Synthesis, X-ray analysis and computational studies of two novel thiophene derivatives

Thiophene is a core structure in many marketed drugs, such as Duloxetine, Tiotropium, Raloxifene, Dorzolamide, Tioconazole, Citizolam, Sertaconazole Nitrate and Benocyclidine. Thiophene derivatives are reported to have several types of pharmacological and biological activities. The synthesis of new thiophene derivatives is important to pharmaceutical research, because of their diverse pharmacological activities. The reaction of ethyl 3-oxobutanoate with carbon disulfide and chloroacetone in the presence of K₂CO₃ affords the unexpected thiophene derivative 7. Furthermore, refluxing compound 7 with dimethylformamide-dimethylacetal (DMF-DMA) in DMF affords the enaminone derivative 8. The structures of these newly synthesized compounds were confirmed by means of various spectroscopic techniques, such as IR, MS, and NMR, as well as by X-ray diffraction. In addition, B3LYP/6-311G(d, p) basis sets were employed to optimize the molecular geometry of the two thiophene derivatives. Furthermore, natural atomic charges and frontier molecular orbital analyses were performed. Hirshfeld analysis of the molecular packing showed that H—H, O—H, C—H, and S—H are the most common intermolecular interactions in both compounds. Further analysis suggests that the O—H interactions are the most significant of these in compounds 7 and 8.