2,2-Dimethylcyclohexan-1-one → 2-Isopropyl-3-carboethoxy-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-8,8-dimethylquinoline

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Reaction Steps

To a solution of lithium bis(trimethylsilyl)amide (1.0 M/THF, 2 eq. 13.6 mL) in THF (15 mL) was added 2,2-dimethylcyclohexanone (1.88 mL, 13.6 mmol) at −78° C. The reaction was stirred for 15 minutes, and then the intermediate obtained in Step A (3 g, 11.4 mmol) was added dropwise. The reaction was stirred overnight and allowed to warm to room temperature. To the crude product was added acetic add (19.4 mL), ammonium acetate (2.62 g, 34.0 mmol) and copper acetate (5.14 g, 28.3 mmol). The reaction mixture was heated at 100° C. and the THF was removed by distillation. The reaction was heated to 130° C. and allowed to reflux for 24 hours. Ethyl acetate (100 mL) was added and washed with sodium bicarbonate (2×30 mL), water (2×20 mL), brine (2×20 mL), dried with MgSO4, filtered, and concentrated to afford an oil. Flash chromatography (5% ethyl acetate/hexane) afforded a white solid (1.36, 3.7 mmol, 32%). 1H NMR (300 MHz, CDCl3): δ 7.17 (m, 2H), 7.08 (m, 2H), 3.98 (q, J=7.4 Hz, 2H), 3.03 (septet, J=7.0 Hz, 1H), 2.35 (t, J=5.9 Hz, 2H), 1.70 (m, 4H), 1.36 (s, 6H), 1.31 (d, J=4.1 Hz, 6H), 0.965 (t, J=7.4 Hz, 3H). FAB-MS: calculated for (C23H28FNO) 369, found 370 (M+H. mp 124-126° C. Rf=0.6 (50% CH2Cl2/hexane).

Provenance & Evidence