General procedure for the synthesis of 2-chloro-5-nitro-4-methylpyridine from 2-hydroxy-4-methyl-5-nitropyridine:
1. 2-Hydroxy-4-methyl-5-nitropyridine (500 mg, 3.24 mmol), POCl3 (0.5 mL) and PCl5 (200 mg) were mixed and stirred at 150°C for 2 hrs.
2. After completion of the reaction, cooled to room temperature, the reaction mixture was poured into ice and extracted with dichloromethane (DCM, 3 x 20 mL).
3. The organic phases were combined, washed with water to pH 7, dried over Na2SO4 and concentrated under reduced pressure.
4. The obtained residue was dried under reduced pressure to give the crude product 2-chloro-4-methyl-5-nitropyridine (480 mg, 86% yield).
In the presence of PdCl2(PPh3)2 (42 mg, 0.06 mmol), P(t-Bu)3 (16 mg, 0.08 mmol) and TEA (1.5 mL), 2-chloro-4-methyl-5-nitropyridine (172 mg, 1.00 mmol) was mixed with 3-ethynyl-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one (199 mg, 1.00 mmol) in DMF (3 mL) at 100°C for 3 hours.
The crude product was purified by column chromatography (silica gel) to afford the intermediate 7,7-dimethyl-3-((4-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one (115 mg, 34% yield).
A solution of 7,7-dimethyl-3-((4-methyl-5-nitropyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one (114 mg, 0.34 mmol) and SnCl2-2H2O (380 mg, 1.70 mmol) in EtOH (10 mL) was stirred at reflux for 6 hours.
After completion of the reaction, it was cooled to room temperature, poured into ice, adjusted to pH 7-8 with saturated aqueous NaHCO3 solution and extracted with EtOAc (3 × 30 mL).
The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure.
The resulting residue was purified by washing with hexane and acetonitrile to afford the target product 2-chloro-5-nitro-4-methylpyridine (60 mg, 58% yield).
1H NMR (DMSO-d6) δ: 1.07 (s, 6H), 2.08 (s, 3H), 2.60 (s, 2H), 3.02 (s, 2H), 5.51 (s, 2H), 7.23 (s, 1H), 7.90 (s, 1H), 8.17 (s, 1H), 8.80 (s, 1H).
LC/MS (M+H)+ = 306.
