In this paper, a new and efficient method was developed to prepare 2-aminothiophene derivatives through improved Gewald reaction. Thirty-one final products were synthesized under microwave radiation for 30 min with 57%-95% isolated yields. All the products could be used as building blocks in drug discovery.2-Aminothiophenes are important organic intermediates, which are often found in drug research. 1,2 Due to the broad activities of the derivatives including anti-microbial, anti-tumor, anti-oxidation, and anti-inflammatory, it has been greatly interested in development of new 2-aminothiophenes for organic chemists and medicinal chemists. [3][4][5] In 2013, Davis reported a new drug candidate CaCCinh-A01, 6 which was used as inhibitor for treatment of glioblastoma. In addition, Ballatore studied ATTZ-15 and 2-TCU 7 in the next year, which were performed significant effects in neurological diseases. Recently, Sim also developed a series of 2-aminothiophene-3-carboxamide derivatives as calcium-activated chloride ion channel blockers. 8