N-bromobutanimide → (E)-4-bromo-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester

Participants

Reaction Steps

A solution of (E)-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (prepared as in Example 239, 0.500 g, 1.80 mmol) in dichloromethane (50 mL) was treated with N-bromosuccinimide (0.350 g, 1.97 mmol) and 2,2′-azobis(2,4′-dimethylvaleronitrile) (0.045 g, 0.18 mmol) and heated to reflux for 5.5 h under a nitrogen atmosphere. The mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) to afford (E)-4-bromo-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester which was immediately dissolved in acetonitrile (30 mL) and treated with (S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide (0.341 g, 1.64 mmol) and N,N-diisopropylethylamine (0.230 g, 17.9 mmol). The resulting mixture was sealed in a tube and heated at 90° C. for 14 h. The mixture was cooled to room temperature and partition between water and ethyl acetate. The layers were separated and the ethyl acetate layer was concentrated in vacuo. The residue was purified by consecutive flash column chromatography (silica gel, 0% to 50% ethyl acetate/hexanes; silica gel, 0% to 30% ethyl acetate/dichloromethane) and the material obtained dissolved in tetrahydrofuran. The mixture was sealed in a tube and heated at 160° C. for 19 h. At this time, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (67 mg, 9%) as a white solid: HR-ES-MS m/z calculated for C24H30N4O4 [M+H]+ 439.234, observed 439.2341; 1H NMR (300 MHz, CDCl3) δ ppm 1.01 (d, J=6.3 Hz, 3H), 1.03 (m, J=6.3 Hz, 3H), 1.24 (s, 6H), 1.55-1.72 (m, 1H), 1.68-2.06 (m, 3H), 2.79 (s, 2H), 4.12 (d, J=18.1 Hz, 1H), 4.25 (d, J=18.1 Hz, 1H), 4.93 (dd, J=8.8, 6.6 Hz, 1H), 5.01 (s, 1H), 7.09 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 8.27 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 9.09 (s, 1H), 9.49 (s, 1H).

Provenance & Evidence