Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

Abstract

Rhodanines and their derivatives are known to have many pharmacological activities that can be modulated through different functionalization sites. One of the most studied modification in those scaffolds is the introduction of a benzylidene moiety on C5 via a Knoevenagel reaction. Here, a facile synthesis of 5-arylidenerhodanines via a Knoevenagel reaction in an ʟ-proline-based deep eutectic solvent (DES) is reported. This method is fast (1 h at 60 °C), easy, catalyst-free and sustainable as no classical organic solvents were used. The expected compounds are recovered by a simple filtration after hydrolysis and no purification is required. Those derivatives were studied for their antioxidant activities and the results are consistent with those reported in the literature indicating that phenolic compounds are the more active ones.

L‐proline‐based DES in Knoevenagel synthesis of arylidene rhodanines, thiazolidine‐2,4‐diones, and barbituric derivatives

“…First, we used the conditions developed for rhodanine condensation with aldehydes (i.e., 0.8 g Proline:Glycerol (1:2), 0.5 mmole of aldehyde and 0.5 mmole of rhodanine, heating at 60°C for 1 h) [20] and applied them to rhodanine‐3‐acetic acid (Table 1). One more time, we do not use any volatile solvent as the reaction workup involved addition of water for separating the crude product from the aqueous phase containing the DES.…”

“…Compounds 1a-7a are described in Reference [20]. [33,36] Yellow solid obtained after 1 h at 60 C in 72% yield (117 mg).…”

“…The most common DES are based on choline chloride but others are also very powerful [17][18][19]. We recently used a L-Proline:Glycerol (1:2) DES to perform a Knoevenagel reaction on rhodanine and form 5-arylidenerhodanine derivatives in a zero VOC strategy [20]. In this former study, we have shown that this L-proline-based DES was the most effective DES compared to classical ChCl:urea and ChCl:glycerol DES.…”

How Can Deep Eutectic Systems Promote Greener Processes in Medicinal Chemistry and Drug Discovery?

“…A recent study carried out by Hesse [ 96 ] reported the preparation of rhodanine derivatives via Knoevenagel condensation using the eutectic system ChCl:U (1:2). The author was inspired by others’ work, where L-proline-based DESs were used as reaction media in Knoevenagel condensations for the synthesis of other classes of compounds.…”

Synthesis of (Z)-3-Allyl-5-(4-nitrobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one and Determination of Its Crystal Structure

“…Arylidene-functionalized rhodanines were also recently screened to evaluate their anticancer activity against several cancer cell lines [19,20] or their propensity as antibacterial, antifungal or antioxidants agents [21][22][23]. In this context, we have reacted a series of 4-arylidene-5-thioxo-thiazolidin-2-ones with the secondary cyclic amine tetrahydroisoquinoline (THIQ) to convert them to (Z)-5-ylidene-2-aminothiazol-4(5H)-ones [18].…”