5-(Bromomethyl)benzo[b]thiophene

Synthesis

1. 5-methylbenzo[b]thiophene (0.37 g, 2.58 mmol) was dissolved in carbon tetrachloride (4 mL). 2. N-bromosuccinimide (0.46 g, 2.58 mmol) and 2,2'-azobisisobutyronitrile (10 mg) were added to the solution. 3. The reaction mixture was stirred and heated under reflux conditions for 3 hours. 4. After completion of the reaction, the mixture was cooled to room temperature and allowed to stand overnight. 5. The reaction mixture was filtered and the filtrate was concentrated to dryness under vacuum at 40 °C. 6. 6. The residual brown oil was treated with isohexane, heated until dissolved and cooled. 7. after cooling scrape the inside of the vessel to induce crystallization and after formation of crystalline solids, warm to room temperature. 8. The solids are separated by filtration and washed with isohexane. 9. the filtrate is concentrated to half the original volume, cooled again and scraped to induce crystallization. 10. 10. The re-formed solid is separated by filtration and air-dried to give a white solid product, which is used as a "seed" crystal. 11. 11. Scale up the reaction: 5-methylbenzo[b]thiophene (51.3 g, 0.35 mol) was dissolved in carbon tetrachloride (540 mL), N-bromosuccinimide (63.8 g, 0.36 mol, 1.04 eq.) and 2,2'-azobis(isobutyronitrile) (0.4 g) were added. 12. 12. The crude product is crystallized from isohexane using "seed" crystals (without heating). 13. 13. The immediately formed crystals are separated by filtration and dried. 14. 14. The product was dried under vacuum at room temperature to give the target product (69.62 g). 15. 15. The product was recrystallized from hot isohexane and cooled. 16. The solid was separated by filtration and dried under vacuum at room temperature to give 5-(bromomethyl)benzo[b]thiophene (59.6 g, 76% yield). 17. The structure of the product was investigated by 1H NHPA. 17. The structure of the product was confirmed by 1H NMR (300 MHz, CDCl3): δ= 7.88-7.81 (2H, m), 7.50-7.45 (1H, m), 7.41-7.35 (1H, m), 7.34-7.30 (1H, m), 4.65 (2H, s).

References

[1] Patent: WO2005/92885, 2005, A1. Location in patent: Page/Page column 56; 57
[2] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 65 - 73
[3] Patent: US5183825, 1993, A
[4] Patent: US5194435, 1993, A
[5] Patent: US5776983, 1998, A