Trimethyl phosphite → 7-Bromo-6-methoxyisoquinoline

HRID 228877Notes

Reaction equation

HRID 228877 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.CO[CH:14](OC)[CH2:15][NH2:16].ClC(OCC)=O.P(OC)(OC)OC.[OH-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:14]=[CH:15][N:16]=[CH:5]2)=[CH:8][C:9]=1[O:10][CH3:11]

Participants

8

Reactant 5

HCID 8472Trimethyl phosphiteHCID 10928Ethyl chloroformateHCID 14798Sodium HydroxideHCID 89728Aminoacetaldehyde dimethyl acetalHCID 986623-Bromo-4-methoxybenzaldehyde

Product 1

HCID 230784917-Bromo-6-methoxyisoquinolineYield 26.2%

Reagents, catalysts & solvents 2

HCID 24193Titanium TetrachlorideCatalystHCID 241BenzeneSolvent

Conditions

Temperature
-10 °C

Procedure

3-Bromo-4-methoxybenzaldehyde (10.0 g) was dissolved in benzene (100 ml) to prepare a solution. 2,2-Dimethoxy-ethylamine (4.89 g) was added to the solution, and the mixture was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, and the residue was then dissolved in tetrahydrofuran (100 ml) to prepare a solution which was then cooled to −10° C. Ethyl chloroformate (5.05 g) and trimethyl phosphite (6.92 g) were added thereto, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, the residue was then dissolved in dichloromethane (100 ml) to prepare a solution. Titanium tetrachloride (53.0 g) was added to the solution, and the mixture was heated under reflux for 36 hr. The reaction solution was cooled to room temperature, was then neutralized with a 1 N aqueous sodium hydroxide solution, and was extracted with 3 N hydrochloric acid. The aqueous layer was made basic with a 3 N aqueous sodium hydroxide solution, was then extracted with dichloromethane, and the solvent was removed by distillation under the reduced pressure to give 7-bromo-6-methoxyisoquinoline (2.90 g, yield 26%).

Workup

  1. customto prepare a solution
  2. temperaturethe mixture was heated
  3. temperatureunder reflux overnight
  4. customThe solvent was removed by distillation under the reduced pressure
  5. dissolutionthe residue was then dissolved in tetrahydrofuran (100 ml)
  6. customto prepare a solution which
  7. customThe solvent was removed by distillation under the reduced pressure
  8. dissolutionthe residue was then dissolved in dichloromethane (100 ml)
  9. customto prepare a solution
  10. temperaturethe mixture was heated
  11. temperatureunder reflux for 36 hr
  12. temperatureThe reaction solution was cooled to room temperature
  13. extractionwas extracted with 3 N hydrochloric acid
  14. extractionwas then extracted with dichloromethane
  15. customthe solvent was removed by distillation under the reduced pressure

Sources & evidence

ORD record
ord-de25ba9881644dd79fa32f2df0fad604
Source dataset
uspto-grants-2009_07
Patent number
US07560558B2

Reaction notes

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