Acetone → 3-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

Participants

Reaction Conditions

Reaction Steps

Ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (1.05 g, 2.471 mmol, Example 58C) was dissolved in THF (100 mL) in a 250-ml round bottom flask and cooled to 0° C. Methylmagnesium bromide (1.4 M solution in 25%THF+75%toluene) (26 mL, 36 4 mmol) was added and the mixture stirred at 0° C. for 1 hour, than the reaction was allowed to warm to room temperature during 1 hour. The reaction mixture was cooled to −78° C. and excess Grignard reagent quenched by the addition of acetone (5 mL, 68.1 mmol). The mixture was stirred for 30 minutes at -78° C., then quenched with sat. aq. NH4Cl solution (at −78° C.). The flask was transferred into a water/ice bath and stirred for 10 minutes. The reaction mixture was poured into a separating funnel loaded with water and ethyl acetate. The layers were separated, the aqueous extracted once more with EtOAc (pH of aqueous ˜9) The organic layer was washed once with water, once with brine, then dried over Na2SO4, filtered and concentrated in vacuum. (bath temp <30° C.). The crude product was purified by flash column chromatography on silica (25 g BIOTAGE® cartridge, eluent gradient from 5% EtOAc in DCM to 75% EtOAc in DCM during 96 fractions a 21 ml). Product eluted in fractions 57-80. Product containing fractions were combined and evaporated to give 395.5 mg 3-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide. 1H NMR (DMSO-d6) δ ppm 11.38 (s, 1H), 8.48 (d, 1H, J=1.8), 8.22 (b, 1H), 8.09-8.09 (m, 2H), 7.88 (d, 1H, J=1.0), 7.54 (b, 1H), 7.33 (dd, 1H, J=8.3, 1.5), 5.05 (s, 1H), 1.52 (s, 6H). MS (ESI) m/e+=347/349 (1 Br isotope pattern) consistent with [M+H]+ and m/e+=330/332 (1 Br isotope pattern) consistent with [M+H−NH3]+. HPLC retention time 9.89 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).

Provenance & Evidence