Reaction #792227

Reaction equation

5-bromoisoquinoline 2-oxide

potassium carbonate

[4-(methylsulphanyl)phenyl]boronic acid

3-chloroperoxybenzoic acid monohydrate

5-bromoisoquinolin-1(2H)-one

5-bromoisoquinoline

→

5-[4-(Methylsulphanyl)phenyl]isoquinolin-1(2H)-one

Solvents

water

water

1,2-dimethoxyethane

ethanol

acetic anhydride

dichloromethane

Conditions

Workup

1. 1
   ExtractionThe solution was extracted with saturated sodium bicarbonate solution
2. 2
   OtherThe phases were separated
3. 3
   workup.STIRRINGthe organic phase was stirred with solid sodium sulphite
4. 4
   Filtrationthe solution was filtered off
5. 5
   DryingThe organic phase was dried over magnesium sulphate
6. 6
   Otherthe solvent was removed under reduced pressure
7. 7
   Temperatureheated at the boil for 3 h
8. 8
   TemperatureAfter cooling
9. 9
   Otherthe solvent was removed under reduced pressure
10. 10
    workup.DISSOLUTIONthe residue was dissolved in 80 ml of 10% strength aqueous sodium hydroxide solution
11. 11
    workup.STIRRINGthe mixture was stirred at a temperature of 60° C. for 1 h
12. 12
    Filtrationthe crystals were filtered off with suction
13. 13
    Washwashed with water
14. 14
    OtherThe crystals were dried in a vacuum
15. 15
    Otherdrying cabinet
16. 16
    OtherThe crystals were triturated first with ethyl acetate/ethanol
17. 17
    OtherThe crystals were then recrystallized from methanol
18. 18
    OtherThis reaction vessel was closed with
19. 19
    Othera cap
20. 20
    TemperatureAfter cooling
21. 21
    Extractionextracted with dichloromethane
22. 22
    OtherThe phases were separated
23. 23
    Dryingthe organic phase was dried over sodium sulphate
24. 24
    Otherthe solvent was removed under reduced pressure
25. 25
    OtherThe crude product was suspended in acetonitrile in an ultrasonic bath
26. 26
    Filtrationthe crystal slurry was filtered off with suction

Procedure

5.45 g (26.19 mmol) of 5-bromoisoquinoline were dissolved in 250 ml of dichloromethane, and 6.78 g (27.50 mmol) of 3-chloroperoxybenzoic acid monohydrate were added a little at a time over a period of 20 min. The suspension was stirred at room temperature for 2 h. The solution was extracted with saturated sodium bicarbonate solution. The phases were separated, the organic phase was stirred with solid sodium sulphite and the solution was filtered off. The organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. This gave 4.94 g (84% of theory) of the desired 5-bromoisoquinoline 2-oxide. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 9.02 (s, 1H), 8.26 (d, 1H), 7.99-7.90 (m, 3H), 7.58 (t, 1H). 5.87 g (26.19 mmol) of 5-bromoisoquinoline 2-oxide were then suspended in 50 ml of acetic anhydride and heated at the boil for 3 h. After cooling, the solvent was removed under reduced pressure, the residue was dissolved in 80 ml of 10% strength aqueous sodium hydroxide solution and the mixture was stirred at a temperature of 60° C. for 1 h. The cold suspension was adjusted to pH=6 using 5% strength citric acid solution and the crystals were filtered off with suction and washed with water. The crystals were dried in a vacuum drying cabinet. The crystals were triturated first with ethyl acetate/ethanol and then with acetonitrile. The crystals were then recrystallized from methanol. This gave 4.27 g (72% of theory) of the desired 5-bromoisoquinolin-1(2H)-one. 1H-NMR (400 MHz, CDCl3 δ, ppm) 11.55 (br. s, 1H), 8.20 (d, 1H), 8.02 (d, 1H), 7.39 (t, 1H), 7.33 (d, 1H), 6.57 (d, 1H). Under an atmosphere of inert nitrogen gas, 0.20 g (0.89 mmol) of 5-bromoisoquinolin-1(2H)-one, 0.18 g (1.07 mmol) of [4-(methylsulphanyl)phenyl]boronic acid, 0.04 g (0.06 mmol) of bis(triphenylphosphine)palladium dichloride and 0.370 g (2.678 mmol) of potassium carbonate were then suspended in 1.37 ml of 1,2-dimethoxyethane, 0.22 ml of ethanol and 0.27 ml of water in a microwave tube. This reaction vessel was closed with a cap and stirred in a Biotage Initiator sixty© microwave at 175° C. (pressure at most 13 bar) for 45 min. After cooling, the mixture was diluted with water and extracted with dichloromethane. The phases were separated, the organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. The crude product was suspended in acetonitrile in an ultrasonic bath, and the crystal slurry was filtered off with suction. This gave 91 mg (37% of theory) of the desired 5-[4-(methylsulphanyl)phenyl]isoquinolin-1(2H)-one. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.32 (br. s, 1H), 8.22 (d, 1H), 7.61 (d, 1H), 7.54 (t, 1H), 7.39-7.35 (m, 4H), 7.12 (t, 1H), 6.35 (d, 1H), 2.53 (s, 3H).

Source