A Facile, Mechanochemical, Solvent-, and Catalyst-Free Synthesis of Functionalized 4-Thiazolidinones

A highly eco-friendly greener approach based on the mech-anochemical method using mortar and pestle is explored for the preparation of a variety of functionalized 4-thiazolidinones. The developed methodology does not require the use of harmful or expensive reagents and organic solvents and requires very less reaction time with easy isolation. The explored greener approach for the synthesis of 4-thiazolidi-nones is an important in terms of their usefulness for their valuable pharmacological properties.

One of the main challenges for the medicinal chemistry is to develop the useful therapeutic agents for the treatment of various types of infections against increasing multidrug resistant microbial pathogens as well as applications against different disorders.In the literature, there are numerous small-membered biologically active molecules which has druglike properties.[7][8] The conventional methods for the preparation of 4-thiazolidinones involves the high-temperature conditions, the use of organic solvents, expensive catalysts, the use of column chromatography for the separation and purification process (Figure 1). 9,10The impact of global warming and interest towards the decrease in usage of harmful chemicals have encouraged researchers to revisit and further developing simple, economical, and environment-friendly pathways for the synthesis of the 4-thiazolidinone moiety.Keeping in mind, the biological activities of 4-thiazolidinones 1-8 (Figure 2) and realizing the importance of the green methodologies in organic synthesis, it was thought worthwhile to explore the greener methods for the preparations of functionalized 4-thiazolidinones.

Letter SynOpen
0][21] Since the reaction does not result in the formation of any byproduct, the yield of the reaction is also remarkably higher as compared to conventional methods employed.
Keeping in view of the diverse pharmacological profile of functionalized 4-thiazolidinones and the upsurge in their synthetic developments, [22][23][24][25][26][27] we have explored the facile and greener approach for the synthesis of functionalized thiazolidin-4-ones.The methodology involved the simple grinding method using mortar and pestle.The developed methodology did not involve the use of any expensive catalyst, solvent, or high-temperature conditions, and the reaction completed within few minutes.Moreover, the reaction did not result in the formation of any byproduct and afforded a variety of 4-thiazolidinone derivatives 1a-k in high yield.
The starting materials were procured commercially.The variety of functionalized amines and aldehydes were explored in the initial synthesis of the functionalized imines by traditional methods. 28The functionalized imines 4a-j were explored in the synthesis of functionalized thiazolidin-4-ones.The optimizations of the employed methodology were performed based on achieving better yields of the desired product as well as the time required to complete the reactions with varying the reaction conditions based on the amount of thioglycolic acid and anhydrous sodium sulfate (dehydrating agent).The investigated reaction model obtained after optimization of the model reaction for the synthesis of 2-(2-nitrophenyl)-3-phenylthiazolidin-4-one is represented in Table 1.It is evident that without the use of dehydrating agent the reaction was quite slow and resulted in poor yield (Table 1, entry 1).Further, the addition of sodium sulfate to the reaction mixture during grinding not only increased but also enhanced the product yield (Table 1, entry 2).It is evident that on further grinding the product yield was found to be marginally improved (Table 1, entry 3).Increasing the amount of thioglycolic acid and the dehydrating agent a product yield was reported (Table 1, entry 4).At last (Table 1, entry 5), grinding time-period was recorded and a maximum product yield of 95% was obtained after 12 min of grinding.0][31] A wide range of electron-withdrawing and electron-donating 2,3-diphenyl-substituted thiazolidin-4-one derivatives were obtained in good yield (Table 2, entries 1-11).However, in the case of glyoxal the desired thiazolidin-4-one derivative was not obtained probably due to steric crowding because of the presence of two thiazolidine-4-one rings (bis-thiazolidin-4-ones).The imines derived from aliphatic amine afforded better yield of thiazolidin-4-ones 1a-k (Table 2, entries 9-11).However, the imines with aryl substituents afforded slightly low yield of thiazolidin-4-ones 1 (Table 2, entries 1-8).However, the formation of thiazolidin-4-ones 1 did not occur using glyoxaldehyde as aldehyde counterpart of imine (Table 2; entry 12).All the prepared 2,3-diphenyl-substituted thiazolidin-4-ones 1a-k were characterized with the help of spectroscopic evidences.The 1 H NMR spectra of all prepared thiazolidin-4-ones 1a-k were confirmed by the presence of singlet peak of CH-bonded to substituted phenyl ring in the range of  = 6.14-6.44 ppm and a doubledoublet due to methylene hydrogens at  = 3.80-4.00ppm. 32The probable mechanism for the solvent-free synthesis of 2,3-diphenyl-substituted thiazolidin-4-one derivatives in illustrated in Scheme 2. The mechanism involved initial attack of nucleophilic nitrogen of amines to electrophilic carbonyl carbon of benzaldehydes with the release of a water molecule and the formation of a double bond.Further, nucleophilic sulfur of thioglycolic acid attacks the iminic carbon with the shifting of electrons followed by an attack of the nucleophilic nitrogen on the carboxylic carbon resulting in the formation of a thiazolidinone ring with release of a water molecule.Hence, the use of anhydrous sodium sulfate as mediator in the reaction absorbs the released water molecules thereby enhances and shifts the reaction in the forward direction.
Scheme 2 Proposed mechanism for the synthesis of 2,3-diphenyl-substituted thiazolidin-4-one derivatives In conclusion, the current manuscript describes the facile solvent-free and green mechanochemical approach for the synthesis of functionalized thiazolidin-4-ones.The employed green approach has a broader substrate scope and afforded the thiazolidin-4-ones in good yields in comparatively short reaction time with easy isolation.The current approach is also an important in terms of the diverse pharmacological profile of functionalized thiazolidin-4-ones.

Figure 1
Figure 1 Earlier methods for the formation of functionalized 4-thiazolidinones

Table 1
Optimization of the Reaction Conditions for the Synthesis of

Table 2
Substrate Scope in the Synthesis of 2,3-Diphenyl-Substituted a Isolated yields.