1. A stirred solution of thiophene (185 mL, 2.3 mol) in chloroform was treated dropwise with bromine (500 mL, 1560 g, 9.75 mol) for 5 hours at 0°C. The solution was then cooled to a temperature of 0.5°F. During the last hour, cooling was stopped and the addition of bromine continued.
2. The reaction mixture was stirred and heated to reflux for 5 h. After cooling to room temperature, the reaction mixture was quenched with 3 M aqueous NaOH solution with vigorous stirring to consume excess bromine. The aqueous layer was separated and the organic phase was washed sequentially with water and acetone (150 mL) to remove residual water.
3. After drying the organic residue, it was dissolved in chloroform (1 L) at reflux. After cooling, tetrabromothiophene precipitated as colorless crystals (693 g, 75% yield).
4. Tetrabromothiophene (47 g, 0.12 mol) was dissolved in anhydrous ethyl ether (300 mL), cooled to 0 °C, and butyllithium solution (150 mL, 0.24 mol, 1.6 M) in hexanes was added drop-wise under argon protection over 80-90 min.
5. After continued stirring for 20 min, ice water (250 mL) was carefully added. The organic phase was separated and the aqueous phase was extracted twice with ether, the organic extracts were combined, dried with anhydrous calcium chloride and concentrated in vacuum.
6. The residue was distilled at 15 mmHg to give 3,4-dibromothiophene (22 g, 77% yield).
7. 3,4-dibromothiophene (72 g, 0.3 mol) was dissolved in anhydrous ether (120 mL), cooled to -78 °C, a solution of nBuLi (206 mL, 0.33 mol, 1.6 M) was added, and stirred at -78 °C for 5 min.
8. slowly add anhydrous ether (120 mL) solution of DMF (35 mL, 0.45 mol) cooled to -78 °C. After 10 min remove the cold bath and carefully add aqueous 6N HCl (150 mL), warm to 23 °C.
9. The aqueous phase was separated, the organic phase was washed with ether, the organic extracts were combined, washed with saturated aqueous sodium bicarbonate and the organic solvent was evaporated.
10. The residue was distilled twice under vacuum to give pure 3-bromothiophene-4-carbaldehyde (40 g, 69% yield).
