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.

Introduction

4-Thiazolidinones are a promising class of heterocyclic scaffolds in the field of pharmaceutical chemistry [1-4]. In particular, 2-amino-5-arylidene-1,3-thiazol-4(5H)-one derivatives exhibited potential and interesting broad medicinal activities, for example, antiviral, antibacterial, anti-inflammatory and cardiotonic [5-9]. In order to prepare such heterocyclic moiety, several synthetic strategies have been established [10-12], but these reported protocols necessitate multi-steps, elevated temperature, laborious work-up and long reaction times. Anderluh et al. [6] reported an acid-catalysed multi-component preparation of 2-amino-5-alkylidenethiazol-4-ones under microwave irradiation at high temperatures using an excess amount of aldehyde in order to obtain acceptable yields. Consequently, this methodology cannot be considered as a green method. Also, Shariati & Baharfar [13] reported a method for synthesizing 2-amino-5-arylidenethiazol-4-ones using MgO nanoparticles. Despite an acceptable yield being obtained, the reaction took more time to complete in addition to the hazards resulted from using metal oxides, especially when the product is directed to human use. In green chemistry, ionic liquids (ILs) have been identified as environmentally friendly dual reagents (catalyst and solvent) in respect of their notable properties, for example, low cost, availability, recyclability, capability to dissolve a broad scope of compounds in addition to their potential to be used in gram-scale production [14,15]. They have been introduced in several organic conversions, for example, Michael addition, Aldol reaction, Mannich reaction, borane reductions, Knoevenagel condensation and Friedel–Crafts alkylation reactions [16-18]. The dicationic ILs containing two head groups linked by a rigid or flexible spacer have been explored as a powerful catalyst for several transformations. This type of IL demonstrates unique merits compared to monocationic ILs [19,20]. In recent years, DABCO, as a cage-like molecule, has been used as a green catalyst for several organic conversions [21,22]. This cage-like structure makes the nitrogen lone pair precisely localized, and consequently, DABCO becomes more attuned for quaternization. Accordingly, this merit has been used for the assembly of several types of DABCO-based ILs [23-27]. Latterly, two new ILs based on DABCO were prepared by our group (figure 1) and used successfully as catalysts in the Claisen–Schmidt condensation [28] and multisubstituted imidazoles synthesis [29]. As one-pot multi-component reactions (MCRs) can lead to robust and green synthetic protocols for the rapid preparation of small drug-like compounds [30], the combination of both ILs and MCRs in a single strategy would lead to rapid assembly of highly substituted heterocyclic compounds with high potential applications in pharmaceutical chemistry [31]. Recently, many industrial and scientific investigations have relied mainly on the use of ultrasound-assisted multi-component reactions [32]. Sonochemical preparations have numerous advantages compared to conventional warming strategies such as straightforward reaction routes and enhanced reaction rates and yields [32]. During the sono-synthesis reaction, the energy required to improve the rate is supplied by cavitation in which, on collapsing, the generated bubbles inside the solution release a significant amount of energy in a short reaction time. Chemically, the cavitation impacts are basically reliant on the substances inside the collapsing bubbles and thus on the solvent nature [33]. As the ILs have low vapour pressure and high miscibility with water, they can control the chemicals inside the collapsing bubbles via reducing the vapour pressure of the solvent. Consequently, the reactant's compressional heating is elevated and that in turn improves the reaction rates [34]. Accordingly, development of an effective protocol for the preparation of thiazol-4(5H)-one cores sounds interesting from the medicinal and chemical standpoint. As a part of our interest in developing novel strategies for heterocycles assembly [28,29,35-37], herein we present the synthesis of a broad scope of mono- and bis-2-amino-5-arylidenethiazol-4-ones using new DABCO-based ILs under sustainable reaction conditions. In this context, recyclability and recoverability of the IL as well as the reaction mechanism were also investigated. To the best of our knowledge, this is the first report claiming new bis-2-amino-5-arylidenethiazol-4-ones (schemes 2–4).

Figure 1.

Structures of the [DABCO-EtOH][AcO] and [DABCO-DOL][X] ILs.

Scheme 2.

Synthesis of derivatives 7a–d.

Scheme 4.

Ultrasound-assisted one-pot protocol for the preparation of bis-arylidenethiazolidinones 7k–m.

Structures of the [DABCO-n class="Chemical">EtOH][AcO] and [DABCO-DOL][X] ILs.

Results and discussion

At the outset, we began our investigation with the synthesis of a novel category of DABCO-based ILs designated as n class="Chemical">[DABCO2-C3-OH]2X (bis-DILs). The multistep strategy for synthesizing novel bis-DIL 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 NaBF4 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 H2O, EtOH and CH3CN while being immiscible with n-hexane. The chemical structure of the prepared bis-DILs 3a,b was elucidated by IR, 1H, 13C, 19F NMR and high-resolution mass spectra (HRMS). In 19F NMR of compound 3b, the singlet at δ −148.61 ppm established the presence of BF4− 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).

