New dicationic DABCO-based ionic liquids: a scalable metal-free one-pot synthesis of bis-2-amino-5-arylidenethiazol-4-ones

Herein, a novel DABCO-based dicationic ionic liquid (bis-DIL) was easily prepared from the sonication of DABCO with 1,3-dichloro-2-propanol and then characterized by several techniques. Thereafter, under the ultimate green conditions, the performance of the bis-DIL was examined for the sono-synthesis of a new library of bis-2-amino-5-arylidenethiazol-4-ones via one-pot pseudo-five-component Knoevenagel condensation reaction of appropriate dialdehydes, rhodanine and amines. This protocol is tolerant towards several mono- and dialdehydes, excellently high yielding and affording access to the desired products in a single step within a short reaction time. Compared with the conventional methodologies, the proposed method displayed several remarkable merits such as milder reaction conditions without any side product, green solvent media, recording well in a variety of green metrics and applicability in gram-scale production. The recyclability of the bis-DIL was also investigated with an average recovered yield of 97% for six sequential cycles without any significant loss of the activity.


Results and discussion
At the outset, we began our investigation with the synthesis of a novel category of DABCO-based ILs designated as [DABCO 2 -C 3 -OH]2X (bis-DILs). The multistep strategy for synthesizing novel bis-DIL royalsocietypublishing.org/journal/rsos R. Soc. open sci. 6: 190997 catalysts is displayed in scheme 1. Under sonication (US), two moles of DABCO were quaternized with one mole of 2,3-dichloropropan-1-ol (1) in EtOH to afford the corresponding chloride salt 2 in 98% yield (scheme 1). Next, the chloride salt 2 underwent an anion-exchange reaction on reacting with NaOAc or NaBF 4 in ethanol to afford the required dense bis-DILs 3a,b in excellent yields under ultrasound irradiation (scheme 1). The bis-DILs 3a,b were easily miscible with H 2 O, EtOH and CH 3 CN while being immiscible with n-hexane. The chemical structure of the prepared bis-DILs 3a,b was elucidated by IR, 1 H, 13 C, 19 F NMR and high-resolution mass spectra (HRMS). In 19 F NMR of compound 3b, the singlet at δ −148.61 ppm established the presence of BF 4− group (electronic supplementary material, S5). As outlined in scheme 1, the novel bis-DILs 3a,b comprise two free tertiary amine units and one free hydroxyl group on the same molecule. These active sites can easily activate Knoevenagel condensation reactions (scheme 5).
To demonstrate our assumption, we initially investigated the efficiency of bis-DILs (3a,b) as powerful ILs in promoting the Knoevenagel condensation reaction of commercially obtainable rhodanine 5a (2.0 mmol), piperidine (2.0 mmol) and 2-hydroxy-5-methylisophthalaldehyde 6a (1.0 mmol) (scheme 2). To assess the methodology from a greener perspective, the ultrasound conditions were combined under regimes of aqueous solvent. Then, in order to obtain the optimum reaction conditions, several variables were thoroughly investigated such as energy source type, reaction time, IL loading, IL composition and solvent system. It was observed that, in the absence of IL, a poor yield of the hitherto unreported bis-2-(piperidin-1-yl)thiazol-4(5H )-one (7a) was observed at 40°C (table 1, entry 1). Whereas, when the model reaction proceeded using 2.0 equiv of bis-DIL 3a, the reaction profile was very clean, derivative 7a was obtained as the sole Knoevenagel condensation product (scheme 2), and no by-product was produced as was observed from the 1 H NMR spectrum of the crude product (table 1, entry 2).
A comparative result was observed on employing bis-DIL (3b) but with a slight decrease in the reaction rate (  Subsequently, the important role of the ILs hydroxyl group in stimulating the carbonyl groups of both rhodanine and aldehydes was also studied to have a better understanding of the catalytic system under investigation [23,38]. To do this, [DABCO-H][OAc] (DIL) 4 was synthesized [28,38] (scheme 1) and employed for catalysing the model reaction (scheme 2) instead of bis-DILs 3a,b. It was found that the obtained yield of 7a was diminished to 62% (table 1, entry 6) which is much lower than the yield obtained by using bis-DILs (approx. 92%). The aforementioned observation affirmed the essential role of the ILs hydroxyl group in stimulating the carbonyl groups (scheme 5). Also, the reaction yield was decreased on performing the reaction using the promising bis-DIL[OAc] under stirring instead of ultrasonication (table 1, entry 7). Furthermore, the model reaction was examined employing another two catalysts, ZnO and TiO 2 nanoparticles (2.0 equiv; electronic supplementary material, S36-S39). The latter catalysts were found to be less effective and delivered the required product 7a in only 55 and 67% yields, respectively (table 1, entries 8 and 9). Moreover, increasing the catalyst loading of TiO 2 to 3.0 equiv neither increases the reaction yield nor the reaction rate. Thereby, in the next investigations, the bis-DIL[OAc] 3a will be used as the optimal choice for further studies under ultrasonic irradiation.
In continuation of our trials to promote the results, the effect of bis-DIL[OAc] loading on the aforementioned process (scheme 2) was also studied. Increasing the bis-DIL[OAc] loading to 2.5, 3.0 and 3.5 equiv enhanced both the reaction rate and the yield (table 2, entries 2-4). Nevertheless, it was observed that a higher bis-DIL[OAc] loading (4.0 and 5.0 equiv) did not enhance the reaction rate (table 2, entries 5 and 6).
In order to probe the impact of the solvent on the reaction rate, various solvents were screened to select the optimal one. It was found that the selection of the solvent had a considerable impact on this conversion (scheme 2). When the reaction was performed in a polar protic solvent like EtOH at different temperatures, the reaction yield was slightly decreased (table 3, entries 1 and 2). A further lowering in the yield was observed when the reaction was conducted in polar aprotic solvents such as CH 2 Cl 2 (DCM) and MeCN (     afforded full conversion (99%) in only 10 min (table 3, entry 5). These experimental results indicate that the present reaction (scheme 2) belongs to the 'on water' type and is thus eco-friendly [25].
