4-FLUORO-2-METHYLPHENYLMAGNESIUM BROMIDE synthesis

Yield:-

Reaction Conditions:

with iodine;magnesium;magnesium bromide in tetrahydrofuran; for 1 h;Reflux;Inert atmosphere;Grignard Reaction;

Steps:

19.1 1-Benzyl-4-(4-fluoro-2-methylphenyl)-1,2,3,6-tetrahydropyridine (10)

A mixture of Mg (turnings, 48.6 mg, 2.00 mmol), 1-bromo-4-fluoro-2-methylbenzene (Tokyo Chemical Industry, 253 μL, 2.00 mmol), iodine (25.4 mg, 0.100 mmol), and MgBr₂ (7.0 μL, 0.10 mmol) in anhydrous THF (5.0 mL) was stirred under reflux conditions under N₂ for 1 h, and cooled to room temperature.
To the resulting solution of Grignard reagent (4-fluoro-2-methylphenylmagnesium bromide) was added a solution of 1-benzyl-4-piperidone (Tokyo Chemical Industry, 371 μL, 2.00 mmol) in anhydrous THF (7.0 mL) at room temperature under N₂ within 5 min.
The mixture was stirred at room temperature under N₂ for 10 min, then stirred under reflux conditions for 6 h.
The reaction solution was cooled to 0 °C then poured into ice-cooled aqueous NH₄Cl (40 mL).
The mixture was extracted with CH₂Cl₂ (40 * 4), then the combined extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to afford 658.5 mg of 1-benzyl-4-(4-fluoro-2-methylphenyl)piperidin-4-ol 9 (crude). TLC: R_f = 0.4, AcOEt/hexane = 1:8.
To a stirred solution of 1-benzyl-4-(4-fluoro-2-methylphenyl)piperidin-4-ol 9 (658.5 mg, crude) in toluene (50.0 mL) was added p-toluenesulfonic acid monohydrate (760.1 mg, 4.00 mmol) under N₂ at room temperature.
The resulting solution was heated to reflux and stirred under N₂ for 10 h.
The solution was cooled to 0 °C, basified by adding 2 N NaOH (30 mL), then the mixture was extracted with chloroform (50 mL * 2).
The combined extracts was dried over anhydrous MgSO₄, and concentrated in vacuo.
The residue was purified by flash column chromatography (silica gel, CH₂Cl₂/MeOH = 36:1) to afford 343.3 mg of the title product 10 in 61% yield (2 steps) as a yellow oil. ¹H NMR (270 MHz, CDCl₃) δ 7.40-7.24 (5H, m, Ar H), 7.05 (1H, dd, J = 8.24 Hz, J = 6.10 Hz, Ar H), 6.88-6.77 (2H, m, Ar H) 5.53-5.49 (1H, m, CH), 3.65 (2H, s, Ph-CH₂-N), 3.13 (2H, dd, 5.91 Hz, 2.81 Hz, N-CH₂), 2.68 (2H, t, 5.62 Hz, N-CH₂), 2.36-2.29 (2H, m, CH₂), 2.28 (3H, s, Ar-CH₃).

References:

Hayashi, Shigeo;Ohashi, Katsuyo;Nakata, Eriko;Emoto, Chie [European Journal of Medicinal Chemistry,2012,vol. 55,p. 228 - 242]