1 Introduction

The development of the environment-friendly, non-toxic and energy-efficient methodology for the synthesis of organic molecules is a major attraction of current researchers. In this context, using novel, greener, and sustainable protocols, instead of older and traditional methods has been a major challenge from an ecological and economic point of view. One way to find the solution for this challenge is using a biodegradable catalyst and a greener solvent to carry out the chemical transformation without sacrificing the desirable outcome of the procedure.1,2,3,4,5

Recently, meglumine has been used as an extremely useful homogeneous catalyst in various organic reactions such as the synthesis of pyrazoles,6 2-amino-4H-pyrans,7 dihydropyrimidines,8 etc. Structurally, meglumine is a sugar alcohol derived from glucose molecules with a modified amino group on it. It possesses various advantages such as safe, stable, non-corrosive, easily available, economical, recyclable, non-inflammable, and having high heat capacity.9,10,11,12,13,14,15 Also, water as a reaction medium has gained much attention as it shows great diversity in the process of synthetic reactions.

The one-pot and single-step synthesis of Aza heterocyclicpyridines has captured a lot of attention of medicinal chemists in recent years due to their major impact on the drug discovery of complex, highly functionalized molecules.16,17,18 Among other triazole derivatives, 1,2,4-triazolidines-3 thiones derivatives have shown a vibrant pharmacological profile and have been surveyed deliberately for a variety of biological properties such as antiepileptic,19 anticancer,20 analgesic and anti-inflammatory,21 antiviral,22 anti-HIV,23 anti-tuberculosis,24 antidepressant,25 anticonvulsants,26 antimicrobial,26 antibacterial,27 and antiproliferative activities.28 Also substituted 1,2,4-triazolidines-3 thiones show therapeutic agents in the treatment of diabetes,29 influenza infection,30 and cancer metastatis20 (Figure 1).

Figure 1
figure 1

Pharmacologically active 1,2,4-triazoles.

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Further, its vital role in the growth and overall development of plants has brought an interesting application in the field of agrochemistry as well. Due to their multifarious applications and widespread interest, it has become the most important area of current synthetic chemistry.31Among all reported procedures for the synthesis of 1,2,4-triazolidines-3 thiones, the most convenient and straightforward method involves one-pot two-component cyclo-condensation of aromatic aldehydes or ketones with thiosemicarbazides utilizing various catalysts such as biomass husk derived activated carbon under metal-free conditions,32 Envirocat EPZ-10,33 L-proline,34 P-TSA,34 ceric ammonium nitrate,35 Sulfamic acid.34 Also, efficient ionic liquids like [(Py)2SO[HSO4]36 and [C16MPy]AlCl3Br37 in water as a solvent have been reported. Some of these procedures involve the use of solvents like Ethanol, Acetonitrile, PEG-400, DCM.38

Moreover, many of these protocols suffer drawbacks and limitations like poorer yield, use of harsh reaction conditions, expensive reagents, and longer duration. Therefore, inventing an efficient, environmentally benign, and cost-effective novel method is still in demand. In the course of our study and continuous interest in synthesizing heterocyclic molecules,39,40,41,42 we found a more convenient, efficient, milder reaction condition for the synthesis of 1,2,4, -triazolidines - 3 thiones, using meglumine as a reusable catalyst under aqueous conditions.

2 Experimental

2.1 Materials

All the chemicals were purchased from Sigma Aldrich, SD Fine chemicals, and Spectrochem companies. Thin-layer chromatography (TLC) was performed on 0.25 mm, silica gel 60F254 plates and viewed on UV light (254 nm). Nuclear magnetic resonance (1H NMR and 13C NMR) was recorded by using DMSO-d6 solvent on Agilent Technology (400 Mz), respectively, with Tetramethylsilane (TMS) as an internal standard. Mass spectra were recorded on the insertion probe on Agilent Technologies 5975 series. The melting point of all compounds was recorded on the AnalabThermoCal melting point apparatus in the one-end open capillary tube. All reagents used are analytically pure and directly without any further purification.

