2-Fluoro-5-methylpyridine synthesis

4synthesis methods

Product Name:2-Fluoro-5-methylpyridine
CAS Number:2369-19-9
Molecular formula:C6H6FN
Molecular Weight:111.12

1603-41-4
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$7.00/25g

2369-19-9
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$6.00/1g

Yield:2369-19-9 37%

Reaction Conditions:

with tetrafluorohydroboric acid;sodium nitrite in water at -10 - 50; for 1 h;Balz-Schiemann Reaction;

Steps:

2-Fluoro-5-methylpyridine (14).
To a solution of 2-amino-5-methylpyridine (13) (20.0 g, 185 mmol) in fluoroboric acid (50 wt% in water, 50 mL), was added portionwise at -10 °C, sodium nitrite (16.6 g, 240 mmol), while maintaining the temperature below 0 °C. The reaction was stirred at 0 °C for 30 min, then at 50 °C for 30 min. After cooling to room temperature, the mixture was basified (pH 9-10) with a saturated aqueous sodium carbonate solution (250 mL) and extracted with dichloromethane (4 x 125 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on alumina (dichloromethane) to give 2-fluoro-5-methylpyridine (14) (7.50 g, 69 mmol) as a yellow oil. Yield 37%; R_f (Al₂O₃, dichloromethane) 0.92; IR (NaCl plates) ν 1246, 1379, 1486, 2929 cm^-1; ¹H NMR (200 MHz, CDCl₃) δ 2.25 (s, 3H, CH₃), 6.75 (dd, 1H, J = 8.2 Hz, ³J_H-F = 3.0 Hz, H-3), 7.52 (m, 1H, H-4), 7.94 (s, 1H, H-6); ¹³C NMR (50 MHz, CDCl₃) δ 17.4 (CH₃), 108.8 (d, ²J_C-F = 38 Hz, C-3), 130.6 (C-5), 141.7 (d, ³J_C-F = 8 Hz, C-4), 147.2 (d, ³J_C-F = 14 Hz, C-6), 162.1 (d, ¹J_C-F = 236 Hz, C-2).

References:

Billaud, Emilie M.F.;Maisonial-Besset, Aurélie;Rbah-Vidal, Latifa;Vidal, Aurélien;Besse, Sophie;Béquignat, Jean-Baptiste;Decombat, Caroline;Degoul, Fran?oise;Audin, Laurent;Deloye, Jean-Bernard;Dollé, Frédéric;Kuhnast, Bertrand;Madelmont, Jean-Claude;Tarrit, Sébastien;Galmier, Marie-Josèphe;Borel, Michèle;Auzeloux, Philippe;Miot-Noirault, Elisabeth;Chezal, Jean-Michel [European Journal of Medicinal Chemistry,2015,vol. 92,p. 818 - 838] Location in patent:supporting information

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