5-Bromo-3-methylindole

Synthesis

General procedure for the synthesis of 5-bromo-3-methyl-1H-indole from 5-bromoindole-3-carboxaldehyde: 5-bromo-1H-indole-3-carboxaldehyde (13.12 g, 58.6 mmol) was dissolved in THF (100 mL) and slowly added to a reflux mixture of THF (100 mL) with LiAlH4 (4.89 g, 129 mmol). The reaction setup was equipped with a reflux condenser in a 30 mm two-neck flask. After refluxing the reaction mixture for 8 h, it was cooled to room temperature and the reaction was quenched with ether (50 mL). The reaction mixture was acidified to pH 3 with 1 N HCl under cooling in an ice bath.Subsequently, the reaction mixture was diluted with ethyl acetate (125 mL), transferred to a dispensing funnel, and washed sequentially with water (2 × 50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to obtain the crude product. The crude product was dissolved in a small amount of dichloromethane (DCM) and purified by an ISCO silica gel column (80 g) using a 0-50% ethyl acetate/heptane gradient elution for 15 min. The elution fractions containing the target product were combined and concentrated to give 5-bromo-3-methyl-1H-indole (5.5 g, 44.7% yield). the LC retention time was 1.0 min [Method A1]. m/z MS (E): 210/212 (M-H).

References

[1] Patent: US2004/43965, 2004, A1. Location in patent: Page/Page column 21-22
[2] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 3, p. 333 - 336
[3] Patent: WO2012/119046, 2012, A2. Location in patent: Page/Page column 184
[4] ChemMedChem, 2012, vol. 7, # 12, p. 2179 - 2193
[5] Patent: WO2018/26620, 2018, A1. Location in patent: Page/Page column 77; 78