3-FLUORO-4-METHYLANISOLE synthesis
- Product Name:3-FLUORO-4-METHYLANISOLE
- CAS Number:405-06-1
- Molecular formula:C8H9FO
- Molecular Weight:140.15
50868-72-9
405-06-1
The general procedure for the synthesis of 3-fluoro-4-methylanisole from 5-methoxy-2-methylaniline was as follows: a mixed system of 5-methoxy-2-methylaniline (5.0 g; 36 mmol), concentrated hydrochloric acid (7.6 mL, 12 M solution; 91 mmol), and deionized water (11 mL) was heated and stirred at 60 °C for 15 min until complete dissolution. After the reaction solution was cooled to 0 °C, aqueous sodium nitrite (2.5 g; 36 mmol) was slowly added dropwise to control the internal temperature ≤7 °C. The reaction solution was then stirred at 0 °C for 15 min. The reaction solution was continued to be stirred at 0 °C for 30 min, followed by cautious addition of pre-cooled tetrafluoroboric acid solution (5.3 mL, 48% solution; 40 mmol). The reaction mixture was stirred at 0 °C for 20 min before the resulting brown solid was collected by filtration and washed sequentially with ice water (3 × 10 mL) and deionized water (2 × 10 mL). The solid was dried under high vacuum for 20 h. The solid was then heated with a heat gun until the release of white fumes of boron trifluoride was stopped. The resulting brown oil was extracted with ethyl acetate and water in liquid-liquid extraction, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and finally purified by short distillation to obtain the colorless oily product 3-fluoro-4-methylanisole (1.6 g; 31% yield).
Yield: 65%
Reaction Conditions:
with potassium carbonate in N,N-dimethyl-formamide at 20; for 16 h;Inert atmosphere;
Steps:
10 2-Fluoro-4-methoxy-1-methylbenzene
To a solution of 1.00 g (7.93 mmol) of 3-fluoro-4-methylphenol in 20 ml of dehydrated DMF, 3.30 g (23.9 mmol) of potassium carbonate and 0.750 ml (12.0 mmol) of methyl iodide were added at room temperature in an argon atmosphere and reacted at room temperature for 16 hours with stirring.
After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate.
The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The obtained concentration residue was subjected to preparative column chromatography (apparatus 1, silica gel, elution solvent: n-hexane:ethyl acetate=100:0→80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 725 mg of the title compound (yield: 65%) as a colorless oil.
Mass spectrum (CI, m/z): 141 [M+1]+.
1H-NMR spectrum (400 MHz, CDCl3) δ: 7.10-7.01 (m, 1H), 6.62-6.55 (m, 2H), 3.77 (s, 3H), 2.21-2.18 (m, 3H).
References:
UBE INDUSTRIES, LTD.;IWASE, Noriaki;AGA, Yasuhiro;USHIYAMA, Shigeru;KONO, Shigeyuki;SUNAMOTO, Hidetoshi;MATSUSHITA, Takashi;OGI, Sayaka;UMEZAKI, Satoshi;KOJIMA, Masahiro;ONUMA, Kazuhiro;SHIRAISHI, Yusuke;OKUDO, Makoto;KIMURA, Tomio US2018/186818, 2018, A1 Location in patent:Paragraph 1130; 1131; 1132; 1133; 1134
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