Deep eutectic solvents with ultrasonic energy as an environmentally benign and green approach for the synthesis of bisthioglycolic acid derivatives

The present methodology explored the effectiveness and versatility of deep eutectic solvent with ultrasonic energy as an eco-friendly protocol for the synthesis of bisthioglycolic acid derivatives. Bisthioglycolic moiety holds its role as a potent scaffold in sulfur-containing drugs. The presented strategy offers significant advantages such as green catalyst as well as solvent, excellent yield, short reaction time, and simple reaction workup. This methodology shows a wide range of substrate scope that contain both electron-donating as well as electron-withdrawing groups. GRAPHICAL ABSTRACT


Introduction
One of the challenging and active areas of research is to develop a greener and more atom-economical route for organic synthesis [1,2].In the past few decades, ultrasonic irradiations have been increasingly utilized in organic transformations and chemical synthesis.Ultrasound-assisted chemical reactions have been one of the promising pathways in environment-benign, economical, and green synthetic processes.It offers a large number of organic conversions with high to excellent yield under mild reaction conditions and short reaction time [3][4][5][6][7][8][9][10][11][12][13].Ultrasound irradiations have shown wide application in carbon-carbon and carbon-heteroatom bond formation [14][15][16][17][18][19].
Carbon-sulfur bond formation strategies are significant due to the importance of linkages in the sulfur-containing scaffolds which are found in biologically active compounds, natural products, and pharmaceutically important moieties [20][21][22].Sulfones, thioethers, and sulfonamides are common sulfur-containing scaffolds that are found in medicinal drugs [21,23].For instance, 1,3-oxathiolan-5-one has shown antiviral activity [24] and PLA2 inhibitory activity [25].Moreover, bisthioglycolic acid and its derivatives have been reported to play a significant role as a precursor in the formation of many sulfur-containing heterocyclic compounds [26,27].
Keeping in view the abovementioned significance of sulfur-containing heterocycles, Our research group also reported the mechanochemical synthesis of bisthioglycolic acid in good yields [28].In pursuit of finding an alternative route to these compounds, we in this paper present the application of ultrasound irradiation using deep eutectic solvents (DESs) for the fabrication of bisthioglycolic acid derivatives.DESs have been widely explored in the literature owing to their extraordinary properties like biodegradability, lower vapor pressure, good thermal stability, cost-effectiveness, easy workup, and high ionic conductivity [29].DESs exhibit dual behavior acting as solvent as well as catalyst in many reactions [30][31][32] including carbon-carbon and carbon-heteroatom bond-forming reactions [33][34][35][36].

