6-Chloro-2-fluoropyridine-3-carboxaldehyde Chemical Properties

Melting point:

49-50 °C(Solv: hexane (110-54-3))

Boiling point:

255.5±35.0 °C(Predicted)

Density 

1.444±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

pka

-4.44±0.10(Predicted)

Safety Information

HS Code 

2933399990

6-Chloro-2-fluoropyridine-3-carboxaldehyde Usage And Synthesis

Uses

6-Chloro-2-fluoropyridine-3-carbaldehyde is used as a reactant in the synthesis of phantasmidine via a tandem intramolecular aldol reaction-intramolecular nucleophilic aromatic substitution sequence to yield the tetracyclic lactam.

Synthesis

The general procedure for the synthesis of 6-chloro-2-fluoronicotinaldehyde from 6-fluoro-2-chloropyridine and N,N-dimethylformamide was as follows: to a solution of diisopropylamine (5.80 mL, 41.5 mmol) in anhydrous THF (100 mL) at -78 °C was added n-BuLi (2.1 M solution in hexane, 18.0 mL, 37.8 mmol). The cold bath was removed and the resulting light yellow solution was stirred at 0 °C for 30 min. Subsequently, the solution was cooled again to -78 °C and a solution of 2-chloro-6-fluoropyridine (3.80 g, 29.0 mmol) in anhydrous THF (20 mL) was added slowly and dropwise. The reaction mixture was continued to be stirred at -78 °C for 1 hour. After that, N,N-dimethylformamide (4.49 mL, 58.0 mmol) was added dropwise and stirred for another 1 h at the same temperature. Next, an ether solution of saturated HCl was slowly added until the pH of the reaction mixture reached 1. The reaction mixture was warmed up to 25 °C and layered by adding water (50 mL). The aqueous layer was extracted with EtOAc (50 mL × 2) and the combined organic layers were washed sequentially with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated to give the crude product 8b. The crude product was recrystallized by hexane to give the pure product 8b (4.14 g, 90% yield). The product was characterized as follows: Rf = 0.27 (10:1 hexane/EtOAc); melting point 49-50 °C; 1H NMR (δ, ppm): 10.27 (s, 1H), 8.27 (dd, 1H, J = 8.8, 8.0 Hz), 7.41 (d, 1H, J = 8.0 Hz); 13C NMR (δ, ppm): 185.0, 162.6 (d, J = 8.0 Hz). 162.6 (d, J = 254 Hz), 154.8 (d, J = 15 Hz), 141.3, 123.0 (d, J = 5.3 Hz), 116.9 (d, J = 17 Hz).1H NMR spectroscopic data are in agreement with the literature reports.

References

[1] Organic Letters, 2011, vol. 13, # 3, p. 526 - 529
[2] Patent: WO2012/78608, 2012, A1. Location in patent: Page/Page column 30-31
[3] Heterocycles, 2014, vol. 88, # 1, p. 779 - 787
[4] Patent: WO2015/75023, 2015, A1. Location in patent: Page/Page column 112-113
[5] Patent: WO2016/177690, 2016, A1. Location in patent: Page/Page column 75-76

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