[C₁₆MPy]AlCl₃Br: an efficient novel ionic liquid for synthesis of novel 1,2,4-triazolidine-3-thiones in water

Abstract

An efficient novel ionic liquid, [C₁₆MPy]AlCl₃Br has been synthesized and explored as a catalyst for an eco-friendly synthesis of novel 1,2,4-triazolidine-3-thiones in water at ambient temperature. A variety of aldehydes undergo smooth reaction with thiosemicarbazide and substituted thiosemicarbazides. In the case of substituted thiosemicarbazides the corresponding 1,2,4-triazolidine-3-thiones are obtained as products instead of 1,3,4-oxadiazoles. A broad variety of functional groups are tolerated and a large number of substrates can be applied with this protocol. Rapid eco-friendly reactions with high yields, use of ambient temperature and water as a solvent, easy work-up procedure as well as isolation of product, excellent catalyst recyclability, high atom economy, novelty of ionic liquid as well as the protocol are the auxiliary advantages of the protocol.

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In the past decade, aqueous-mediated reactions have been extensively pursued due to their efficiency, atom-economy, non toxic nature, economy, ease isolation of product and green credentials.¹ By utilization of their unique physical and chemical properties it would be possible to realize reactivity or selectivity that cannot be attained in organic solvents.² The significant enhancement in the rate of the reaction in water has been attributed to hydrophobic packing,³ solvent polarity,⁴ hydration,⁵ and hydrogen bonding.⁶ Previously the scant solubility of the reactants and the sensitivity of chemical groups towards hydrolytic degradations were the main reasons that ruled this solvent out from studies.⁷ One of the solutions to circumvent this issue comprises the addition of a phase transfer agent or ionic liquids having surfactant property,^8a as surfactant increase the reactivity of aqueous mediated reactions via the formation of vesicular cavities or micelles with hydrophobic core and hydrophilic corona at ambient conditions.^8b If these surfactants based ionic liquids possess special features required for a particular reaction will attract attention of scientists. Thus, recently, the synthesis of task-specific ionic liquids (TSILs) has become an attractive field.⁹

Triazoles are an important class of heterocycles, the interest in their synthesis stems from their wide range of applications¹⁰ in pharmaceuticals, agro chemicals, dyes, photographic materials, corrosion inhibition, etc. and biological activities such as antiviral,¹¹ antiepileptic,¹² antiallergic,¹³ anticancer,¹⁴ anti HIV,¹⁵ antimicrobial activities against Gram positive bacteria and β₃-adrenergic receptor agonist.¹⁶ Due to these multifarious applications, there is a need for novel, proficient and green approaches to synthesize triazoles by using readily available precursors.

As a part of our ongoing research programme, stimulated by the development of green methods for bioactive heterocycles,¹⁷ the present investigation was undertaken. In continuation with our work on 1,2,4-triazolidine-3-thiones,^17e herein we report an expeditious for green synthesis of 1,2,4-triazolidine-3-thiones from aldehydes and thiosemicarbazides/substituted thiosemicarbazides using catalytic amount of [C₁₆MPy]AlCl₃Br in water at ambient temperature (Scheme 1).

Scheme 1 Synthesis of combinatorial library of 1,2,4-triazolidine-3-thiones.

Initial attempts were focused on synthesis of novel acidic ionic liquid which creates micelles by self-aggregation in water thus achieved the highest level of green chemistry. Geng et al. quoted that a remarkable decrease in the CMC values with increasing the hydrocarbon chain length leads to stronger hydrophobic interactions between the hydrocarbon chains. Hence, the micelles can form easily and the CMC values decreases.¹⁸ As reported for conventional surfactants, the CMC is approximately halved with each addition of one carbon atom to the hydrocarbon chain.¹⁹ In this context we design the synthesis of [C₁₆MPy]AlCl₃Br which possess hydrophobic core, hydrophilic corona required for creation of vesicular cavities or micelles and Lewis acidic counter ion essential to accelerate rate of reaction as well as improve yields [Fig. 1].

Fig. 1 [C₁₆MPy]AlCl₃Br.

The synthesis of TSIL, [C₁₆MPy]AlCl₃Br was carried out by reaction of AlCl₃ and [C₁₆MPy][Br] obtained from N-methyl pyrrolidine and 1-bromohexadecane (Scheme 2). The structure of which was in full agreement with ¹H and ¹³C NMR.

