4-Methylmorpholine → HCID 20096939, compound

Participants

Reaction Steps

A solution of bromoacetyl chloride (2.00 mL, 24.2 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a cold (0° C.) mixture of 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 6.5 g, 24.2 mmol) and N-methylmorpholine (NMM; 2.7 mL, 24.2 mmol) in anhydrous dichloromethane (180 mL). The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h before additional 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (0.5 mL) and NMM (0.6 mL) were added to aid in completion. After 1 h, the mixture was washed with saturated sodium bicarbonate solution, 1N HCl and brine. Following drying and solvent evaporation, the residue was purified by flash chromatography on silica gel (gradient elution with 10% ethyl acetate in hexanes followed by 25% ethyl acetate in hexanes) and furnished 6.10 g (65%) of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone as a pale-yellow oil which was carried on directly. A portion of bromoacetoxy-1,2-di-(4-ethylphenyl)ethanone (3.15 g, 8.09 mmol) was treated with anhydrous sodium carbonate (0.86 g, 8.09 mmol), sodium iodide (0.12 g) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (2.0 g, 8.09 mmol) in anhydrous acetonitrile (120 mL) and the resulting mixture was heated to 80° C. for 5 h before it was cooled and concentrated down in vacuo. Purification of the residue by flash chromatography on silica gel with absolute ethyl acetate gave 3.40 g (76%) of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl) amino]carbonyl]-methyl]-1-piperazineacetate as pale-yellow foam. A portion of 2-oxo-1,2-di-(4-ethylphenyl)ethyl 4-[[[(2,6-dimethylphenyl)amino]carbonyl]-methyl]-1-piperazineacetate (2.50 g, 4.50 mmol) was dissolved in glacial acetic acid (75 mL) and ammonium acetate (1.65 g, 22.5 mmol) was added. The mixture was gently refluxed under nitrogen for 6 h before the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 1N sodium hydroxide solution (until basic) and the organic phase was separated, washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (gradient elution with ethyl acetate followed by 10% methanol in ethyl acetate) and yielded 0.61 g (22%) of the oxazole product I as a white solid and 0.85 g (30%) of the imidazole product I as a white solid after salt formation with ethereal hydrogen chloride.

Provenance & Evidence