Application
2,6-Difluoro-4-iodopyridine can be used as a pharmaceutical synthesis intermediate. It can be prepared by reacting 2,6-difluoropyridine with n-butyllithium and iodine to generate intermediate 3-iodo-2,6-difluoropyridine. Further reaction yields 2,6-difluoro-4-iodopyridine, which can be used in laboratory research and development and chemical production processes.
Synthesis
The general procedure for the synthesis of 2,6-difluoro-4-iodopyridine from 2,6-difluoro-3-iodopyridine was as follows: n-butyllithium (1.66 mL, 4.15 mmol, 2.5 mol/L hexane solution) was slowly added dropwise to a solution of tetrahydrofuran (THF, 2 mL) with diisopropylamine (1.30 mL, 4.15 mmol) at -78 °C. 25 minutes later, a solution of 2,6-difluoro-3-iodopyridine (1.00 g, 4.15 mmol) in THF (5 mL) was added dropwise to the above mixture via cannula. The reaction mixture was kept at -78 °C for 12 h. THF (2 mL) solution in water (0.2 mL, 11 mmol) was subsequently added and slowly warmed up to room temperature over a period of 1 h. The reaction was carried out at -78 °C for 1 h. The reaction was carried out in a controlled manner. Upon completion of the reaction, the reaction mixture was washed with 10% aqueous Na2SO3 solution (5 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and dried over anhydrous magnesium sulfate (MgSO4) and subsequently concentrated under reduced pressure. The target product 2,6-difluoro-4-iodopyridine was obtained by hexane crystallization as colorless crystals (740 mg, 74% yield). The product was characterized as follows: 1H NMR (400 MHz, CDCl3): δ 7.22 (t, 2H, J = 1.2 Hz); 13C NMR (100 MHz, CDCl3): δ 161.1 (dd, J = 250, 16 Hz, 2C), 115.6 (dd, J = 24, 10 Hz, 2C), 110.3; 19F NMR (376 MHz, CDCl3): δ -68.1; GC-MS m/z: Calculated value 241 [M+], measured value 241; Melting point: 78-80 °C.
References
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 18, p. 5026 - 5030
[2] Angew. Chem., 2017, vol. 129, p. 5108 - 5112,5
[3] Chinese Chemical Letters, 2017, vol. 28, # 3, p. 525 - 530
[4] Organic Letters, 2007, vol. 9, # 25, p. 5175 - 5178
