2,4,5-TRIBROMO-1-METHYL-1H-IMIDAZOLE

To a solution of N-methylimidazole (1.64 g, 19.97 mmol) and sodium acetate (25 g, 300 mmol) in acetic acid (180 mL) at room temperature was added bromine (9.6 g, 60.07 mmol) dropwise as a solution in 20 mL acetic acid. The resulting mixture was stirred for 2.5 h at room temperature. Acetic acid was removed in vacuo, the residue was suspended in 500 mL water and stirred at room temperature for 10 minutes. The resultant precipitate was filtered, washed with water and dried under high vacuum to give 2, 4, 5-tribromo-l-methyl- lH-imidazole (1.82 g, 29percent - some product remained in the mother liquor) as a light yellow powder. Used without further characterization. To a suspension of the tribromide (1.82 g, 5.71 mmol) in 45 mL water was added sodium sulfite (13 g, 103 mmol) and the resulting mixture was stirred at rapid reflux for 24 h. After cooling to room temperature, organics were extracted with ether (3 2-(2-Ethynyl-1 -methyl-1 H-imidazol-4-yl)-thiazole  To a solution of compound N-methylimidazole (65.6 g, 0.8 mol) in CHCl3 (1 .5 L), N-bromosuccinimide (NBS; 476g, 2.4 mol) was added in portion and then the mixture was stirred at roomtemperature for 1 .5 hour, filtered and concentrated, the residue was purifiedby column chromatography over silica gel (eluent: EA/PE 1/10) to afford 2, 4, 5-Tribromo-1 -methyl-1H-imidazole (63.76 g, 0.2 mol), which was dissolved in in dry THF (2L) andEtMgBr (220 ml_, 0.22 mol) was added slowly under NTo a solution of Example 69a (82 g, 1.0 mol) and sodium acetate (125 g, 1.52 mol) in acetic acid (2.0 L) at room temperature was added bromine (480 g, 30 mmol) dropwise as a solution in 1.0L acetic acid. The resulting mixture was stirred for 2.5 h at room temperature. Acetic acid was removed in vacuo; the residue was suspended in 1.5L water and stirred at room temperature for 10 minutes. The resultant precipitate was filtered, washed with water and dried under high vacuum to give Example 69b (95.0 g, contained 30percent isomer) as light yellow powder. LCMS [M+H]Step 1. 2, 4, 5-Tribromo-l-methyl-lH-imidazole (0975) [00314] To a suspension of sodium hydride (0.787 g, 19.69 mmol) in DMF (15 mL) was added 2, 4, 5-tribromo-lH-imidazole (5 g, 16.41 mmol) in DMF (10 mL) at ambient temperature. The mixture was stirred at 50 °C for 1 h, cooled to 0 °C, and treated with methyl iodide (1.128 ml, 18.05 mmol). The mixture was warmed to 50 °C and stirred 16 h, the DMF was removed under reduced pressure and EtOAc was added. The mixture was washed with water, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (eluting with a gradient of 10-80percent EtOAc/hexanes) afforded 4.87 g (94percent) of 2, 4, 5-tribromo-l -methyl- lH-imidazole. 1H MR (300 MHz, CDC1To a solution of Example 69b (84 g, 263.3 mmol) in dry THF (2L) was added EtMgBr (88 mL, 263.3 mmol, 3.0M in ether) slowly under N2.The reaction was stirred at r.t. for 2 hours. Then about 2.0L water was added and filtered concentrated and the residue was extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 69d (14.0 g) as white solid 'HNMR (400 MHz, Chloroform- ) delta 7.48 (s, 1H), 3.63 (s, 3H). Example 69c (14.0g) as white solid. NMR (400 MHz, Chloroform- ) delta 6.94 (s, 1H), 3.60 (s, 3H). A solution of Example 69c&d (2.4 g, 10.0 mol) in ether (100 mL) was cooled to -78° C. under nitrogen atmosphere and then a 2.5 M n-BuLi solution in hexane (4.0 mL, 10.0 mol) added dropwise over 15 mins. The mixture was stirred at -78° C. for 30min and then DMF (2.0 mL) was added dropwise over 15 min. The mixture was stirred at -78° C. for 30min and quenched with saturated IN HQ (50 mL) at -78° C. The residue was extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 69e (1.8 g, yield 95percent) as yellow solid. NMR (400 MHz, Chloroform-d) delta 9.77 (d, J = 0.9 Hz, 1H), 7.51 (s, 1H), 3.93 (s, 3H).To a solution of Example 69b (84 g, 263.3 mmol) in dry THF (2L) was added EtMgBr (88 mL, 263.3 mmol, 3.0M in ether) slowly under N2.The reaction was stirred at r.t. for 2 hours. Then about 2.0L water was added and filtered concentrated and the residue was extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 69d (14.0 g) as white solid 'HNMR (400 MHz, Chloroform- ) delta 7.48 (s, 1H), 3.63 (s, 3H). Example 69c (14.0g) as white solid. NMR (400 MHz, Chloroform- ) delta 6.94 (s, 1H), 3.60 (s, 3H).General procedure: [M(PPh3)4] (1.0 equiv.) was added as a solid to a toluene solution (15mL) of 1 or 2 (1.0 equiv.) in a Schlenk flask and was stirred overnight at room temperature. The solvent was removed under the vacuum. The resulted yellow residue was dissolved in DCM (2mL) and was precipitated by addition of n-pentane (15mL), filtered and dried in vacuum to afford the product as yellow powder.General procedure: [M(PPh3)4] (1.0 equiv.) was added as a solid to a toluene solution (15mL) of 1 or 2 (1.0 equiv.) in a Schlenk flask and was stirred overnight at room temperature. The solvent was removed under the vacuum. The resulted yellow residue was dissolved in DCM (2mL) and was precipitated by addition of n-pentane (15mL), filtered and dried in vacuum to afford the product as yellow powder.Step 2. 4-(4, 5-Dibromo-l-methyl-lH-imidazol-2-yl)benzonitrile (0977) [00315] To a solution of 2, 4, 5-tribromo-l-methyl-lH-imidazole (3.94 g, 12.36 mmol), (4- cyanophenyl)boronic acid (1.816 g, 12.36 mmol) and potassium carbonate (3.42 g, 24.72 mmol) in dioxane (40 mL) and water (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (0978) (0.714 g, 0.618 mmol). The mixture was degassed with nitrogen for 10 min, then heated to 90 (0979) °C for 16 h. After cooling to ambient temperature, EtOAc was added, the mixture washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (eluting with a gradient of 5-70percent EtOAc/hexanes) afforded 2.5 g (59percent) of 4- (4, 5-dibromo-l -methyl- lH-imidazol -2 -yl)benzonitrile. 1H NMR (300 MHz, CDC13) delta 7.74 (m, 4H), 3.75 (s, 3H). MS (ESI) m/z 342.00 [M+H]+.

Molecular Weight:318.79
XLogP3:3.1
Hydrogen Bond Acceptor Count:1
Exact Mass:317.78259
Monoisotopic Mass:315.78464
Topological Polar Surface Area:17.8
Heavy Atom Count:9
Complexity:110
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes