5-Chloro-1H-imidazole

Off-White to Pale Yellow Solid

Imidazole (10 g, 0.150 mol) and sodium hydroxide (29.4 g, 0.74 mol) were charged to the reaction flask containing water (250 mL) and stirred vigorously for 15 min at ambient temperature. Step 1.A mixture of 4, 6-dichloropyrimidine (1.8 g, 12mmol), 4-chloro-IH-imidazole (1.23 g, 12.00 mmol), andcesium carbonate (3.91 g, 12.00 mmol) was stirred in DMF (8mL) at room temperature for 18 h. The reaction was dilutedinto water and extracted with EtOAc. The combined organiclayers were concentrated and purified by flash chromatographyon a 120 g silica gel cartridge with 0 to 40% ethyl acetatein hexane to yield 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (1.41 g, 54.6% yield). The positive identificationof the A solution of 2-chloro-l-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (550 mg; 1.74 mmol) and 4- chloroimidazole (214 mg; 2.09 mmol; 1.20 eq) in dry acetonitrile (5.0 mL) was stirred at 80C for 20 h, then at 130C for 1 h under microwave irradiation. Thereafter the reaction mixture was allowed to cool down to room temperature, diluted with water, the organic layer was washed with saturated aqueous sodium bicarbonate, dried (MgSO i) and concentrated to dryness in vacuo. The oily residue was purified by chromatography over silica gel, eluted with a mixture of w-heptane/ethyl acetate (100:0 to 0: 100). After evaporation of the solvents, a second purification by preparative HPLC was performed. Evaporation of the solvents in vacuo afforded 141 mg (21%) of l-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-(5-chloroimidazol- l-yl)ethanone as a colourless solid. MS (ESI): 381.0 ([M+H]+)A magnetically stirred mixture of 4-chloro-1H- imidazole (15.0 g, 146 mmol), i, 2-difluoro-4-nitrobenzene (30 g, 189 mmol), and K2C03 (20.22 g, 146 mmol) in DMSO (50 mE) was heated at 80 C. for 4 h. The resulting dark black solution was allowed to cool to RT. The reaction contents was poured into 800 mE water and vigorously stirred for 15 mi An orange preceipitate immediately crashed out and was collected to give 4-chloro-i-(2-fluoro- 4-nitro-phenyl)-1H-imidazole (34.6 g, 98%). 'H NMR (500 MHz, CHEOROFORM-d) oe 8.23-8.16 (m, 2H), 7.81-7.78 (m, 1H), 7.61-7.56 (m, 1H), 7.26-7.25 (m, 1H). ECMS M+H=242.07.A solution of To a solution of To a solution of 4-Chloro-lH-imidazole (100 mg, 0.975 mmol) was dissolved in DMF (2 mL) in a vial in an ice bath, and purged with nitrogen for 10 min. With the solution at 0 C, sodium hydride (60% dispersion in mineral oil) (50.7 mg, 1.268 mmol) was added and the solution stirred for 30 min. A solution of benzyl bromide (0.139 mL, 1.170 mmol) in DMF (2 mL) was added dropwise. Once all the reactant was added, the reaction mixture was allowed to warm to RT and stirred overnight under an atmosphere of nitrogen. The mixture was quenched with MeOH (0.5 mL) and the solvent removed under a stream of nitrogen. The samples were dissolved in 1 : 1 MeOH :DMSO (3 mL) and purified by MDAP (Method C). The solvent was removed in vacuo to afford the title compound as the minor regioisomer, an off-white solid (38 mg, 0.20 mmol, 20%). LCMS (System B): tET = 0.92 min; MH+ 193, 195.4-Chloro-lH-imidazole (2 g, 19.51 mmol) and potassium carbonate (5.39 g, 39.0 mmol) were added to a round bottomed flask containing a stirrer bar, followed by addition of DMF (25 mL). The reaction mixture was placed under an atmosphere of nitrogen by evacuation-refill, and a solution of (2-(chloromethoxy)ethyl)trimethylsilane (6.91 mL, 39.0 mmol) in DMF (25 mL) added dropwise, before stirring at RT for 3.5 h under an atmosphere of nitrogen. The reaction mixture was quenched with 20 mL water, and the solvents removed under reduced pressure. The residue was dissolved in 50 mL EtOAc, and washed with 30 mL water, then 30mL brine. The organic layer was passed through a hydrophobic frit and the solvent removed under reduced pressure. The sample was loaded in a minimum of DCM and purified by gradient elution column chromatography using a 120g silica (Si) cartridge eluting with an ethyl acetate-cyclohexane solvent system [0%, 1CV; 0-30%, 15CV]. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a pale yellow oil (2.37 g, 10.2 mmol, 52%). LCMS (System B): tRET = 1.15 min; MH+ 233, 235.

Molecular Weight:102.52
XLogP3:1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:101.9984758
Monoisotopic Mass:101.9984758
Topological Polar Surface Area:28.7
Heavy Atom Count:6
Complexity:48.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes