8-Hydroxyquinoline → tert-Butyl 6-methyl-8-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

Participants

Reaction Conditions

Reaction Steps

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.17 g, 0.44 mmol), 4-(6-(methyl)pyridin-3-yl)pyridin-2(1H)-one (90 mg, 0.48 mmol) and Cs2CO3 (0.14 g, 0.44 mmol) were suspended in DMSO (2.5 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (19 mg, 0.13 mmol) and copper iodide (0.12 g, 0.66 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with (5.0:3.5:1.5) NH4Cl(aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (20 mL), and the resulting solution was washed with (5.0:3.5:1.5) NH4Cl(aq.)/NH4OH/H2O (2×20 mL). The resulting 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 2 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 preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (53 mg, 25%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.10-8.08 (m, 1H), 7.76 (d, J=6.5 Hz, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.03-7.01 (m, 1H), 6.84 (s, 1H), 6.71 (d, J=7.0 Hz, 1H), 4.60 (s, 2H), 3.77-3.66 (m, 5H), 3.01-2.99 (m, 2H), 2.54 (s, 3H), 1.99-1.86 (m, 2H), 1.36-1.30 (m, 9H).

Provenance & Evidence