The general procedure for the synthesis of methyl 2-amino-3,5-dimethylthiophene-3-carboxylate from 2-butanone and methyl cyanoacetate was as follows: sulfur powder (160.0 mg, 5.0 mmol) was placed in a single-necked flask and 1.5 mL of DMF was added to dissolve it. Methyl cyanoacetate (495.4 mg, 5.0 mmol) and morpholine (435.6 mg, 5.0 mmol) were then added sequentially, and the reaction solution immediately changed to dark brown color. Then 2-butanone (901.4 mg, 12.5 mmol) was added and the reaction mixture was stirred at 50 °C overnight. After completion of the reaction, the mixture was cooled to room temperature, diluted with an appropriate amount of water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give the crude product. Finally, the crude product was separated and purified by column chromatography to give a light yellow solid target compound in 40.7% yield.
