Lithium Chloride → Pyriofenone

HRID 242438Notes

Reaction equation

HRID 242438 reaction equation
C([Mg]Cl)(C)C.Br[C:7]1[C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[CH3:13].ClC1C(C)=C([Mg]Cl)C(OC)=NC=1.[Cu]C#N.[Cl-].[Li+].ClC1C(C)=C([Cu])C(OC)=NC=1.[CH3:45][O:46][C:47]1[C:55]([O:56][CH3:57])=[C:54]([O:58][CH3:59])[CH:53]=[C:52]([CH3:60])[C:48]=1[C:49](O)=[O:50].N1C=CC=CC=1[Cu].O.N>O1CCCC1.S(Cl)(Cl)=O.O>[CH3:45][O:46][C:47]1[C:55]([O:56][CH3:57])=[C:54]([O:58][CH3:59])[CH:53]=[C:52]([CH3:60])[C:48]=1[C:49]([C:7]1[C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[CH3:13])=[O:50]

Participants

13

Reactant 9

HCID 433294Lithium ChlorideHCID 12896473Azane;hydrateHCID 135314152,3,4-Trimethoxy-6-methylbenzoic acidHCID 231336453-Bromo-5-chloro-2-methoxy-4-methylpyridineHCID 178418546HCID 178418546, compoundHCID 178418918HCID 178418918, compoundHCID 178494192HCID 178494192, compoundHCID 178494194HCID 178494194, compoundHCID 178505376CID 178270706

Product 1

HCID 23082663PyriofenoneYield 107.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 24386Thionyl ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

(b-1) 6.8 ml (13.6 mmol) of isopropylmagnesium chloride (2M tetrahydrofuran solution) was cooled to 0° C., and a solution having 1.6 g (6.6 mmol) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine dissolved in 5 ml of tetrahydrofuran was dropwise added, followed by stirring at the same temperature for 3 hours to prepare 5-chloro-2-methoxy-4-methyl-3-pyridylmagnesium chloride. The reaction solution was cooled to −78° C., and a solution having 1.2 g (13.3 mmol) of copper(I) cyanide and 1.15 g (27.1 mmol) of lithium chloride dissolved in 15 ml of tetrahydrofuran was dropwise added to prepare a 5-chloro-2-methoxy-4-methyl-3-pyridylcopper reagent. Separately, 3.2 g (14.3 mmol) of 2,3,4-trimethoxy-6-methylbenzoic acid prepared in Step (a) was subjected to reflux with heating in 7 ml of thionyl chloride for 3 hours, and the surplus thionyl chloride was distilled off under reduced pressure to prepare 2,3,4-trimethoxy-6-methylbenzoyl chloride, which was dissolved in 7 ml of tetrahydrofuran. The solution thus prepared was dropwise added at −78° C. to the above prepared pyridylcopper reagent, followed by stirring for 1 hour, and the temperature was increased to room temperature, followed by stirring further for 2 hours. Water and ammonia water were added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.6 g (yield: 57%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-chloro-2-methoxy-4-methylpyridine (melting point 85 to 88° C.), and the compound was identified by 1HNMR.

Workup

  1. additionwas dropwise added
  2. additionwas dropwise added
  3. temperatureto reflux
  4. distillationthe surplus thionyl chloride was distilled off under reduced pressure
  5. customto prepare 2,3,4-trimethoxy-6-methylbenzoyl chloride, which
  6. customThe solution thus prepared
  7. additionwas dropwise added at −78° C. to the
  8. stirringby stirring for 1 hour
  9. temperaturethe temperature was increased to room temperature
  10. stirringby stirring further for 2 hours
  11. customto terminate
  12. customthe reaction
  13. extractionfollowed by extraction with ethyl acetate
  14. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  15. filtrationsubjected to filtration
  16. distillationthe solvent was distilled off under reduced pressure
  17. customThe crude product was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-21e4f3d3171747dd9ee2f5ed30f57b1b
Source dataset
uspto-grants-2014_02
Patent number
US08653113B2

Reaction notes

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