Dichloromethane → 7-bromo-5-fluoro-1H-indole

2-Bromo-4-fluoro-aniline (13.8 g, 72.6 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 81.1 mL, 81.1 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (13.5 mL, 87.1 mmol) and aluminum chloride (13.5 g, 98.4 mmol) added, followed by 1,2-dichloroethane (95 mL). The reaction mixture was heated to 70° C. to distill off methylene chloride, and then refluxed for 24 h. After cooling to 0–5° C., the mixture was treated with 2.5 M HCl (130 mL) carefully, and then heated to 80° C. for 1 h until all solids dissolved. The aqueous layer was separated and extracted with methylene chloride. The combined organic solutions were washed with water and brine, dried (sodium sulfate) and concentrated to a yellow solid (11, 56.9%), which was used without further purification. The crude product was taken into dioxane (68 mL) and water (7.6 mL), and treated with sodium borohydride (1.64 g) in portions. After 30 min at room temperature, all the starting material was consumed, and the reaction mixture was heated to reflux for 18 h. The mixture was cooled to room temperature, treated with 0.1 N HCl (70 mL), 2N HCl (20 mL) and concentrated HCl (15 mL), and extracted with ethyl acetate. The organic layer was separated and washed with water and brine, dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 5-fluoro-7-bromoindole (4.4 g, 52.2%). 1H NMR (400 MHz, CDCl3) 6.49, (dd, J1=2.35 Hz, J2=3.13 Hz, 1H), 7.06 (d, J1=2.35 Hz, J2=8.60 Hz, 1H), 7.14˜7.17 (m, 2H), 8.18 (br, 1H); MS (ES, m/z): C8H5BrFN: 211.9 (M+(79Br)−1), 214.0 (M+(81Br)−1).

1. temperatureThe reaction mixture was heated to 70° C.
2. distillationto distill off methylene chloride
3. temperaturerefluxed for 24 h
4. temperatureAfter cooling to 0–5° C.
5. additionthe mixture was treated with 2.5 M HCl (130 mL) carefully
6. temperatureheated to 80° C. for 1 h until all solids
7. dissolutiondissolved
8. customThe aqueous layer was separated
9. extractionextracted with methylene chloride
10. washThe combined organic solutions were washed with water and brine
11. dry with materialdried (sodium sulfate)
12. concentrationconcentrated to a yellow solid (11, 56.9%), which
13. customwas used without further purification
14. additiontreated with sodium borohydride (1.64 g) in portions
15. waitAfter 30 min at room temperature
16. customall the starting material was consumed
17. temperaturethe reaction mixture was heated
18. temperatureto reflux for 18 h
19. temperatureThe mixture was cooled to room temperature
20. additiontreated with 0.1 N HCl (70 mL), 2N HCl (20 mL) and concentrated HCl (15 mL)
21. extractionextracted with ethyl acetate
22. customThe organic layer was separated
23. washwashed with water and brine
24. dry with materialdried (sodium sulfate)
25. concentrationconcentrated

ORD record

ord-6c89cdc29b0940c7a12c5b773aeddc3a

Source dataset

uspto-grants-2006_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07109229B2