Chemical Properties
clear colorless to light yellow liquid
Uses
2-Bromo-3-methylthiophene was used in the preparation of poly(3,3′′′-dimethyl-(2,2′:5′,2′:5′,2′′′)tetrathiophene)). It was also used in the preparation of 2-bromo-3-(bromomethyl)thiophene, lachrymatory compound.
Application
2-Bromo-3-methylthiophene is used as a pharmaceutical intermediate. It is used to prepare pyrazolo[3,4-d]pyrimidine derivatives as inhibitors of human enterovirus, coxsackievirus, echovirus, influenza virus, herpes simplex virus and rhinovirus. It is also used in the synthesis of oral α7 nicotinic receptor agonists.
Preparation
2-Bromo-3-methylthiophene synthesis: To a solution of glacial AcOH (100 mL), acetic anhydride (4.0 g, 0.039 mol), and 3-methylthiophene (9.82 g, 0.100 mol) as a stirred mixture was added NBS (19.6 g, 0.11 mol) in one portion with a slight exotherm to 44 oC. After 20 min the reaction mixture was poured onto ice, neutralized with sodium bisulfite and extracted with ether. The ether layer was washed with water and concentrated to give 11.3 g (64%) of 2-bromo-3-methylthiophene as a tan colored liquid in 88% purity by GC area % analysis: 1H NMR (CDCl3) d 7.1 (d, 1H, J=5.7 Hz), 6.7 (d, 1H, J=5.9 Hz), 2.2 (s, 3H).
General Description
2-Bromo-3-methylthiophene is formed (approx. 90%) by bromination of 3-methyl thiophene with N-bromosuccinimide in the absence of benzoyl peroxide.
Synthesis
General procedure for the synthesis of 2-bromo-3-methylthiophene from 3-methylthiophene: N-bromosuccinimide (NBS, 8.90 g, 50.0 mmol) was added in batches to a stirred solution of 3-methylthiophene (4.90 g, 50.0 mmol) in acetic acid (20 mL) at room temperature. After the addition was completed, the reaction mixture continued to be stirred at room temperature until the reaction was complete. Subsequently, the reaction mixture was slowly poured into ice water and extracted with a 3:1 solvent mixture of hexane and ether. The organic layer was washed sequentially with 1N NaOH aqueous solution and saturated saline. After drying over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure to afford the crude product 2-bromo-3-methylthiophene (8.20 g, 92.7% yield), which could be used in subsequent reactions without further purification.
References
[1] Chemistry Letters, 2014, vol. 43, # 5, p. 640 - 642
[2] Synthetic Communications, 1999, vol. 29, # 9, p. 1607 - 1610
[3] Bulletin of the Chemical Society of Japan, 2016, vol. 89, # 12, p. 1480 - 1486
[4] Patent: WO2012/116452, 2012, A1. Location in patent: Page/Page column 66
[5] Macromolecules, 2013, vol. 46, # 21, p. 8488 - 8499