Optimization of reaction conditions
In this study we used ultrasonic energy in the synthesis of bisthioglycolic acid derivatives using DES.Initially, the suitable reaction conditions were optimized in terms of the amount of the substrates, best green catalyst (DESs), optimal time duration, and yields.4-Chlorobenzaldehyde (1a) and thioglycolic acid (2a) were selected as the model substrates to obtain the corresponding bisthioglycolic acid (3a) using the different reaction conditions depicted in Table 1.
Initially, the model reaction was performed using only ultrasound irradiations (Entry 1, Table 1), but only gave 38% of the product.The same reaction was performed using different salts like ZnCl 2, AlCl 3 , and ChCl, which offered 56%, 30%, 25% yield of the product, respectively (Entry 2-4, Table 1).However, the use of ChCl/ZnCl 2 -DES (2mol%) and ultrasonic energy (Entry 5, Table 1) gave a moderate yield (65%) of the desired product within 2 min.An increase in the time duration of the exposure of the reaction to the ultrasonication energy to 3 min, appreciably improved the yield (82%) (Entry 6, Table 1).The increased amount of 2a also improved the yield of the product.For example, the yield of the product increased to 94% when the amount of 2a was increased from 2.0eq.to 2.5eq (Entry 7, Table 1).However, further increase in the amount of 2a from 2.5 eq. to 3.0eq did not show any significant increase in the yield of the product (Entry 8, Table 1).When the catalyst loading was decreased to 1mol% the yield decreased to 80% (Entry 9, Table 1).Upon increasing the loading of ChCl/ZnCl 2 -DES to 3mol%, there was a small dip in the yield to 91% (Entry 10, Table 1).Since, increasing or decreasing the catalyst loading from 2mol%, did not enhance the yield (Entries 8-10, Table 1), we used the same catalyst loading for the final reactions.To evaluate the competing role of ChCl/ZnCl 2 -DES, three different DESs, ChCl/Urea, ChCl/NH 4 OAc, and ChCl: malonic acid (1: 2) were also screened but the best results were obtained with ChCl/ZnCl 2 (Entries 11-14, Table 1).Moreover, an equimolar ratio (1: 2) of ChCl and ZnCl 2 was found to be superior over other DESs (ChCl: urea, ChCl: NH 4 OAc, and ChCl: malonic acid).
With these optimized conditions in hand, a variety of aldehydes were studied in their reaction with thioglycolic acid (Scheme 2).Several aldehydes including aromatic, hetero-aromatic, and aliphatic aldehydes smoothly provided very good to excellent yields(80-96%).Aromatic aldehydes reacted faster as compared to their aliphatic counterparts under the optimized conditions (Entries 1-13, Table 1).Particularly, the aromatic aldehydes bearing electron-withdrawing groups (3a-3f) are more reactive and gave higher yields (90-96%) than those bearing electron-donating groups (3h-3j) (Entry 1-6, & 8-10 &13 Table 2).After successfully investigating different aromatic aldehydes, we explored the potential of heteroaromatic and aliphatic aldehydes under our optimized reaction conditions (Entries 11-12 & 14, Table 2).Both heteroaromatic and aliphatic aldehydes also showed good reactivity towards thioglycolic acid.Delightfully, the attachment of heteroaromatic and aliphatic aldehydes did not hamper the reaction yield.Structures of all the synthesized compounds were characterized using proton ( 1 H), carbon ( 13 C) and IR spectroscopic techniques.For example, the proton NMR of 3i showed two characteristic singlets; one at δ 2.32 corresponding to the methyl group and another at δ 5.48 for a -CH proton confirming the condensation of thioglycolic acid with the aromatic benzaldehyde.Also, the appearance of 10 carbon resonances in the 13 C spectrum substantiated the assigned structure.Finally, the appearance of two characteristic IR absorptions at 1730 (C = O) and 1156 (C-O) cm −1 also supported the structure.A plausible mechanism has been proposed in the literature [38][39][40][41][42].Although the exact role of DES is not known, it may be that the acidic nature of DES triggers the synthesis of 3a.The DES initiates the reaction by forming a hydrogen bond with the carbonyl group.The ZnCl 3 − activates the 2a molecule by the abstraction of the proton from the -SH group.DES also activates the carbonyl group by increasing the electrophilicity of the carbonyl carbon (Scheme 3).Further, The activated 2a attacks on the aldehyde and the final product is obtained by the releasing of water molecules, zinc chloride, and choline chloride.
Only a few reports have been reported in the literature to date.All reports are summarized in Table 3.

Reusability of DES
For the greener, environmentally benign, and economic methodology, reusability and recycling of DESs (ChCl/ZnCl 2 ) are also important.Hence, the reuse of DESs was carried out by performing a chemical reaction of benzaldehyde and bisthioglycolic acid in ChCl/ZnCl 2 under ultrasonic irradiation.The DES was recovered and recycled by simple workup after the completion of the reaction.On completion of the reaction water was added to the reaction mixture, and the solid product was separated by filtration.Afterward, the DES was separated by evaporating the water and reused for another cycle.The results are summarized in Figure 1.

Optimized protocol-driven synthesis of 3a
An eco-friendly protocol was used for the preparation of 3a using ultrasound waves.Substrate 1 (1.0 eq.) and 2 (2.5 eq.) are sonicated in an ultrasonicator in the presence of ChCl/ZnCl 2 (1:2 molar ratio) (2.0 mol%).The reaction was monitored with the help of Scheme 3. A Plausible mechanism for the synthesis of bisthioglycolic acid.

Conclusion
In summary, we have explored a green and eco-friendly protocol for the synthesis of bisthioglycolic acid, which is an important key step for various pharmaceutical drugs.Notably, our catalyst showed a wide substrate scope towards aromatic, heteroaromatic, and aliphatic aldehydes using ultrasound waves.Aldehydes bearing electron-withdrawing groups provided excellent reactivity.We believe this methodology has remarkable characteristics such as simple reaction workup, the use of a green catalyst that also acts as solvent, shorter reaction time, and excellent yield.

Table 1 .
Optimization studies for synthesis of bisthioglycolic acid.
. Optimization of synthesis of bisthioglycolic acid.

Table 2 .
The synthesis of bisthioglycolic acid and its derivatives.

Table 3 .
Methods for the synthesis of bisthioglycolic acid (3a) to date.