Acetic Acid → Methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate

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A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 200 mg, 1.03 mmol) and 4-chloro-3-(trifluoromethyl)benzaldehyde (148 μL, 1.03 mmol) in isopropanol (4.0 mL) was treated with piperidine (10 μL, 103 μmol) and acetic acid (5.9 μL, 103 μmol) and heated to reflux for 16.5 h. After this time, water (2.0 mL) was added and the solution was slowly cooled to rt, whereupon crystals formed. After standing at rt, the mixture was cooled on ice, and the resulting crystals were collected by filtration and dried to provide methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate as a white crystalline solid (204 mg, 51%). A second crop (47 mg) was obtained from the mother liquor, raising the total yield to 63%. The NMR indicated predominantly the enolic form. 1H NMR (500 MHz, CDCl3) δ ppm 3.79 (s, 3 H) 6.24 (s, 1 H) 6.82 (d, J=8.2 Hz, 1 H) 7.00 (t, J=7.7 Hz, 1 H) 7.31 (t, J=6.9 Hz, 1 H) 7.42 (m, 2 H) 7.70 (m, 2 H) 12.27 (br. s, 1 H). Mass spectrum m/z 407.19, 409.18 (M+Na)+.

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