tert-Butanol → Methyl 4-bromothiophene-2-carboxylate

Temperature

23 °C

A biphasic mixture of 4-bromothiophene-2-carbaldehyde (13.2 g, 69.1 mmol, 1 equiv), sodium chlorite (9.40 g, 104 mmol, 1.50 equiv), sodium phosphate monobasic (9.53 g, 69.1 mmol, 1.00 equiv) in a mixture of t-BuOH (120 mL), 2-methyl-2-butene (20 mL), and water (50 mL) was stirred at 23° C. for 1 hour. More sodium chlorite 3.00 g, 33.2 mmol, 0.480 equiv) and a solution of sodium phosphate monobasic (3.00 g, 21.7 mmol, 0.315 equiv) in water (25 mL) were added. The resulting mixture was stirred for 1 hour, then concentrated. The residue was diluted with aqueous 0.1 N sodium hydroxide solution, and the resulting aqueous mixture was extracted with ethyl acetate (200 mL). The aqueous layer was then acidified to pH 2 with aqueous 1 N HCl solution and extracted with dichloromethane (3×100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in anhydrous methanol (600 mL) and concentrated sulfuric acid (4 mL) was added. The resulting solution was heated at reflux for 48 hours. The reaction mixture was concentrated, then carefully partitioned between aqueous saturated sodium bicarbonate solution (400 mL) and ethyl acetate (2×200 mL). The organic layer was dried over sodium sulfate and concentrated to give methyl 4-bromothiophene-2-carboxylate (5-1) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H, J=1.5 Hz), 7.44 (d, 1H, J=1.5 Hz), 3.90 (s, 3H).

1. stirringThe resulting mixture was stirred for 1 hour
2. concentrationconcentrated
3. additionThe residue was diluted with aqueous 0.1 N sodium hydroxide solution
4. extractionthe resulting aqueous mixture was extracted with ethyl acetate (200 mL)
5. extractionextracted with dichloromethane (3×100 mL)
6. dry with materialThe organic layer was dried over sodium sulfate
7. concentrationconcentrated
8. dissolutionThe residue was dissolved in anhydrous methanol (600 mL)
9. additionconcentrated sulfuric acid (4 mL) was added
10. temperatureThe resulting solution was heated
11. temperatureat reflux for 48 hours
12. concentrationThe reaction mixture was concentrated
13. customcarefully partitioned between aqueous saturated sodium bicarbonate solution (400 mL) and ethyl acetate (2×200 mL)
14. dry with materialThe organic layer was dried over sodium sulfate
15. concentrationconcentrated

ORD record

ord-2a28e37f54984c6aadcca185028b8c90

Source dataset

uspto-grants-2007_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07262199B2