Methanol → 5-(4'-dimethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)2H-tetrazole

참여 물질

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반응 단계

A suspension of magnesium turnings (2.35 g) in anhydrous tetrahydrofuran (66 mL) is cooled to 14° C., treated with a 1 M solution of diisobutylaluminium hydride in tetrahydrofuran (1.8 mL; 1.8 mmol) and stirred for 20 min. At 14° C., 1-bromo-4-dimethoxymethyl-benzene (1.02 g; 4.4 mmol) is added under vigorous stirring. After the reaction starts, more 1-bromo-4-dimethoxymethyl-benzene (19.32 g; 83.6 mmol) is added over 50 minutes. The resulting mixture is further stirred at about 25° C. for 2.5 hours. The concentration of 4-(dimethoxymethyl)phenylmagnesium bromide in the solution above the excess of magnesium turnings is about 0.96 M. In another flask, a mixture of 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (94% content; 4.22 g; 15.0 mmol) is dissolved in anhydrous tetrahydrofuran (2.8 mL) under an inert atmosphere and dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) (80.8 mg; 0.15 mmol) is added. The vigorously stirred resulting suspension is cooled to about 15° C. and the above 0.96 M 4-(dimethoxymethyl)phenylmagnesium bromide solution (18 mL; 17.3 mmol) is added over one hour while keeping the temperature below 25° C. by external cooling. The dark brown reaction mixture is agitated at room temperature for 22.5 hours. After that, about 94% of the starting material are converted. Methanol (1.2 mL; 30 mmol) is added to the mixture followed by isopropyl acetate (35 mL), a solution of ammonium chloride (0.4 g) in water (10 mL) and water (10 mL). The layers are separated. The organic layer is washed with water (10 mL), three times with a solution of sodium hydrogencarbonate (1.0 g) in water (12 mL) and twice with water (10 mL) before it is evaporated in vacuo. The resulting brown oil is purified by column chromatography on silica gel eluting with a 1:4 mixture of ethyl acetate and hexane (in the presence of 0.3 volume-% of triethylamine) to afford the main isomer (N2-isomer) 5-(4′-dimethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)2H-tetrazole as a pale yellow oil.

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