7-Fluoro-1-indanone

Synthesis

898767-04-9

651735-59-0

The general procedure for the synthesis of 7-fluoro-1-indanone from 3-chloro-1-(2-fluorophenyl)propan-1-one is as follows: first, a mixture of SOCl2 (1.5 equiv.) and substituted benzoic acid in benzene is refluxed until no gas escapes. After cooling to room temperature, the mixture was concentrated using a rotary evaporator. The concentrate was dissolved in dichloroethane and a dichloroethane solution of AlCl3 (1.0 eq.) was slowly added at 10-20 °C. Subsequently, ethylene gas was passed into the reaction system for 4 hours, after which the mixture was stirred overnight and the reaction was quenched with 4N HCl. The organic and aqueous layers were separated and the aqueous layer was extracted with Et2O (3 x 250 mL). The organic extracts were combined and washed sequentially with H2O (3 × 150 mL), saturated NaHCO3 (3 × 150 mL) and brine (1 × 150 mL), dried over MgSO4 and concentrated. The concentrate was mixed with a slurry of AlCl3 (9.0 g, 10 eq.) and NaCl (2.4 g, 6 eq.) and stirred at 180 °C for 2 hours. Alternatively, the concentrate was mixed with concentrated sulfuric acid and stirred at 85°C for 1 hour. Upon completion of the reaction, it was cooled to room temperature and ice was slowly added, followed by the addition of concentrated HCl. The reaction mixture was extracted with CH2Cl2 (3 x 500 mL), the organic layers were combined and concentrated, and finally the target product 7-fluoro-1-indanone was purified by column chromatography using hexanes:EtOAc (4:1) as eluent to give the target product 7-fluoro-1-indanone. 1-(2-fluoroethyl)-3-(7-fluoroindan-1-yl)urea was further synthesized from 7-fluoro-1-indanone according to General Method C. The title compound was prepared from commercially available 2-fluorobenzoic acid by General Method E described above. The intermediates 7-fluoro-1-indanone and 7-fluoroindan-1-ylamine were isolated and characterized. 7-fluoro-1-indanone was prepared in 32% yield (6.85 g from 20.00 g, 0.14 mol of 2-fluorobenzoic acid) using SOCl2 (15.60 mL, 0.21 mol), AlCl3 (19.00 g, 0.14 mol), additional AlCl3 (285.50 g, 2.14 mol) and NaCl (75.10 g, 1.29 mol). The spectral data were as follows: 1H NMR (300 MHz, CDCl3) δ 2.67-2.80 (m, 2H), 3.2 (t, 2H, J = 5.9 Hz), 7.0 (t, 1H, J = 8.5 Hz), 7.3 (d, 1H, J = 7.6 Hz), 7.6 (m, 1H).

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