Yield:-

Reaction Conditions:

with iodine;magnesium in tetrahydrofuran; for 3 h;Heating / reflux;

Steps:

4.6.2.11

Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. 3,5-dimethoxy-bromobenzene (2.0 g, 9.0 mmol) in THF (10 mL) was added to a mixture of magnesium turning (0.2 g, 9.0 mmol) in THF (5 mL) with a small piece of iodine. The resulting mixture was refluxed for about 3 h then cooled to room temperature for about 30 min. The (3,5-dimethoxyphenyl)magnesium bromide was then added slowly to a stirred solution of 1,2-dimethoxy-1H-benzoimidazole-5-carbaldehyde (1.3 g, 7.5 mmol) in THF (10 mL) at 0° C. After complete addition, the solution was allowed to stir at room temperature for about 1 h. The mixture was cooled to 0° C. and quenched with saturated NH₄Cl solution (40 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried (MgSO₄). Solvent was removed and the crude product was slurried in hexane to afford (3,5-dimethoxy-phenyl)-(1,2-dimethyl-1H-benzoimidazlo-5-yl)-methanol (2.1 g, 91%) as a off white solid: ¹H NMR (CDCl₃) δ 7.66 (s, 1H), 7.24-7.20 (dd, J=1, 8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 6.56 (d, J=2 Hz, 2H), 6.31 (t, J=2 Hz, 1H), 5.84 (s, 1H), 3.72 (s, 6H), 3.63 (s, 3H), 3.55 (b, 1H), 2.52 (s, 3H). A suspension of (3,5-dimethoxy-phenyl)-(1,2-dimethyl-1H-benzoimidazol-5-yl)-methanol (2.1 g, 6.7 mmol) and MnO₂ (2.9 g, 33.6 mmol) in CH₂Cl₂ (300 mL) was stirred at room temperature for 17 h. The mixture was filtered through celite and solvent was removed. The crude product was slurried with ether to afford (3,5-dimethoxy-phenyl)-(1,2-dimethyl-1H-benzoimidazol-5-yl)-methanone (2.0 g, 99%) as an off white solid: ¹H NMR (DMSO-d₆) δ 7.90 (s, 1H), 7.71-7.62 (m, 2H), 6.80 (s, 3H), 3.80 (s, 3H), 3.35 (s, 3H), 2.58 (s, 3H); ¹³C NMR (DMSO-d₆) δ 195.28, 160.17, 154.83, 141.54, 140.27, 139.15, 130.15, 123.50, 120.73, 109.70, 107.19, 103.62, 55.47, 29.96, 13.52. 3-(3,5-Dimethoxy-phenyl)-3-(1,2-dimethyl-1H-benzoimidazol-5-yl)-acrylonitrile (E and Z isomers) were prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (E and Z isomers) using (3,5-dimethoxy-phenyl)-(1,2-dimethyl-1H-benzoimidazol-5-yl)-methanone (2.0 g, 6.4 mmol), lithium bis (trimethylsilyl)amide (7.7 mL, 7.7 mmol) and diethyl cyanomethylphosphate (1.4 g, 7.7 mmol). The crude product was purified by flash chromatography (silica gel, CH₂Cl₂:CH₃OH 95:5) to afford mixture of isomers of 3-(3,5-dimethoxy-phenyl)-3-(1,2-dimethyl-1H-benzoimidazol-5-yl)-acrylonitrile (1.1 g, 50%) as a white solid: mp 199-201° C.; ¹H NMR (CDCl₃) δ 7.69 (m, 3H), 6.56-6.42 (m, 3H), 5.70 (5.74) (s, 1H), 3.77 (s, 3H), 3.73 (3.74) (s, 6H), 2.61 (s, 3H); ¹³C NMR (CDCl₃) δ 163.76 160.63 (160.60), 153.22 (153.54), 142.35 (142.57), 141.69 (139.43), 137.04 (137.38), 130.69 (132.54), 123.74 (122.64), 120.81 (119.54), 118.23 (118.09), 108.84 (108.80), 107.02 (107.72), 102.08 (102.02), 94.32 (93.47), 55.42 (55.41), 30.05 (30.00), 13.88; Anal Calcd for C₂₀H₁₉N₃O₂+0.2H₂O: C, 71.28; H, 5.80; N, 12.47. Found: C, 71.18; H, 5.86; N, 12.42.

References:

US2006/52596,2006,A1 Location in patent:Page/Page column 43-44