After this primary success the attention was focused towards optimization of reaction conditions for synthesis of novel 1,2,4-triazolidine-3-thiones. In the pilot experiment, the reaction of anisaldehyde (1 mmol) and thiosemicarbazide (1 mmol) was investigated as the model reaction for optimization of reaction parameters such as, choice of catalyst, mole ratio of catalyst and solvent at ambient temperature. Comparison of the catalytic activity of [C₁₆MPy]AlCl₃Br with basic, acidic catalysts and surfactants under the optimal reaction conditions, showed that it has the highest catalytic activity (Table 1, entries 2–16). Due to scant solubility of aldehydes, reactions in water under catalyst-free conditions are sticky resulted into low yield of desired product (entry 1, Table 1). When ethanol is used as solvent the yield of the desired product increased upto 80% (entry 2, Table 1). For basic catalysts such as [BMIM] OH and K₃PO₄, ethanol is required as solvent with very high reaction time (entries 3 and 4; Table 1). We observed that rate of reaction is influenced in presence of acidic catalysts which also required ethanol as a solvent (entries 5–11; Table 1). It is surprising that in the presence of commercially available surfactants such as Triton X-100 in water the corresponding product was obtained in comparatively good yield in 1 h (entry 12, Table 1). The effect of surfactant ionic liquid was studied and observed nearly same results (entries 14 and 15; Table 1). The best result was obtained by using [C₁₆MPy]AlCl₃Br in water at room temperature in very short time (10 min) (entries 16; Table 1), this may be due to [C₁₆ MPy]AlCl₃Br bear hydrophilic corona, hydrophobic core and Lewis acid cites. Thus from Table 1 and green chemistry perspective, [C₁₆MPy]AlCl₃Br is the ideal choice for present transformation.

Table 1 Screening of catalysts in the formation of 3a^a

Sr. no	Catalyst	Catalyst load (mol%)	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: anisaldehyde (1 mmol), thiosemicarbazide (1 mmol), specified catalyst in 5 ml water at room temp.b Isolated yield.
1	—	—	Water	2	57
2	—	—	Ethanol	2	80
3	[BMIM]OH	20	Ethanol	12	79
4	K3PO4	20	Ethanol	10	75
5	[PySoPy][HSO4]2	20	Ethanol	1	81
6	[HSO3(CH2)4MIM] [HSO4]	20	Ethanol	1	82
7	Gly-NO3^−	20	Ethanol	2	85
8	[PySoPy][HSO4]2	20	Water	2	75
9	[HSO3(CH2)4MIM] [HSO4]	20	Water	2	78
10	p-TSA	20	Water	1.5	85
11	NaPTSA	20	Water	1.5	75
12	Triton X 100	20	Water	1	85
13	AlCl3	20	Ethanol	0.58	89
14	[C16MIM]Br	20	Water	1	88
15	[C16Mpy]Br	20	Water	1	90
16	[C16Mpy]AlCl3Br	20	Water	0.167	97
17	[C16Mpy]AlCl3Br	15	Water	0.167	97
18	[C16Mpy]AlCl3Br	10	Water	0.167	96
19	[C16Mpy]AlCl3Br	5	Water	0.5	70

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Encouraged by these results, the effect of load of the catalyst on the reaction rate was studied. It was observed that the 10 mol% of [C₁₆MPy]AlCl₃Br was sufficient to push this reaction forward (entries 16–19; Table 1).

It is noteworthy that, the workup for these very clean reactions involves only a filtration and a simple washing with EtOH resulted highly pure desired product. Identification of which is ascertained by IR, ¹H, ¹³C NMR and MS. In the IR spectrum, the absorption bands at 1710 cm⁻¹ due to carbonyl of aldehyde and 3350 due to primary amines disappears while band at 1594 cm⁻¹ is observed corresponding to thiocarbonyl of 1,2,4-triazolidine-3-thiones. ¹H NMR spectrum indicates three D₂O exchangeable protons at δ = 7.91, 8.10, 11.31 of secondary amine, respectively. In ¹³C NMR, signal due to carbonyl of aldehyde get disappeared and exhibit signal at δ = 178 due to thiocarbonyl confirm the structure of product 3a.

Having the optimized reaction conditions in hand, we extended the scope of the reaction by using various structurally diverse aldehydes (alicyclic, cyclic, aromatic, heteroaromatic and organometallic) with thiosemicarbazides as illustrated in Table 2.²¹ Furthermore, aromatic aldehydes bearing simple and electron-donating as well as electron-withdrawing groups were performed smoothly and the corresponding 1,2,4-triazolidine-3-thiones are attained in excellent yields. Interestingly, excellent yields were observed with heteroaromatic aldehydes such as thiophene-2-carboxyaldehyde (entry (i), Table 2). Fascinatingly, ferocene-2-carboxyldehyde worked well yielded desired product in excellent yield (entries (f), Table 2). Remarkably, the alicyclic aldehydes reacted with thiosemicarbazides resulting the corresponding 1,2,4-triazolidine-3-thiones in excellent yields (entry (b), Table 2).

