A tandem method for the synthesis of 2-hydrazolyl-4-thiazolidinones (5) from commercially available materials in a 3 component reaction has been developed. The reaction connects aldehydes, thiosemicarbazides and maleic anhydride, effectively assisted by microwave irradiation. The synthesis of a new type of compound, 2-hydrazolyl-5,5-diphenyl-4-thiazolidinone (7), obtained by treatment of thiosemicarbazone with benzil in basic media is also reported. HOMO/LUMO energies, orbital coefficients and charge distribution were used to explain the proposed reaction mechanism.Keywords 2-hydrazolyl-4-thiazolidinones; 2-hydrazolyl-5; 5-diphenyl-4-thiazolidinones; microwave; tandem reactions 4-Thiazolidinones are an important group of heterocycles found in numerous natural products and pharmaceuticals. 1 In particular, 2-hydrazolyl-4-thiazolidinones (5) are a class of compounds that combine thiosemicarbazones with 4-thiazolidinones, two building blocks with interesting biological activities. For example, Trypanosoma cruzi ,2 Plasmodium falciparum3 and antitumor 4 activities have been described for thiosemicarbazones, and COX-2 inhibition, 5 anti-HIV, 6 and antibacterial 7 effects as well as human chondrocyte antidegenerative 8 properties have been found for 4-thiazolidinones. In addition, the combination of these two pharmacophores has been used to exhibit anti-Toxoplanma Gondii ,9a antimicrobial, 9b antiviral, 10 and antifungal properties. 11Among the reported methods for 2-hydrazolyl-4-thiazolidinone synthesis is a 2 step sequence: 1) a reaction between aldehydes (1) and thiosemicarbazides (2) to give thiosemicarbazones (3); 2) a thia-Michael addition of thiosemicarbazones (3) to maleic anhydride in dry PhMe and DMF at reflux to give the hydrazolyl-4-thiazolidinone (5) (Scheme 1). 9 As a part of our search for new biologically active heterocyclic compounds, we focused on the possibility of optimizing this procedure by developing a tandem microwave-assisted reaction sequence.Multi-step or cascade reactions can be defined as the combination of two or more reactions in a specific order that occur in one pot. 12
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript traditional single-step processes, the reaction and product isolation are carried out independently and repeatedly to synthesize the target compounds. The former process allows a minimization of waste, and, compared to stepwise reactions, the amount of solvent, reagents, adsorbents, and energy is extensibly decreased. 13 The use of microwave ovens to perform organic synthesis has received a great deal of attention over the last 10 years. Several publications have shown that microwave irradiation can circumvent the need for prolonged heating, 14 and it is generally accepted that this source of energy minimizes side reactions and accelerates the rate of chemical reactions. 15 Herein, we wish to report an efficient tandem procedure for the synthesis of 2-hydrazolyl-4-thiazolidinones under microwave conditions. Different solvents and va...