Reaction #792225

Reaction equation

potassium 5-bromophthalimidate

1-chloroacetone

sodium

sodium

hydrochloric acid

→

3-acetyl-7-bromo-4-hydroxyisoquinolin-1(2H)-one

3-acetyl-6-bromo-4-hydroxyisoquinolin-1(2H)-one

Solvents

N,N-dimethylformamide

methanol

water

methanol

Conditions

Workup

1. 1
   FiltrationThe resulting colourless solid was filtered off
2. 2
   Concentrationconcentrated under reduced pressure
3. 3
   OtherThis gave 5-bromo-2-(2-oxopropyl)isoindolyl-1,3-dione (770 mg, 70% of theory) which was used without further purification for the next reaction step
4. 4
   OtherIn a three-neck round-bottom flask which had been dried
5. 5
   Temperatureby heating
6. 6
   Otherfitted
7. 7
   Temperaturereflux condenser
8. 8
   Temperaturethe reaction solution was heated
9. 9
   Temperatureto reflux conditions
10. 10
    OtherThe resulting reaction solution
11. 11
    Temperatureunder reflux for 2 h
12. 12
    workup.STIRRINGAfter a further 30 min of stirring at room temperature
13. 13
    Filtrationthe precipitated solid was filtered off
14. 14
    Washwashed with water
15. 15
    Otherdried under reduced pressure
16. 16
    OtherSubsequent purification of the light-yellow crude material by column chromatography (236 mg, 47% of theory)

Procedure

A mixture of 5-bromoisobenzofuran-1,3-dione (16.21 g, 17.4 mmol) and formamide (42.5 ml, 48.2 g) was stirred at 120° C. for 3 h and, after cooling to room temperature, added to ice water. The resulting colourless solid was filtered off and concentrated under reduced pressure. This gave 5-bromophthalimide in the form of a colourless solid (12.26 g, 76% of theory). 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.45 (br. s, 1H), 8.01 (dd, 1H), 7.99 (d, 1H), 7.75 (d, 1H). 5-Bromophthalimide (1.76 g, 7.8 mmol) was dissolved in abs. ethanol (75 ml), the mixture was heated to 60° C. and an aqueous solution of potassium hydroxide (4 ml, 10.5 mmol) was added dropwise. After 30 min of stirring at 60° C., the reaction mixture was cooled quickly with the aid of an ice bath, and the resulting precipitated colourless solid was filtered off with suction, washed with cold ethanol and dried under reduced pressure. In this manner, potassium 5-bromophthalimidate (1.04 g, 50% of theory) were obtained in the form of a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 7.59 (dd, 1H), 7.45 (d, 1H), 7.29 (d, 1H). A reaction mixture of potassium 5-bromophthalimidate (1030 mg, 3.9 mmol), 1-chloroacetone (361 mg, 3.9 mmol) in abs. N,N-dimethylformamide (10 ml) was stirred at room temperature and an atmosphere of nitrogen for 2 h, and water was then added. The resulting colourless solid was filtered off and concentrated under reduced pressure. This gave 5-bromo-2-(2-oxopropyl)isoindolyl-1,3-dione (770 mg, 70% of theory) which was used without further purification for the next reaction step. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 8.12 (d, 1H), 8.08 (dd, 1H), 7.85 (d, 1H), 4.58 (s, 2H), 2.24 (s, 3H). In a three-neck round-bottom flask which had been dried by heating and fitted with dropping funnel and reflux condenser, sodium (45 mg, 2.0 mmol) was dissolved in abs. methanol (5 ml) under an atmosphere of nitrogen. After the sodium had been dissolved completely, the reaction solution was heated to reflux conditions, and a solution of 5-bromo-2-(2-oxopropyl)isoindolyl-1,3-dione (500 mg, 1.8 mmol) in abs. methanol was then added dropwise. The resulting reaction solution was stirred under reflux for 2 h and then, after cooling to room temperature, adjusted to pH 3 by addition of 1M hydrochloric acid. After a further 30 min of stirring at room temperature, the precipitated solid was filtered off, washed with water and dried under reduced pressure. Subsequent purification of the light-yellow crude material by column chromatography (236 mg, 47% of theory) gave 3-acetyl-7-bromo-4-hydroxyisoquinolin-1(2H)-one and 3-acetyl-6-bromo-4-hydroxyisoquinolin-1(2H)-one as colourless solids. 1H-NMR (3-acetyl-7-bromo-4-hydroxyisoquinolin-1(2H)-one) (400 MHz, d6-DMSO δ, ppm) 12.56 (br. s, 1H), 10.68 (br. s, 1H), 8.36 (d, 1H), 8.10 (d, 1H), 8.07 (dd, 1H), 2.63 (s, 3H); 1H-NMR (3-acetyl-6-bromo-4-hydroxyisoquinolin-1(2H)-one) (400 MHz, d6-DMSO δ, ppm) 12.56 (br. s, 1H), 10.48 (br. s, 1H), 8.28 (d, 1H), 8.18 (d, 1H), 7.95 (dd, 1H), 2.62 (s, 3H).

Source