Methanol → 2,4-Dimethoxy-3,5,6-trifluorobenzonitrile

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Reaction Steps

A solution of sodium methoxide (18 g, 83 mmol, 25% in methanol) is added dropwise to a solution of pentafluorobenzonitrile (7.72 g, 40 mmol) in 60 mL methanol over 15 min. The reaction is heated to reflux for 3 hours, cooled to room temperature and then poured into 150 mL ice water. The product is then extracted with diethyl ether (100 mL×2), and the combined organic layers are washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue is then chromatographed on silica gel, eluting with hexane:ethyl acetate (97:3 to 88:12 gradient) to yield 6.18 g (71%) of Compound 43 as a colorless oil. 1H-NMR (CDCl3) 4.16 (s, 3H); 4.10 (s, 3H). 19F NMR (CDCl3) 134.39 (dd, J=10.1 and 20.3 Hz, 1F); 150.80 (d, J=7.1 Hz, 1F); 158.00 (d, J=21.4 Hz, 1F). Anal. calc. for C9H6F3NO2: C, 49.78; H, 2.78; N, 6.45. Found: C, 49.71; H, 2.78; N, 6.56. A second product, 3,5-difluoro-2,4,6-trimethoxybenzonitrile, is also isolated from the reaction mixture as a colorless solid (1.09 g; 12%). 1H-NMR (CDCl3) 4.12 (s, 3H); 4.07 (s, 6H). 19F-NMR (CDCl3) 152.11 (s).

Provenance & Evidence