Hydroquinone → 9-methyl-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole

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Reaction Conditions

Reaction Steps

Sodium dispersion in paraffin (30%, 46 mg, 0.60 mmol; Aldrich) was combined with 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (100 mg, 0.442 mmol; Example 2B) in a 20 mL vial with stir bar and septum cap. Dimethyl sulfoxide (2.5 mL) was added, and the vial was evacuated and purged with nitrogen (10 cycles). The mixture was stirred at room temperature for 10 minutes, and a solution of the product of Example 143A (115 mg, 0.663 mmol) and hydroquinone (12 mg, 0.110 mmol) in dimethyl sulfoxide (0.5 mL) was added. The vial was evacuated and purged with nitrogen (5 cycles) and the mixture was stirred with heating at 115° C. for 39 hours. The dark brown mixture was cooled to room temperature, applied directly to a column of silica gel and eluted with chloroform, followed by CHCl3—CH3OH-14.8 M aqueous NH4OH (90:10:1). The product-containing fractions were combined and concentrated under vacuum, and the residue was purified by HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-90% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ 1.46-1.64 (m, 2H), 1.79-1.98 (m, 2H), 2.38 (s, 3H), 2.84-3.01 (m, 3H), 3.05-3.22 (m, 4H), 4.16 (s, 2H), 4.42 (t, J=6.27 Hz, 2H), 6.89 (dd, J=8.48, 1.02 Hz, 1H), 7.09 (d, J=7.80 Hz, 1H), 7.10 (d, J=0.68 Hz, 1H), 7.54 (dd, J=8.10, 1.70 Hz, 1H), 7.59 (d, J=8.10 Hz, 1H), 8.12 ppm (s, 1H); MS (ESI) m/z 400 (MH)+.

Provenance & Evidence