Microwave-Assisted Synthesis of 1,3-Thiazolidin-4-ones and 2-Aryl-1,3-oxathiolan-5-ones

Abstract

A microwave-enhanced, rapid, three-component one-pot condensation method has been developed for the synthesis of 1,3-thiazolidin-4-ones using toluene in open vessels at atmospheric pressure. Applying this methodology, eleven 1,3-oxathiolan-5-ones were also synthesized in good yields. Thiazolidinones belong to an important group of heterocyclic compounds possessing diverse biological activities such as insecticidal, anticonvulsant, tuberculostatic, antiinflammatory, antiviral, etc. [1]. The anti-HIV biological activity of thiazolidinones has been associated with the ability to assume “butterfly-like” conformation [2-4]. These compounds have been previously prepared from three components (an aldehyde, an amine and mercapto acetic acid), by various oneand two-step syntheses [1]. Such reactions have also been carried out using microwave irradiation [5,6]. The reactions proceed by initial imine formation, which undergoes attack by the sulfur nucleophile, followed by intramolecular cyclization on elimination of water. The most common protocol to remove the water is by azeotropic distillation. Recently we published the formation of 4thiazolidinones by cyclocondensation reactions of an aminoacid, arenealdehydes and mercaptoacetic acid in moderate to good yields [7-9]. In the current work, we studied the formation of these heterocycles using microwave irratiation. *Address correspondence to this author at the Instituto de Tecnologia em Farmacos – Farmanguinhos FIOCRUZ. R. Sizenando Nabuco 100, Manguinhos, 21041-250, Rio de Janeiro-RJ, Brazil; E-mail: wjcunico@far.fiocruz.br Microwave irradiation is an alternative heating method based on the ability of compounds to transform electromagnetic energy into heat. This method, which can increase chemical reaction rates, yields and can form cleaner products, can be sucessfully applied in pharmaceutical chemistry [10,11]. Considering that MW irradiation using commercial domestic ovens has been recently used to accelerate organic reactions [12-14], we have compared the results of formation of 1,3-thiazolidin-4-ones and 1,3-oxathiolan-5-ones performed by the microwave-assited method and conventional procedures. The 1,3-thiazolidin-4-ones were synthesized from the reaction of arenealdehydes and valine with an excess of mercaptoacetic acid, using toluene in microwave oven, for six minutes (Scheme 1). When the nitrobenzaldehydes were used, the major products were 2-aryl-3-benzyl-1,3thiazolidin-4-ones 2a-c in excellent yields (Table 1). However, when 4-methoxyben-zaldehyde (entry 5) and 4fluorobenzaldehyde (entry 4) were used as precursors, a mixture of heterocycles 2, 3 and 4 was detected by GC and their separation was difficult due to similar retention times as stated in previous works (Table 1) [7,8]. CHO