Table 2 Synthesis of combinatorial library of 1,2,4-triazolidine-3-thione^a

Entry	Thiosemicarbazide (1)	Aldehyde (2)	Product (3)	Time (min)	Yield^b (%)
a Reaction conditions: aldehydes (1 mmol), thiosemicarbazide/4-substituted thiosemicarbazide (1 mmol), catalyst (10 mol%), water, room temp.b Isolated yield.
a				10	96
b				5	90
c				5	96
d				10	90
e				10	96
f				45	94
g				10	95
h				10	96
i				10	94
j				10	96
k				10	94
l				10	96

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It is worthy to note that in case of substituted thiosemicarbazides the corresponding 1,2,4-triazolidine-3-thiones are obtained as products instead of 1,3,4-oxadiazoles²⁰ (entries (g), (i–l), Table 2).

Finally, we decided to study the scope of the reaction with isophthalaldehyde as well as terephthalaldehyde and realized that the reaction worked well with thiosemicarbazide Scheme 3 (entries (e) and (h); Table 2).

Scheme 2 Synthesis of novel TSIL, [C₁₆MPy]AlCl₃Br.

The reaction in ionic liquid is more advantageous as it can be recycled and reused in subsequent reactions. After completion of reaction the product was separated by simple filtration and the filtrate was washed with diethyl ether and used for next cycle. Filtrate was used for five cycles without any substantial loss in activity, while the reactivity gradually decreases for the next few cycles afforded 96, 95, 95, 94 and 93%, respectively over five cycles. The efficiency of catalyst while reusability study was supported by UV visible analysis for which the filtrate after each cycle of 0.1 ml have been analyzed by recording UV-vis spectrum in water and compared with that of thiosemicarbazide, and fresh ionic liquid (Fig. 2). The absorption at 236 nm due to thiosemicarbazide disappeared from the reaction mixture indicates its complete utilization. From Fig. 2 it seems that there is no change in properties of ionic liquid at least up to five cycles.

Fig. 2 UV-vis spectra analysis illustrating efficacy of catalyst while reusability study.

Scheme 3 Synthesis of bis-1,2,4-triazolidine-3-thione.

Experimental

General

Various aldehydes (Sigma-Aldrich) and thiosemicarbazide (Alfa Aesar) were used as received. M.P. recorded were determined and are uncorrected. The absorption spectrum was recorded at room temperature on a UV 3600 Shimadzu UV-vis-NIR spectrophotometer with the use of a 1.0 cm quartz cell. NMR spectra were recorded on Bruker AC-300 (300 MHz for ¹H NMR and 75 MHz for ¹³C NMR) spectrometer in DMSO-d₆ using TMS as an internal standard and δ values are expressed in ppm and mass spectra were recorded on a Shimadzu QP2010 GCMS.

Thus, we conclude that the present manuscript explicates the synthesis of novel 1,2,4-triazolidine-3-thione from aldehydes and thiosemicarbazide in presence of catalytic amount of [C₁₆MPy]AlCl₃Br in water at ambient temperature. This reaction covers a great range of substrates with excellent yield of 1,2,4-triazolidine-3-thiones within short time. It is noteworthy that in case of substituted thiosemicarbazides the corresponding 1,2,4-triazolidine-3-thione are obtained instead of 1,3,4-oxadiazoles. This protocol provides a sustainable route for the synthesis of novel 1,2,4-triazolidine-3-thione as it is simple, rapid, high-yielding, involve room temperature, use of water as solvent, reusable novel ionic liquid catalyst, high atom economy and does not involve any purification techniques like column chromatography.

Acknowledgements

Author DMP thank UGC, New Delhi for financial assistance [F. no. 42-394/2013 (SR)].

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21. The general procedure for the synthesis of 1,2,4-triazolidine-3-thione [3]: A mixture of aldehyde (1 mmol), thiosemicarbazide/substitutedthiosemicarbazide (1 mmol) and 10 mol% of [C₁₆MPy]AlCl₃Br in water (5 ml) was stirred at ambient temperature for the time specified in Table 2. The progress of reaction was monitored by TLC. After completion of the reaction, the precipitated product was isolated by simple filtration. All products 3a–l were characterized (¹H, ¹³C NMR, IR and MS).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra46916f

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