Preparation
Preparation by Fries rearrangement of 2-chlorophenyl acetate with aluminium chloride,
without solvent, between 110° and 180° (40–21%)
in tetrachloroethane at 70–80°.
Synthesis
General procedure for the synthesis of 1-(3-chloro-2-hydroxyphenyl)ethan-1-one and 1-(3-chloro-4-hydroxyphenyl)ethanone from 2-chlorophenol acetic acid: 2-chlorophenol acetic acid (152.5 g, 893.7 mmol) was slowly added dropwise to a solution of dichlorobenzene (120 mL) containing aluminum chloride (119.0 g, 893.7 mmol) at room temperature. The reaction mixture was stirred continuously at 100 °C for 5 hours. Upon completion of the reaction, it was cooled to room temperature and diluted with the addition of dichloromethane, after which the mixture was slowly poured into a 2N sulfuric acid solution at 0°C. The precipitated 3-chloro-4-hydroxyacetophenone was removed by filtration. The aqueous layer was separated and extracted with dichloromethane. All organic phases were combined, washed sequentially with water, dried and concentrated. The residue was recrystallized by cyclohexane to give additional 3-chloro-4-hydroxyacetophenone (23.6 g) as a pale yellow solid. By concentrating the crystallized mother liquor, 47.3 g (31.0% yield) of the target product 1-(3-chloro-2-hydroxyphenyl)ethan-1-one was obtained as a yellow oil.1H NMR (CDCl3) δ 12.84 (broad single peak, 1H, exchangeable with D2O), 7.67 (double-double peak, 1H), 7.57 (double-double peak, 1H), 6.87 (double-double peak, 1H), 6.87 (double-double peak, 1H), 6.87 (double-double peak, 1H), 6.87 (double-double peak, 1H), 6.87 (double-double peak, 1H), 6.87 (double-double peak, 1H). 1H), 2.66 (single peak, 3H).The melting point of 3-chloro-4-hydroxyacetophenone was 109 °C; 1H NMR (CDCl3) δ 7.98 (double peak, 1H), 7.81 (multiple peaks, 1H), 7.08 (multiple peaks, 1H), 6.30 (broad single peak, 1H, exchangeable with D2O), 2.56 (single peak, 3H).
References
[1] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 184 - 191
[2] Journal of the Indian Chemical Society, 1959, vol. 36, p. 784
[3] Journal of Chemical Research, Miniprint, 1989, # 11, p. 2713 - 2739
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 1, p. 132 - 140
