Methanol → 2,4-Dimethoxy-3,5,6-trifluorobenzonitrile
Reaction equation
[CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10]([C:11]#[N:12])=[C:9](F)[C:8]([F:14])=[C:7](F)[C:6]=1[F:16].[CH3:17][OH:18]>>[CH3:1][O:2][C:9]1[C:8]([F:14])=[C:7]([O:18][CH3:17])[C:6]([F:16])=[C:5]([F:4])[C:10]=1[C:11]#[N:12]Participants
Procedure
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).
Workup
- temperatureThe reaction is heated
- temperatureto reflux for 3 hours
- extractionThe product is then extracted with diethyl ether (100 mL×2)
- washthe combined organic layers are washed with brine (50 mL)
- dry with materialdried over magnesium sulfate
- concentrationconcentrated in vacuo
- customThe residue is then chromatographed on silica gel
- washeluting with hexane:ethyl acetate (97:3 to 88:12 gradient)
Sources & evidence
- ORD record
- ord-21d3dc0b65664dd8ba39d490d2486a11
- Source dataset
- uspto-grants-2001_05
- Patent number
- US06229055B1
Reaction notes
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