Tetrabutylammonium Fluoride → 5-(Thiophen-2-ylmethyl)imidazole-1-sulfonic acid dimethylamide

Participants

Reaction Conditions

Reaction Steps

2-(Tert-butyldimethylsilyl)-1-(dimethylsulfamoyl)imidazole (1) (3.3 g, 11.4 mmol) is taken up in 38 mL of anhydrous THF and cooled to −78° C. n-BuLi (7.2 mL, 11.4 mmol) is added dropwise to the solution of (1). The resultant solution is stirred at −78° C. for 30 min. 2-Furfural (2) (0.94 mL, 11.4 mmol) is added to the reaction. The reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) affords 4.4 g (11.4 mmol) of 2-(t-butyldimethylsilyl)-5-(furan-2-ylhydroxy-methyl)imidazole-1-sulfonic acid dimethylamide (3). (3) (4.4 g, 11.4 mmol) is taken up in 110 mL of THF and cool to 0° C. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (11.4 mL, 11.4 mmol) is added dropwise to the solution of (3). The reaction is stirred overnight at rt. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. 3.9 g of crude 5-(furan-2-ylhydroxymethyl)imidazole-1-sulfonic acid dimethylamide (4) is recovered. (4) (1.0 g, 3.7 mmol) is taken up in 37 mL of dichloromethane, to the solution is added 1.6 g (18.5 mmol) of manganese dioxide. The reaction is stirred at rt overnight and then filtered through celite. The eluent is collected and the solvent removed under reduced pressure. Flash chromatography using a 1:1 mixture of ethyl acetate and hexane affords 0.69 g (2.6 mmol) of 5-(furan-2-ylcarbonyl)imidazole-1-sulfonic acid dimethylamide (5). (5) (0.69 g, 2.6 mmol) is taken up in 26 mL of THF. The solution is cool to −78° C. 1.7 mL (5.1 mmol) of a 3M solution of methylmagnesium chloride is added. After stirring at −78° C. for 1.5 h reaction is warmed to rt and stirred for an additional hour. The reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Crystallization from ether/hexane affords 0.39 g (1.4 mmol) of 5-(1-furan-2-yl-1-hydroxyethyl)imidazole-1-sulfonic acid dimethylamide (6). An additional 0.19 g of (6) is recovered. (6) (0.58 g, 2.0 mmol) is taken up in 27 mL of dichloromethane, to the solution is added 2.6 mL (16.3 mmol) of triethylsilane and 5.5 mL (71.4 mmol) of trifluoroacetic acid. The reaction is stirred at rt overnight and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using a 2:1 mixture of ethyl acetate and hexane affords 0.53 g (2.0 mmol) of 5-(1-furan-2-ylethyl)imidazole-1-sulfonic acid dimethylamide (7). (7) (0.34 g, 1.3 mmol) is taken up in 10 mL of a 1.5N HCl solution and heated at reflux for 30 min and then stirred at rt overnight. The reaction is diluted with ethyl acetate and then made basic with 2N NaOH. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (10:1 chloroform/methanol) affords 0.1 g (0.62 mmol) of 4(5)-(1-furan-2-ylethyl)-1H-imidazole (8) (L).

Provenance & Evidence