To assess the effect of temperature on the reaction rate, the reaction was conducted at varied temperatures. Performing the model reaction (scheme 2) at ambient temperature (23°C) diminished the reaction yield (table 3, entry 7). While on lowering the reaction temperature from 40 to 30°C, the reaction gave access to derivative 7a in comparable yield (97%) but in longer reaction time (table 3, entry 8). By continuously increasing the reaction temperature to 60 and 70°C, the reaction yields were dramatically decreased with the appearance of Cannizzaro product [12] as a side product (table 3, entries 9 and 10). The mass spectrum of this Cannizzaro product showed the characteristic peak at m/z 248.1288 (M-H) corresponding to (2-hydroxy-3-(hydroxymethyl)-5-methylphenyl)( piperidin-1yl)methanone (electronic supplementary material, S31). Also, the structure of this product was confirmed by 1 H NMR spectrum (electronic supplementary material, S30).
Furthermore, the influence of the molar ratios and the type of used amines on the above-mentioned model reaction was tested (table 4). As outlined in table 4, the isolated yields of 7a differed considerably when varying the molar ratios of piperidine (entries 1-4). Equimolar amounts of piperidine and 5a (2.0 mmol) were found to be enough to produce the desired product 7a in excellent yield (table 4, entry 1). Unexpectedly, a large amount of piperidine (more than 2.0 mmol) was detrimental to the reaction yields (table 4, entries 2 and 3) even at longer time (table 4, entry 4). Accordingly, a plausible explanation for the latter behaviour could be that a competitive Cannizzaro reaction took place in which aldehydes were consumed under basic conditions [6]. Therefore, it is preferable to perform the model reaction (scheme 2) at low temperature (40°C) and using an exact molar ratio of amine. Likewise, the other amines provided the corresponding derivatives 7b-d in good yields (table 4, entries 5-7).   Finally, the influence of the power intensity of ultrasonic irradiation on the aforesaid reaction (scheme 2) was investigated. The model reaction was screened at a variety of operating intensities, i.e. 20%, 40%, 60%, 80% and 100%, and the desired derivative 7a was obtained in 92%, 92%, 96%, 99% and 97% yields, respectively (table 5, entries 1-5). Accordingly, the optimal power intensity was selected to be 80% as it gave excellent yield in a shorter reaction time (table 5, entry 4).
Furthermore, it is worth noting that both the reaction rate and yield were slightly affected by the steric nature of the dialdehydes. For example, terephthalaldehyde 6h was smoothly involved in the reaction and afforded the desired product 7k in excellent yield. Likewise, isophthalaldehyde 6i provided the respective product 7l in comparable yield (91%). Notwithstanding, phthalaldehyde 6j relatively hampered the reaction and furnished the required product 7m in 82% yield (scheme 4), which might be possibly due to steric factors.
Thereafter, the efficiency of bis-DIL (3a) to promote Knoevenagel condensation was compared with the previously reported methodologies in order to clear up the generality and feasibility of the present IL. A focused library of 2-amino-5-arylidenethiazol-4-ones (9a-m) was prepared with three-component reaction of rhodanine (5a, 1.0 mmol), piperidine (1.0 mmol) and various aromatic and heteroaromatic aldehydes (8a-m, 1.0 mmol) under the optimum conditions (table 6). In all examples, the desired products (9a-m) were obtained as the sole products without the isolation of any side products in better yields and faster reaction rates than other reported protocols (table 6).
Furthermore, it was essential that the effectiveness of the as-synthesized bis-DIL (3a) be compared with other ILs in order to clear up its accessibility and merits. For this reason, the synthesis of compound 9a was selected as the model reaction and was compared in terms of reaction time and yield with some commercially available ILs [39][40][41]. As shown in table 7, compound 9a was obtained in a shorter time and higher yield when bis-DIL (3a) was used, clarifying its applicability as an adequate IL for the promotion of these MCRs. The structure of all the newly prepared compounds 7a-m was interpreted by IR, NMR spectroscopy, as well as HRMS. The above-mentioned preparations could afford two isomers, Z and E. However, 1 H NMR spectra displayed only one type of methine proton at around δ 7.9 ppm, at lower chemical shifts than those anticipated for the E-isomers. Therefore, we can infer that the current method proceeds stereoselectivity to furnish the more stable thermodynamic Z-isomer [42].
According to the obtained experimental results and previous reports [18,25,38], a tentative mechanistic pathway is displayed in scheme 5. Presumably, the active hydrogen of compound 5a was removed by the nitrogen lone pair of the bis-DIL (3a); as a result, the corresponding carbanion 10 was generated. At the same time, the OH group of the bis-DIL enhanced the electrophilicity of the carbonyl carbon atom of aldehyde due to intermolecular hydrogen bonding, which in turn reacted with intermediate 10 to yield the Knoevenagel condensation product 11. Posteriorly, piperidine underwent a nucleophilic attack on the thiocarbonyl carbon of compound 11 owing to its increased electrophilicity due to the hydroxyl group of bis-DIL to afford the non-isolable intermediate 12 that finally performed an elimination reaction to afford the isolable derivatives 7-9 (scheme 5).
Additionally, in order to evaluate the potential of scaling up the present strategy, MCR was proceeded on the gram scale under the optimized conditions that in turn provided the desired derivative 7a in excellent yield (98%; scheme 6). Also, to evaluate the current process in terms of carbon efficiency (CE) and waste, diversified green metrics including CE, process mass intensity (PMI), E-factor (EF), reaction mass efficiency (RME) and atom economy (AE) have been studied (scheme 6) [43]. The higher environmental compatibility parameters, for example, smaller values of both PMI and EF in     Finally, to test the possibility of bis-DIL (3a) recycling, the assembly of 7a was chosen for this task. Under the optimized conditions, the recyclability of the bis-DIL (3a) was investigated by conducting the model reaction (scheme 2) repeatedly. After each cycle, the reaction product was isolated by filtration and the bis-DIL was recovered by the removal of H 2 O under reduced pressure then reused in the next cycle. Under the optimized reaction conditions, the bis-DIL was found to be very stable and can be reused up to six times without observing a remarkable loss of activity ( figure 2). Moreover, the recycled IL after the sixth run was isolated from aqueous medium and characterized by 1 H NMR spectroscopy, which was the same as that of the original one.

