2-Chloro-1-methyl-1H-imidazole

A literature procedure for the synthesis of the title compound was adopted.1 A solution of N-methyl-1H-imidazole (1.5 mL, 1.56 g, 19 mmol) in anhydrous THF (12 mL) was cooled to -78 °C and n-BuLi (2.5 M in hexanes, 14 mL, 21 mmol) was added dropwise by syringe understirring. The resulting yellow solution was stirred for 30 minutes where upon a solution of hexachloroethane (5.00 g, 21 mmol) in anhydrous THF (12 mL) was added dropwise by syringe resulting in the formation of a pale grey solid. The reaction mixture was stirred for 1h at -78 °C, then a saturated solution of aqueous ammonium chloride (25 mL) was added.The resulting mixture was allowed to return at room temperature, and diluted with ethylacetate (150 mL). The organic layer was separated, washed with water and brine, and driedover anhydrous Na2SO4. After filtration, the solvents were evaporated under reducedpressure, the residue was dissolved in hexane (50 mL) and HCl (20percent, 50 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes, then the organic layer was separated and extracted with HClStep A: Preparation of 2-Chloro-1-methyl-1H-imidazole. To a 300-mL, three-necked, round-bottomed flask equipped with a magnetic stirrer, and nitrogen inlet was added N-methylimidazole (4.1 g, 0.05 mol) and anhydrous THF (25 mL). The stirrer was started and the solution was cooled to -78° C. n-BuLi (2.5 M in hexanes, 22 mL, 0.055 mol) was added via syringe resulting in a golden yellow solution. This solution was stirred for 30 min whereupon a solution of hexachloroethane (13 g, 0.055 mol) in THF (25 mL) was slowly added via syringe. The reaction mixture was stirred for 1 h and then was quenched with satd. aq. NHTo a solution of 1-methyl-1H-imidazole (200 g, 2.44 mol) in anhydrous THF (2 L) was added dropwise n-BuLi (2.5M, 1.07 L, 2.68 mol) at -78 ° C with stirring over 2 h. Then perchloroethane (800 g, 0.845 mol) in dry THF (1L) was added dropwise to above solution over 1h at the same temperature. After the starting material was consumed, the mixture was poured into saturated ammonium hydrochloride, extracted with ethyl acetate (800 mL x 3), washed with brine, the organic phase was dried and concentrated to give crude product which was purified by column chromatography on silca gel (PE/ EtOAc = 20:1~5:1) to give the title compound (170 g, 60percent) as a yellow oil.Step C: (2-Chloro-3-methyl-3H-imidazol-4-yl)-(4-chloro-phenyl)-methanone. To a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and an addition funnel was added General procedure: To a solution of 2-disubstituted 1-methyl-1H-imidazole 1 (1 mmol) in DMF (5 mL), NBS(169 mg, 0, 95 mmol) was added and the resulting reaction mixture was stirred in the dark at room temperature for 3h. Then, Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 2 mol%), CuI (8 mg, 0.04mmol, 4 mol%), an alkyne 3 (1, 1 mmol) and piperidine (300 muL, 255 mg, 3 mmol) were added and the resulting reaction mixture was stirred at 80C (when trimethylsilylacetylene was employed as the alkyne, the reaction was carried out at 50C) for 3 h. The reaction mixture was diluted with EtOAc (100 mL), then saturated aqueous NH4Cl (100 mL) was added. The resulting mixture was stirred for 30 minutes and extracted with EtOAc (3x 25mL). The organic extracts were washed with water (3 x 25 mL) and brine (1 x 25 mL), driedover anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatogaraphy on silica gel. This procedure was employed to prepare compounds 4a-l. GLC analysis showed that all these compounds had chemical purity higherthan 98%.A literature procedure for the synthesis of the title compound was adopted.1 A solution of N-methyl-1H-imidazole (1.5 mL, 1.56 g, 19 mmol) in anhydrous THF (12 mL) was cooled to -78 C and n-BuLi (2.5 M in hexanes, 14 mL, 21 mmol) was added dropwise by syringe understirring. The resulting yellow solution was stirred for 30 minutes where upon a solution of hexachloroethane (5.00 g, 21 mmol) in anhydrous THF (12 mL) was added dropwise by syringe resulting in the formation of a pale grey solid. The reaction mixture was stirred for 1h at -78 C, then a saturated solution of aqueous ammonium chloride (25 mL) was added.The resulting mixture was allowed to return at room temperature, and diluted with ethylacetate (150 mL). The organic layer was separated, washed with water and brine, and driedover anhydrous Na2SO4. After filtration, the solvents were evaporated under reducedpressure, the residue was dissolved in hexane (50 mL) and HCl (20%, 50 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes, then the organic layer was separated and extracted with HClaq 20% (2 x 10 mL). The collected acidic aqueous extracts were neutralized with solid KOH, filtered and extracted with diethyl ether (3 x 25mL). The organic extracts were then concentrated under reduced pressure to afford the desired product 1e (1.97 g, 90%).Step A: Preparation of 2-Chloro-1-methyl-1H-imidazole. To a 300-mL, three-necked, round-bottomed flask equipped with a magnetic stirrer, and nitrogen inlet was added N-methylimidazole (4.1 g, 0.05 mol) and anhydrous THF (25 mL). The stirrer was started and the solution was cooled to -78 C. n-BuLi (2.5 M in hexanes, 22 mL, 0.055 mol) was added via syringe resulting in a golden yellow solution. This solution was stirred for 30 min whereupon a solution of hexachloroethane (13 g, 0.055 mol) in THF (25 mL) was slowly added via syringe. The reaction mixture was stirred for 1 h and then was quenched with satd. aq. NH4Cl (25 mL). The cooling bath was removed and when the reaction flask reached rt the contents were transferred to a 500 mL separatory funnel, washing with EtOAc (150 mL). The organic layer was separated, washed with water, brine, and dried over anhydrous Na2SO4. After filtration, the solvents were evaporated under reduced pressure resulting in an oily residue. This crude product was distilled under reduced pressure to afford 2-chloro-1-methyl-1H-imdazole (4.75 g, 80%) as a colorless liquid. bp 54 C./2 Torr. IR (film): 1515, 1420, 1367, 1277, 1127, 912, 740, 689, 665 cm-1. 1H NMR (400 MHz, CDCl3): delta6.92 (d, J=1.5 Hz, 1H), 6.85 (d, J=1.5 Hz, 1H), 3.55 (s, 3H). 13C NMR (100 MHz, CDCl3): delta132.4, 128.0, 122.3, 33.5. HRMS (EI): m/z calcd for C4H6ClN2 [M+H]+, 117.0223; found, 117.0220To a solution of 1-methyl-1H-imidazole (200 g, 2.44 mol) in anhydrous THF (2 L) was added dropwise n-BuLi (2.5M, 1.07 L, 2.68 mol) at -78 C with stirring over 2 h. Then perchloroethane (800 g, 0.845 mol) in dry THF (1L) was added dropwise to above solution over 1h at the same temperature. After the starting material was consumed, the mixture was poured into saturated ammonium hydrochloride, extracted with ethyl acetate (800 mL x 3), washed with brine, the organic phase was dried and concentrated to give crude product which was purified by column chromatography on silca gel (PE/ EtOAc = 20:1~5:1) to give the title compound (170 g, 60%) as a yellow oil.To a solution of General procedure: To a solution of

Molecular Weight:116.55
XLogP3:0.1
Hydrogen Bond Acceptor Count:1
Exact Mass:116.0141259
Monoisotopic Mass:116.0141259
Topological Polar Surface Area:17.8
Heavy Atom Count:7
Complexity:66.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes