1 Introduction

Rhodanine heterocyclic skeletons are known to possess multiple biological activities, including the inhibition of numerous targets, such as PMT1 manosyl transferase [1], PRL-3 and JSP-1 phosphatases [2]. Classical methods for the preparation of alkylidine rhodanine need several steps and generally involve the preparation of the rhodanine moiety followed by a Knoevenagel condensation with aldehydes [3]. Recent methods are limited by the requirement of highly reactive functional groups in the substrates and by the fact that they do not proceed in smooth and mild conditions. Several methods have been reported for the synthesis of rhodanines [3]. However, they all rely on multistep reactions with either hard conditions or low yields, and the reaction times are long. Thus, the development of new synthetic methods remains an attractive goal.

Organic processes catalyzed by non-toxic magnetic nanoparticles (MNPs), such as Fe₃O₄ and Fe₂O₃, are often considered as following the principles of green chemistry, i.e. they consume a minimum of energy and reagents or auxiliaries, and minimize wastes [4]. Magnetic separation of MNPs is simple, economical and promising for industrial applications. From both economic and environmental viewpoints, organic reactions in aqueous medium using recoverable catalysts have gained attention in recent years [5].

For the above reasons, we were, thus, intrigued by the possibility of applying nano- and green chemistry to the design of an active, recyclable, and magnetically recoverable dispersed nano-γ-Fe₂O₃ catalyst in EtOAc-medium for the synthesis of alkyl rhodanines under mild reaction conditions.

2 Results and discussion

Recently, we have developed synthetic methods for the synthesis of biologically interesting heterocycles via multicomponent reactions [6]. The challenge in this field was to develop efficient and rapid green methods. Moreover, the synthesis of these heterocycles has usually been carried out in polar solvents, such as DMF and DMSO, leading to complex isolation and recovery procedures. Also, based on our recent success in the preparation of MNPs as catalysts [6], combined with our achievments in this area, we present, in this paper, the results of an extended investigation on the activity of dispersed γ-Fe₂O₃ in EtOAc-medium as a green magnetic separable nanocatalyst in a domino three-component process leading to the formation of alkyl rhodanines without any salts or additives. We have developed a synthetic method for the preparation of 5-oxo-2-thioxo-3-thiophenecarboxylate via the condensation of an aliphatic amine, carbon disulfide and the electron-deficient acetylene using a dispersed tecnique of small size (∼30 nm range, Fig. 1) of γ-Fe₂O₃ as the active catalyst. Herein, the condensation of benzyl amine, carbon disulfide and dimethyl acetylenedicarboxylate (DMAD) was selected to be the model (Table 1). Also, the MNP to form γ-Fe₂O₃ was synthesized by basic precipitation from the iron source [8].

Initial studies of the influence of the reaction conditions were carried out with the model reaction. By screening a wide range of iron sources, mol% of catalyst and different solvents and temperatures, we found that the product 3a could be obtained in yields ranging from 17 to 95% (entry 1–12, Table 1). When we have changed the amount of the catalysts from 5 mol% to 15 mol%, finding out that 10 mol% was enough for the best yield.

With these results in hand and to demonstrate the diversity of the dispersed MNPs (DMNPs) of γ-Fe₂O₃ as a nanocatalyst and to expand the scope of the process, the optimized conditions were applied to a series of substrates 1 and 2, as shown in Table 2.

The catalytic activity of γ-Fe₂O₃ in the domino three-component process for synthesizing rhodanine 3a and 4 was also studied under optimized conditions. When we set the reaction with a mixture of an aromatic amine (aniline) and an aliphatic amine (benzyl amine) in the presence of carbon disulfide and dimethyl acetylenedicarboxylate (DMAD), the yield of 3a was 89% after 15 min, without any detected product 4 (Scheme 1).

The possibility of recycling the dispersed magnetic catalyst was also studied. When the reaction was completed, the catalyst was easily separated from the product by attaching an external magnet onto the reaction vessel. As illustrated in Table 3, the catalyst could be still reused after the sixth run.

Although we have not established the exact mechanism for our method in an experimental manner, the following rationalization may be advanced to explain the product formation [6e,7]. Presumably, the γ-Fe₃O₄ stabilized zwitterion 5 from amine and carbon disulfide was attached by active acetylene to furnish a cumulene 6 or dithiocarbamate 7 intermediate. The final product 3a is produced by γ-Fe₃O₄ accelerated methanol elimination and cyclization of 6 or 7 (Scheme 2).

3 Conclusion

In summary, an extensive and systematic study allowed us to identify MNPs of γ-Fe₂O₃ as a heterogeneous, green and reusable catalyst for the synthesis of rhodanines via a domino process. This rapid, green method, in which the catalyst can be recycled, should be an interesting alternative to other synthesis methods. The method has several advantages, including high yields of products, recyclability of the catalyst, non-toxicity, easy experimental work-up procedure, and the fact that the catalyst is environmentally friendly.

4 Experimental

All the reagents were obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification. IR spectra were recorded on a Shimadzu IR- 460 spectrometer. The melting points were measured on an Electrothermal 9100 apparatus. The progress of reactions was monitored by thin layer chromatography (TLC).