6-Chloro-2-methyl-3-nitropyridine

28489-45-4

22280-60-0

General procedure for the synthesis of 2-chloro-5-nitro-6-methylpyridine from 2-hydroxy-6-methyl-5-nitropyridine: 1. 2-Hydroxy-6-methyl-5-nitropyridine (500 mg, 3.24 mmol), phosphorus trichloride (POCl3, 0.5 mL) and phosphorus pentachloride (PCl5, 200 mg) were mixed and the reaction was stirred for 2 hours at 150 °C. After completion of the reaction, it was cooled to room temperature, the reaction mixture was poured into ice water and extracted with dichloromethane (DCM, 3 x 20 mL). The organic phases were combined, washed with water to pH 7, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting residue was dried under reduced pressure to give 6-chloro-2-methyl-3-nitropyridine (430 mg, 78% yield) as a light brown solid. 2. 3-Ethynyl-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one (199 mg, 1.00 mmol) was mixed with 6-chloro-2-methyl-3-nitropyridine (172 mg, 1.00 mmol) in the presence of PdCl2(PPh3)2 (42 mg, 0.06 mmol), P(t-Bu)3 (16 mg , 0.08 mmol) and triethylamine (TEA, 1.5 mL) in a solution of N,N-dimethylformamide (DMF, 3 mL), and the reaction was stirred at 100 °C for 3 hours. The crude product was purified by silica gel column chromatography to afford the intermediate 7,7-dimethyl-3-((6-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one (80 mg, 16% yield) as a yellow solid. 3. 7,7-Dimethyl-3-((6-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one (194 mg, 0.58 mmol) was dissolved in ethyl acetate (EtOAc, 10 mL) and cooled to 0°C. A concentrated aqueous hydrochloric acid solution (1 mL) of stannous chloride dihydrate (SnCl2-2H2O, 650 mg, 2.90 mmol) was slowly added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice water, adjusted to pH 9-10 with 15% aqueous sodium hydroxide and extracted with ethyl acetate (EtOAc, 3 × 25 mL). The organic phases were combined, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (silica gel, dichloromethane/ethanol, 40:1) to afford the target product 2-chloro-5-nitro-6-methylpyridine (34 mg, 19% yield). Product characterization: 1H NMR (DMSO-d6) δH: 1.05 (s, 6H), 2.29 (s, 3H), 2.59 (s, 2H), 3.03 (s, 2H), 5.51 (br s, 2H), 6.92 (d, 1H), 7.24 (d, 1H), 8.15 (s, 1H), 8.83 (s, 1H). LC/MS (M+H)+ = 306.