2.2 General procedure for the synthesis of 1,2,4-triazolidine-3-thiones

A mixture of aldehydes (1 mmol) or ketones (1 mmol) and thiosemicarbazide was stirred in water (8 mL) in the presence of meglumine as a catalyst (15 mol%) at room temperature for 5 min. The reaction was monitored by thin-layer chromatography. After completion of the reaction, the product was isolated by filtration, dried under vacuum, and recrystallized from ethanol to afford the pure product. The final confirmation of the product was done by spectroscopic methods 1H, 13C NMR, and MS. The filtrate-containing catalyst was isolated8 under the reduced pressure, and the recovered catalyst was then washed with diethyl ether and used at least four times without losing its catalytical activity as well as the yield of the product (Figure 2).

Figure 2
figure 2

Recycling of catalyst.

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2.3 Characterization

2.3.1 5-Phenyl-[1,2,4]triazolidine-3-thione (3a)

White solid; M.p. 152-153 °C (Lit43152-154 °C); 1H-NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.75 (d, J=6.4 Hz, 2H), 7.37-7.36 (m, 3H); MS: 179 (M+) (m/z).

2.3.2 5-Thiophene-2-yl-[1,2,4]triazolidine-3-thione(3c)

Yellow solid; M.p. 219-221 °C (Lit44 220-222 °C); 1H-NMR (400 MHz, DMSO-d6): δ 11.41 (s, 1H), 8.18 (d, J=21.1 Hz, 2H), 7.61 (d, J=5.0 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J=3.5 Hz, 1H), 7.10-7.05 (m, 1H). MS: 185 (M+) (m/z). Current approach for the synthesis of 1,2,4-triazolidine-3-thiones.

Scheme 1
scheme 1

Current approach for the synthesis of 1,2,4-triazolidine-3-thiones.

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2.3.3 5-methyl-5-phenyl-1,2,4-triazolidine-3-thione (5a)

White solid; M.p. 216-218 °C (Lit36 215-218 °C); 1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.23 (s, 1H), 7.88 (s, 3H), 7.35 (s, 3H), 2.46 (s, 3H); MS: 193 (M+) (m/z).

2.3.4 5-methyl-5-(p-tolyl)-1,2,4-triazolidine-3-thione (5b)

White solid; M.p. 175-177 °C (Lit45 175 °C); 1H NMR (400 MHz, DMSO-d6): δ 10.11 (s, 1H), 8.19 (s, 1H), 7.89-7.74 (m, 3H), 7.15 (d, J=8.0 Hz, 2H), 2.29 (s, 3H), 2.23 (s, 3H); MS: 207 (M+) (m/z).

2.3.5 1,2,4-triazaspiro [4.5] decane-3-thione (5c)

White solid; M.p. 156-157 °C (Lit47 156-158 °C); 1H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 2.35 (s, 2H), 2.23-2.12 (m, 2H), 1.54 (d, J=26.0 Hz, 6H); 13C NMR (100 MHz, DMSO-d6): δ 178.97, 157.47, 35.30, 27.60, 27.30, 26.11, 25.44; MS: 171 (M+) (m/z).

3 Results and Discussion

Initially, we commenced our experiment with a reaction of thiosemicarbazide (1) with benzaldehyde (2) as a model reaction stirred under the aqueous condition at room temperature in the presence of the meglumine as a catalyst. Surprisingly, within 5-6 mins, the pale white crude product was obtained, which was purified by recrystallization with ethanol and further characterized using different analytical techniques such as NMR, MS to confirm 1,2,4-triazolidine-3-thiones (3a).

