Bromine → 5-Bromo-3-methylthiophene-2-carboxylic acid

To a stirred solution of 3-methyl-2-thiophenecarboxylic acid (6.00 g, 42.20 mmol) in tetrahydrofuran (90 mL) under nitrogen atmosphere at −78° C. was added dropwise n-butyllithium (2.5 M solution in hexanes, 40.5 mL, 101.2 mmol). The resulting reaction mixture was stirred at the same temperature for 1 h, and then bromine (3.00 mL, 58.38 mmol) was added dropwise. After 1 h at −78° C. the cooling bath was removed, and the mixture was allowed to warm to ambient temperature during 1 h, and then quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), and the combined aqueous layer was acidified at 0° C. with 37% aqueous hydrochloric acid to pH˜1-2. The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate in hexanes to afford 5-bromo-3-methylthiophene-2-carboxylic acid as a beige solid (3.44 g, 37%): 1H NMR (300 MHz, CDCl3) δ 6.94 (s, 1H), 2.52 (s, 3H); MS (ES−) m/z 219.1 (M−1), 221.1 (M−1).

1. customThe resulting reaction mixture
2. customAfter 1 h at −78° C. the cooling bath was removed
3. customquenched with water (100 mL)
4. extractionThe aqueous layer was extracted with ethyl acetate (100 mL)
5. washThe organic layer was washed with water (100 mL)
6. customwas acidified at 0° C. with 37% aqueous hydrochloric acid to pH˜1-2
7. extractionThe aqueous layer was extracted with ethyl acetate (2×100 mL)
8. dry with materialthe combined organic layer was dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe residue was triturated with ethyl acetate in hexanes

ORD record

ord-28275ef093004fb6a75735b2892d27b4

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08258160B2