-MS: m/e=318.1 ([M+H]+).

Workup

  1. customformed
  2. customto collect in a Dean-Stark trap
  3. temperatureafter cooling insoluble material
  4. customwas removed by filtration
  5. customthe filtrate evaporated
  6. dissolutionThe residue was dissolved in Dowtherm® A (25 mL)
  7. additionadded dropwise to hot (ca. 250° C.) Dowtherm® A
  8. customto reach room temperature
  9. additionheptane (150 mL) was added
  10. filtrationthe precipitate collected by filtration
  11. customThis material was triturated in ethyl acetate
  12. customto afford
  13. customThe solution obtained
  14. additioncarefully poured upon ice
  15. extractionAfter extraction with ethyl acetate
  16. washthe organic layer was washed with brine
  17. dry with materialdried (MgSO4)
  18. customevaporated
  19. customRecrystallization of the product mixture

Sources & evidence

ORD record
ord-9f8b65491b224b47a05f9e055b0b8397
Source dataset
uspto-grants-2004_02
Patent number
US06696467B2

Reaction notes

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