Conclusion
In a promising approach, new DABCO-based dicationic ILs (bis-DILs) were synthesized and used for the first time as base ILs offering a considerable activity in Knoevenagel condensations at milder reaction conditions. Later, the developed bis-DILs were used to prepare a novel series of bis-2-amino-5-arylidenethiazol-4-ones by multi-component reaction of several aromatic dialdehydes, rhodanine and amines. The newly established strategy was successfully screened with other aromatic aldehydes and afforded the desired products in excellent yields. It was demonstrated that the presence of the hydroxyl group and two tertiary nitrogen motifs in the bis-DIL scaffold is crucial to increase the overall efficiency of the IL. Moreover, remarkable features of the developed protocol including high stereoselectivity, mild conditions, scalability, broad substrate scope, green solvent usage, chromatographic techniques avoidance, and step economy and AE would make this method attractive for green chemistry as well as organic synthesis. The developed bis-DILs could be recycled and  royalsocietypublishing.org/journal/rsos R. Soc. open sci. 6: 190997 regenerated many times without any appreciable loss of effectiveness. Finally, several green metrics were studied and our protocol perfectly fitted in this grid.

Material and methods
Compounds 6a-g were synthesized according to our previously reported method [44]. All chemicals were delivered and used without any further purification. 1 H, 19 F and 13 C NMR spectra were recorded at 400 MHz, 377 MHz and 100 MHz, respectively. High-resolution mass spectra (HRMS) were recorded on a Bruker Daltonics microTOF spectrometer with an electrospray ionizer. FT-IR spectra were measured on a Perkin-Elmer Spectrum One spectrometer (KBr). Ultrasonication was done in a SY5200DH-T ultrasound cleaner. Melting points were measured by using the capillary tube method with an Electrothermal IA9100 apparatus (UK).

Synthesis of derivatives 7a-j
A 25.0 ml round flask was charged with dialdehydes, 6a-j (0.5 mmol), and/or aldehydes, 8a-m (1.0 mmol), rhodanine (5a) and/or thiazolidine-2,4-dione (5b), amine (2.0 mmol in the case of 6a-j and 1.0 mmol in the case of 8a-m) and 3a (3.5 equiv in the case of 6a-j and 2.0 equiv in the case of 8a-m) in 10.0 ml water. The reaction vessel was placed in the ultrasonic bath and sonicated at 40°C for an appropriate time. After completion of the reaction (confirmed by TLC, eluent: MeOH/DCM = 1 : 9 vol.), the solid that separated out was filtered and washed with H 2 O, dried and recrystallized from a proper solvent to afford the analytically pure product. The catalyst was recovered from the aqueous layer under vacuum, washed with n-hexane, and reused for the next reactions. All known products (9a-m) were confirmed by comparing their melting points, IR, 1 H NMR spectra and HRMS (see electronic supplementary material, S31-S36).