8-Hydroxyquinoline → 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

Participants

Reaction Conditions

Reaction Steps

8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (0.20 g, 0.68 mmol), 4-benzyloxy pyridinone (0.18 g, 0.89 mmol), and Cs2CO3 (0.24 g, 0.75 mmol) were suspended in DMSO (4.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar and the process repeated. 8-Hydroxyquinoline (30 mg, 0.21 mmol) and copper iodide (0.17 g, 0.89 mmol) were added to the suspension, and the evacuation/Ar flushing process was repeated twice more. The reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) followed by flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 70:30 over 20 column volumes and held for 4 column volumes; increased to 25:75 over 10 column volumes) followed by trituration in hot EtOH provided the title compound (19 mg, 7%) as an off-white powder: mp 178-181° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.53 (t, J=5.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.00 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.21-3.10 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), 2.08-2.07 (m, 2H); ESI MS m/z 414 [M+H]+; HPLC (Method A) 97.2% (AUC), tR=16.5 min.

Provenance & Evidence