Pyrrolidine → 6-Bromoindole

Temperature

110 °C

To a solution of 4-bromo-2-nitrotoluene (7.9 g, 36.6 mmol) in dimethylformamide (73 mL) were added N,N-dimethylformamide dimethylacetal (14.5 mL, 110 mmol) and pyrrolidine (4.7 mL), and the mixture was heated at 110° C. for 90 minutes. The cooled reaction mixture was diluted with diethyl ether, and washed with water. The aqueous layer was re-extracted with diethyl ether twice, and the combined organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was dissolved in aqueous acetic acid (245 mL, 80%), and heated to 75° C. Zinc powder (20.8 g, 318 mmol) was added to the hot solution in small portions over 2 hours. The reaction mixture was then heated at 85° C. for 3 hours and 30 minutes, cooled to room temperature and then to 0° C. The precipitate formed was removed by filtration, and the filtrate was diluted with ethyl acetate and washed with water twice. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate, then 90:10 hexanes/ethyl acetate) to give 6-bromoindole as a grey solid (2.61 g, 36%): 1H NMR (500 MHz, CDCl3) δ 8.14 (br s, 1H), 7.53 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.17-7.15 (m, 1H), 6.53-6.51 (m, 1H).

1. customThe cooled reaction mixture
2. washwashed with water
3. extractionThe aqueous layer was re-extracted with diethyl ether twice
4. extractionthe combined organic extract
5. dry with materialwas dried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. customThe residue obtained
9. temperatureheated to 75° C
10. temperatureThe reaction mixture was then heated at 85° C. for 3 hours and 30 minutes
11. temperaturecooled to room temperature
12. customto 0° C
13. customThe precipitate formed
14. customwas removed by filtration
15. additionthe filtrate was diluted with ethyl acetate
16. washwashed with water twice
17. extractionThe organic extract
18. dry with materialwas dried over sodium sulfate
19. filtrationfiltered
20. concentrationconcentrated under reduced pressure
21. customto give a brown oil
22. customThe crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate

ORD record

ord-65c53192e29c4cbca4f47ac8f4b36d1c

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08236796B2