The general procedure for the synthesis of N-Boc-3-bromo-4-oxopiperidine from N-Boc-4-piperidone was as follows:
1. triethylamine (TEA, 7.7 mL, 55 mmol) and trimethylchlorosilane (TMSCl, 3.5 mL, 27.6 mmol) were sequentially added to a solution of N,N-dimethylformamide (DMF, 30 mL) containing tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol) at room temperature.
2. The reaction mixture was stirred at 75 °C overnight.
3. After completion of the reaction, the reaction solution was cooled to room temperature and pre-cooled saturated aqueous sodium bicarbonate (200 mL) and hexane (200 mL) were added sequentially.
4. Separate the organic phase, wash it with saturated aqueous sodium chloride solution, and subsequently dry and concentrate it with anhydrous sodium sulfate to obtain a crude product, which was directly used in the next step of the reaction.
5. The above crude product was dissolved in tetrahydrofuran (THF, 15 mL) and stirred at 0 °C for 15 min.
6. A solution of N-bromosuccinimide (NBS, 4.47 g, 25 mmol) dissolved in THF (80 mL) was slowly added dropwise to the above reaction solution.
7. After the dropwise addition, the reaction mixture was stirred at room temperature overnight.
8. At the end of the reaction, water (200 mL) and hexane (200 mL) were added to the reaction solution.
9. The organic phase was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
10. The crude product was purified by silica gel column chromatography (60 g of silica gel, gradient elution of petroleum ether/ethyl acetate=20/1 to 8/1) to afford tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate as a white solid (5.56 g, 78% yield).
