| 69% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 95℃; for 5h;Inert atmosphere; |
2-Fuoro-5-methylpyridine (5.0 g, 45 mmol) was dissolved in 1,2-dichloroethane (120 mL). To this solution was added N-bromosuccinimide (9.61 g, 54 mmol) and azobisisobutyronitrile (739 mg, 4.5 mmol). The reaction was stirred at reflux (95 C) for 5 hours then the reaction was cooled to rt. The reaction mixture was diluted with CHCl3 (50 mL) and was washed with sat. NaHCO3 (1 x 20 mL), water (1 x 20 mL), followed by brine (1 x 20 mL), dried (Na2SO4) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica), eluting with 10% EtOAc, 90% Pet. Ether, to give a colourless oil identified as 5-bromomethyl-2-fluoro-pyridine, 5.9g, 69% yield. [MH]+ = 191.76 NMR (CDCl3): 4.46 (2H, s), 6.93 (1H, dd, J = 8.4, 3.0 Hz), 7.84 (1H, td, J = 7.8, 2.6 Hz), 8.23 (1H, d, J = 2.2 Hz) |
| 69% |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 95℃; for 5h; |
2-Fuoro-5-methylpyridine (5.0 g, 45 mmol) was dissolved in 1,2-dichloroethane (120 mL). To this solution was added N-bromosuccinimide (9.61 g, 54 mmol) and azobisisobutyronitrile (739 mg, 4.5 mmol). The reaction was stirred at reflux (95 C) for 5 hours then the reaction was cooled to rt. The reaction mixture was diluted with CHCI3 (50 mL) and was washed with sat. NaHC03 (1 x 20 mL), water (1 x 20 mL), followed by brine (1 x 20 mL), dried (IN^SC ) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica), eluting with 10% EtOAc, 90% Pet. Ether, to give a colourless oil identified as 5-bromomethyl-2-fluoropyridine, 5.9g, 69% yield. [MH]+ = 191.876NMR (CDCI3): 4.46 (2H, s), 6.93 (1H, dd, J = 8.4, 3.0Hz), 7.84 (1H, td, J = 7.8, 2.6Hz), 8.23 (1H, d, J = 2.2Hz) |
| 54% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux; |
Add N-bromo succinimide (98.9 mmol, 17.6 g), benzoyl peroxide (4.49 mmol,1.10 g) to a solution of <strong>[2369-19-9]2-fluoro-5-methyl-pyridine</strong> (90 mmol; 10 g) in CCI4 (100 mL).Heat to reflux for 2h, cool, filter, and concentrate. Purify by LC (330g silica): dissolvecrude mixture in minimum volume of DCM, add to column and elute with a gradient ofEtOAc/Hexanes (1:9) to 1:1 over 50 minutes to afford the title intermediate (9.2 g, 54%)as a pale yellow oil. Mass spectrum (mlz): 190 (M+1). |
| 48.7% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 2h; |
To a stirred solution of <strong>[2369-19-9]2-fluoro-5-methylpyridine</strong> (1.44 g, 12.95 mmol) in dry carbon tetrachloride (13 ml), N-bromo succinimide (2.32 g, 12.95 mmol) and Benzoyl peroxide(157 mg, 0.64 mmol) was added. The reaction mixture was stirred at 80 C for 2h. The progress of the reaction was monitored by TLC (1:9, Ethyl acetate : pet. ether). The reaction mixture was cooled to ambient temperature and filtered under suction. The solid was washed with Carbon tetrachloride. The solvent was removed under reduced pressure. The crude was purified by column chromatography (60-120 mesh silica gel)using 3% Ethyl acetate in pet ether as eluent to yield pure 5-(bromomethyl)-2- fluoropyridine (1.2 g, 48.7%) as a pale yellow oil. |
| 41% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 20℃; for 1.5h;Reflux;Product distribution / selectivity; |
Step-1: 5-Bromomethyl-2-fluoro-pyridineTo a solution of 2-Fluoro-5-methyl-pyridine (500 mg, 4.5 mmol) in 10 ml of CCl4 NBS (800 mg, 4.5 mmol) and benzoyl peroxide (25 mg) was added in cold condition. The resulting mixture was allowed to stir at room temperature for 30 minutes and then refluxed for one hour.The reaction mixture was cooled and diluted with water. The organic layer was separated and washed with sodium bicarbonate solution followed by water and brine, then dried over Na2SO4 and concentrated under vacuum. The crud mass was purified by column chromatography (Si-gel, 5% ethyl acetate) to afford 350 mg (41%) of 5-Bromomethyl-2-fluoro-pyridine.GCMS (M/z): 189. 1H-NMR (400 MHz, DMSO-d6) delta (ppm): 8.34 (s, H), 8.04 (m, H), 7.21 (dd, 1H), 4.76 (s, 2H). |
| 35% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2.5h;Reflux; |
Synthesis Example 17 N-[1-((6-fluoropyridin-3-yl)methyl)pyridin-2(1H)-ylidene)-2,2,2-trifluoroacetamide (Compound 229) <strong>[2369-19-9]2-fluoro-5-methylpyridine</strong> in an amount of 500 mg (4.50 mmol) was dissolved in 50 mL of carbon tetrachloride, following which 1.20 g (6.76 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added and refluxing under heating was carried out for 2.5 hours. Following reaction completion, the reaction mixture was returned to room temperature, the solvent was removed by distillation under reduced pressure, and purification was carried out by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 300 mg of 5-bromomethyl-2-fluoropyridine (yield, 35%). |
| 35% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2.5h;Reflux; |
500 mg (4.50 mmol) of <strong>[2369-19-9]2-fluoro-5-methyl pyridine</strong> was dissolved in 50 ml of carbon tetrachloride, 1.20 g (6.76 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 2.5 hours. After the reaction was completed, the reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 300 mg (yield 35%) of 5-bromomethyl-2-fluoropyridine |
| 35% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2.5h;Reflux; |
500 mg (4.50 mmol) of <strong>[2369-19-9]2-fluoro-5-methyl pyridine</strong> was dissolved in 50 ml of carbon tetrachloride, 1.20 g (6.76 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 2.5 hours. After the reaction was completed, the reaction solution was returned to room temperature, and the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 300 mg (yield 35%) of 5-bromomethyl-2-fluoropyridine. |
|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 16h; |
Into a flask containing <strong>[2369-19-9]2-fluoro-5-methylpyridine</strong> (1g, 10.30 mmol, 1 eq) was added carbon tetrachloride (100 mL, 0.1 M), N-Bromosuccinimide (2.01 g, 11.33 mmol, 1.1 eq) and benzoyl peroxide (125 mg, 0.052 mmol, 0.05 eq). The reaction was refluxed at 80 C. for 16 h. The reaction was cooled and the solid filtered off. The filtrate was concentrated in vacuo. Flash column chromatography was used to purify the product using hexanes/ethyl acetate (4/1) as eluent. Bromide 95 was obtained. 1H NMR (300 MHz) CDCl3 delta: 8.24 (s, 1H), 7.85 (dt, J1=8.4, J2=2.4 Hz, 1H), 6.95 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H). |
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