Pyridinium hydrobromide perbromide (198 g, 619 mmol) was added to a solution of 5 (195 g, 618 mmol)
in chloroform (1800 mL) and the mixture stirred at an internal temperature of 15-30˚C for 1 h. The
mixture was washed with water and 5% aqueous sodium bicarbonate solution, then concentrated. The
resulting residue was dissolved in ethanol at reflux, then cooled to 0˚C and stirred for 1 h. The resulting
crystals were isolated by filtration and dried to give 10 (216 g, 89%) as a slightly yellowish-white powder.
mp: 128-130˚C.12 HPLC assay: 96.0% (area). 1H NMR (400 MHz, DMSO-d6): δ 2.19 (1H, m), 2.40 (3H,
s), 2.53 (1H, m), 3.74 (1H, m), 4.13 (1H, dt, J = 4.8, 14.4 Hz), 4.93 (1H, dd, J = 4.4, 7.8 Hz), 7.30-7.62
(8H, m). 1H NMR (400 MHz, CDCl3): δ 2.16 (1H, m), 2.42 (3H, s), 2.66 (1H, m), 3.70 (1H, m), 4.36 (1H,
dt, J = 4.4, 14.8 Hz), 4.58 (1H, dd, J = 4.4, 7.6 Hz), 7.25-7.59 (8H, m). IR (KBr): 1697 cm−1. MS m/z:
394 (M+ +1).
2-Methyl-6-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (4)
Ethanimidamide monohydrochloride (14.5 g, 153 mmol) and potassium carbonate (21.2 g, 153 mmol)
were added to a solution of 10 (12.1 g, 30.7 mmol) in chloroform (480 mL), and the resulting mixture
stirred at reflux for 4 d, using Dean-Stark apparatus to remove water by azeotropic distillation. The
mixture was washed with water, then concentrated. The resulting residue was purified by column
chromatography on silica gel, eluting with CHCl3/AcOEt (2:1), then recrystallized in ethanol to provide 4
(5.71 g, 53%) as a slightly brownish-white powder and the oxazole, 2-methyl-6-[(4-methylphenyl)-
sulfonyl]-5,6-dihydro-4H-[1,3]oxazolo[4,5-d][1]benzazepine (3.04 g, 28%) as a slightly yellowish-white
1
powder. Imidazole (4): mp: 111-112˚C. HPLC assay: 99.6% (area). H NMR (400 MHz, DMSO-d6): δ
2.20 (3H, s), 2.30 (3H, s), 2.99 (2H, br s), 3.33 (2H, s), 7.12-7.41 (7H, m), 8.00 (1H, br s), 11.61 (1H, br
s). Anal. Calcd for C19H19N3O2S·0.5C2H6O·0.5H2O: C, 62.32; H, 6.01; N, 10.90; S, 8.32. Found: C,
62.32; H, 5.92; N, 10.86; S, 8.39. MS m/z: 354 (M+ +1). Oxazole: mp: 109-110˚C. HPLC assay: 98.2%
1
(area). H NMR (500 MHz, CDCl3): δ 2.29 (3H, s), 2.38 (3H, s), 2.82 (1H, m), 3.20 (2H, m), 4.60 (1H,
m), 7.02 (2H, d, J = 10.0 Hz), 7.27-7.35 (4H, m), 7.64 (2H, m). Anal. Calcd for C19H18N2O3S: C, 64.39;
H, 5.12; N, 7.90; S, 9.05. Found: C, 64.19; H, 5.08; N, 7.81; S, 9.03. MS m/z: 355 (M+ +1).
2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (11)
Imidazole (4) (3.00 g, 8.49 mmol) was heated in a mixture of acetic acid (9.3 mL) and concentrated
sulfuric acid (6.0 mL) at 70˚C for 51 h. The mixture was cooled, then water was added dropwise at 10-35
˚C. Ethyl acetate was added to the mixture, and the organic and aqueous layers were separated. The
aqueous layer was basified with 25% sodium hydroxide solution, and ethyl acetate was added to the
mixture. The organic layer was separated, then concentrated. The resulting residue was dissolved in ethyl
acetate at reflux, then cooled to 0˚C and stirred for 30 min. The resulting crystals were isolated by