Background and overview of two preparation methods of 5-bromo-3-fluoropyridine
5-Bromo-3-fluoropyridine is an organic intermediate that can be prepared from 3,5-dibromopyridine through a one-step reaction with NFSI, or through a two-step reaction from 5-bromonicotinamide.
Two preparation methods of 5-bromo-3-fluoropyridine
Two preparation methods of 5-bromo-3-fluoropyridine reported 1.
Under nitrogen, add 3,5-dibromopyridine (1.21 g) to a 50 mL Schlenk flask containing THF (5.0 mL). Add i-PrMgCl·LiCl (5.5 mmol) in THF (1.16 M, 4.7 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Remove solvent in vacuo (0.5 mbar, 40°C, 0.5 h). CH2Cl2 (5 mL) was added to the reaction mixture, and NFSI (1.89 g, 6 mmol) in CH2Cl2 (15 mL) and perfluorodecalin (5 mL) was slowly added to the reaction mixture at -78 °C. . The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice-cooled saturated aqueous NH4Cl solution (50 mL), the reaction mixture was extracted with CH2Cl2 (3 × 50 mL), and the organic layer was dried over Na2SO4. The organic layer was filtered, concentrated in vacuo, and the crude residue was purified by column chromatography (SiO2) using pentane/Et2O (20:1) as eluent to give 5-bromo-3-fluoropyridine.
Two preparation methods of 5-bromo-3-fluoropyridine report 2.
Step 1: 3-amino-5-bromopyridine:
To an ice-cold solution of 31.8g (0.79mol) sodium hydroxide and 40.7g (0.255mol) bromine in 340ml water was added 42.0g (0.209mol) of commercially available 5-bromonicotinamide. The mixture was allowed to warm to room temperature and then heated at 70°C for 1 hour. The resulting brown suspension was cooled to room temperature. The aqueous phase was saturated with brine and extracted three times with a 1:1 mixture of THF and tert-butyl-methyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. Concentration in vacuo gave 39.1 g of dark brown residue, which was purified by flash chromatography (heptane/ethyl acetate 1:1) to give the title compound as a brown solid (total 70.2 g, 70%), MS (ISP): m/e=173.1, 175.1(M+H+).
Step 2: 5-bromo-3-fluoropyridine:
10.0g (0.058mol) 3-amino-5-bromopyridine in 59ml 50% tetrafluoroboric acid cooled at -10°C was treated by dropwise addition of a solution of 4.19g (0.06mol) sodium nitrite in 13ml water. The solution. After stirring at -8°C for 1 hour, 150 ml of diethyl ether was added to the brown suspension. The crude diazonium salt was filtered off and washed with diethyl ether. This coarse salt was then added portionwise to 200 ml of toluene heated at 80°C. After stirring at 90° C. for 1 hour, the organic phase was concentrated. The pale yellow residue was suspended in 150 ml of water and the pH was adjusted to 11 with 32% sodium hydroxide solution. The resulting solution was extracted three times with 200 ml of dibromomethylphenylboronic acid pinacol ester methane chloride. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated. Purify the crude material 15.4g (brown oil) by vacuum distillation (10mBar, 35°C) to obtain 5.6g (0.032mol, 55%) of the title compound as a colorless oil (ISP): m/e=176.1, 178.1 ( M+H+).
References
[1]Shigeyuki, Yamada, Andrei, et al. Convenient Electrophilic Fluorination of Functionalized Aryl and Heteroaryl Magnesium Reagents[J]. Angewandte Chemie International Edition, 2009.
[2] From U.S. Pat. Appl. Publ., 20060199960, 07 Sep 2006
