1,2-Dibromoethane → Methyl 5-bromo-3-(2,2,2-trifluoroacetamido)thiophene-2-carboxylate

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Reaction Steps

To a stirred solution of i-Pr2NH (6.2 mL, 3.2 mmol) in THF (100 mL) in a dry ice-i-PrOH bath was added, dropwise, n-butyllithium (2.5 N in hexanes, 17 mL, 43 mmol). After 5 min, the mixture was placed in an ice-water bath. After an additional 5 min, the mixture was cooled in a dry ice-i-PrOH bath. To this stirred solution was added, dropwise over 2 min, a solution of the methyl 3-(trifluoroacetylamino)-2-thiophenecarboxylate (3.5 g, 14 mmol) in THF (15 mL). After 5 min, 1,2-dibromoethane (4 mL) was added in one portion. After 5 min, MeOH (3.5 mL) and saturated NaHCO3 (150 mL) containing sodium thiosulfate (5 g) were sequentially added. The mixture was removed from the cold bath and allowed to warm to room temperature whereupon EtOAc (250 mL) was added. After partition, the aqueous layer was extracted with EtOAc (2×100 mL). The three combined organic layers were washed with brine (2×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was absorbed onto Celite® 545 and chromatographed (12 g silica gel, 10% EtOAc-hexanes to 25% EtOAc/hexanes, 50 mL/min). The product-containing fractions were combined and rechromatographed (12 g silica gel, 10% EtOAc-hexanes, 50 mL/min) to provide methyl 5-bromo-3-(trifluoroacetylamino)-2-thiophenecarboxylate as a pale yellow solid 0.98 g (21%).

Provenance & Evidence