Thus, to further determine the optimal reaction condition, we screened the different concentrations of meglumine in above model reaction. Initially, 5 mol% of meglumine at room temperature gives a trace amount of product even after 15 min of constant stirring. After carrying out the reaction with 8 mol%, 10 mol%, 15 mol%, 18 mol% of meglumine, it was observed that 15 mol% concentration of meglumine gives an excellent yield of 90% within 5 min of stirring at room temperature (Table 1).

Table 1 Solvent Optimization study.
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Then, the reaction condition was optimized under different solvents and also solvent-free conditions. Reaction in a neat environment does not show any formation of the desired product, while the use of different solvents such as ethanol, THF, methanol, acetonitrile gave lesser yield as compared to an aqueous environment. Consequently, 15 mol% concentration of meglumine under aqueous conditions at room temperature was considered as optimized reaction conditions for this procedure.

Table 2 Comparison of catalysts.
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The above-optimized reaction conditions were utilized to extend the scope of reaction to ketones as starting substrates instead of aldehydes and found to give satisfactory results. With the optimized reaction condition, different substituted aromatic aldehydes and ketones reacted smoothly with thiosemicarbazide and ended in excellent product yield (Table 3, 4). To show the versatility of the reported protocol, cyclic ketones like cyclohexanone (5c) and cycloheptanone (5g) and cyclic diketone such as isatine (5i), were allowed to react with thiosemicarbazide individually to give the respective desired products in an excellent yield. In the case of aromatic aldehydes, we have used five-membered heterocyclic rings, which do not show any changes in the final product under optimized conditions. Further, the reaction with a dialdehyde such as terephthaldehyde underwent satisfactorily to give the expected final compound when 2 equivalent of thiosemicarbazide is used (3k), while at 1 equivalent of thiosemicarbazide lower yield of the expected compound was observed. The other advantage of this protocol is the clean isolation of the product and catalyst, and the isolated catalyst further successfully recycled without affecting the yield of the product.

Table 3 Various aldehyde scaffolds of 1,2,4-triazolidine-3-thiones.a
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Table 4 Various ketone scaffolds of 1,2,4-triazolidine-3-thiones.a
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3.1 Plausible mechanism

As we used Meglumine as a catalyst for the synthesis of 1,2,4-triazolidine-3-thiones, the catalytic mechanism was shown in (Scheme 2). In our consideration, meglumine containing amine and hydroxyl groups play a significant role in promoting the reactions. In the initial step, meglumine increases the electrophilicity by protonating the carbonyl carbon of aldehyde (a) through hydrogen bonding (b), followed byanucleophilic attack of one of the amino groups of thiosemicarbazide to form an intermediate (c), which on the further loss of water molecules to gives imine product (d). Finally, another free amino group of thiosemicarbazide attacks on imine carbon. Their subsequent reaction, followed by intramolecular interaction, leads to cyclization to give the final desired product (e).

Scheme 2
scheme 2

Plausible mechanism.

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3.2 Comparative study

As per the previous literature, 1,2,4-triazolidine-3-thiones can be synthesized by various reaction models as shown in (Table 2), like glycin nitrate, DMAP, L-proline, ceric ammonium nitrate, etc., which was in the presence of aqueous as well as ethanol-treated with reactants. But here, we discover various drawbacks like using temperature or reaction time which was the main concern of our reaction model. From the study, it is evident that our current approach has numerous key features over others, including shorter reaction time, environmentally benign reaction, metal-free catalyst, simple purification methods, and high yield. Thus, all these factors contribute to the increase in its utility in the pharmaceutical industry.

4 Conclusions

In this report, we enclosed a highly efficient, one-pot. synthesis of 1,2,4-triazolidine-3-thiones by the cyclo condensation of an aldehyde or ketone with thiosemicarbazide at room temperature using meglumine as a catalyst in an excellent yield. The pure products were obtained by recrystallizing with ethanol. This reaction model offers numerous attractive features such as reduced reaction time, recovery, reusability of the catalyst, use of water as a solvent, and atom efficiency.