Scheme 1.

Synthesis of bis-DILs (3a,b) and DIL (4).

Scheme 5.

Tentative mechanism for the assembly of derivatives 7–9.

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 1H NMR spectrum of the crude product (table 1, entry 2).

Table 1.

Preparation of 7a using various conditions.a

entry	additives	conditions	time (min)	yield (%)
1	none	USb	120	17
2	3a: bis-DIL[OAc]	US	30	93
3	3b: bis-DIL[BF4]	US	35	91
4	2: bis-DIL[Cl]	US	45	88
5	DABCO	US	120	67
6	4: [DABCO-H][OAc]	US	120	62
7	3a: bis-DIL[OAc]	stirring	200	86
8	NP-ZnO	US	120	55
9	NP-TiO2	US	120	67

a5a (2.0 mmol), 6a (1.0 mmol), piperidine (2.0 mmol) and IL (2.0 equiv) in water (10.0 ml) at 40°C.

bUltrasonic irradiation.

a5a (2.0 mmol), n class="Chemical">6a (1.0 mmol), piperidine (2.0 mmol) and IL (2.0 equiv) in water (10.0 ml) at 40°C.

A comparative result was observed on employing bis-DIL (3b) but with a slight decrease in the reaction rate (table 1, entry 3). The other ILs furnished lower yields of the required product 7a in longer reaction times (table 1, entries 4 and 5) with the relative efficiency following the order n class="Chemical">bis-DIL[OAc] ≈ bis-DIL[BF4] > bis-DIL[Cl] > DABCO.

Subsequently, the important role of the ILs hydroxyl group in stimulating the carbonyl groups of both n class="Chemical">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 TiO2 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 TiO2 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).

Table 2.

Impact of bis-DIL[OAc] 3a loading during the preparation of 7a.a

entry	bis-DIL[OAc] (equiv)	time (min)	yield (%)
1	2.0	30	93
2	2.5	15	96
3	3.0	12	99
4	3.5	10	99
5	4.0	10	99
6	5.0	10	99

aThe mixture of 5a (2.0 mmol), 6a (1.0 mmol), piperidine (2.0 mmol) and 3a in water (10.0 ml) was sonicated at 40°C.

aThe mixture of 5a (2.0 mmol), n class="Chemical">6a (1.0 mmol), piperidine (2.0 mmol) and 3a in water (10.0 ml) was sonicated at 40°C.

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 CH2Cl2 (DCM) and MeCN (table 3, entries 3 and 4). Moreover, a moderate yield was obtained on employing solvent-free conditions (table 3, entry 6). It was obvious that H2O is the appropriate solvent for this conversion as it almost 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].

Table 3.

The impact of temperature and solvents on the preparation of 7a.a

entry	solvent	temperature (°C)	yield (%)
1	EtOH	40	94
2	EtOH	60	75
3	DCM	40	45
4	MeCN	30	49
5	H2O	40	99
6	None	40	77
7	H2O	23	67
8	H2O	30	97b
9	H2O	60	72
10	H2O	70	55

aThe mixture of 5a (2.0 mmol), 6a (1.0 mmol), piperidine (2.0 mmol) and 3a (3.5 equiv) in solvent (10.0 ml) was sonicated for 10 min at different temperatures.

b20 min.

aThe mixture of 5a (2.0 mmol), n class="Chemical">6a (1.0 mmol), piperidine (2.0 mmol) and 3a (3.5 equiv) in solvent (10.0 ml) was sonicated for 10 min at different temperatures.

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-1-yl)methanone (electronic supplementary material, n class="Gene">S31). Also, the structure of this product was confirmed by 1H 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).

Table 4.

The impact of amines on the preparation of 7a–d.a

entry	amine	mmol	time (min)	product	yield (%)
1	piperidine	2.0	10	7a	99
2	piperidine	2.5	10	7a	93
3	piperidine	3.0	10	7a	85
4	piperidine	3.0	20	7a	82
5	morpholine	2.0	10	7b	93
6	pyrrolidine	2.0	30	7c	92
7	benzyl amine	2.0	17	7d	88

aThe mixture of 5a (2.0 mmol), 6a (1.0 mmol), amine and 3a (3.5 equiv) in water (10.0 ml) was sonicated at 40°C.

aThe mixture of 5a (2.0 mmol), n class="Chemical">6a (1.0 mmol), amine and 3a (3.5 equiv) in water (10.0 ml) was sonicated at 40°C.

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).

Table 5.

The impact of US power intensity on the preparation of 7a.a

entry	power intensity (%)	Watt (W)	time (min)	yield (%)
1	20	40	25	92
2	40	80	20	92
3	60	120	15	96
4	80	160	10	99
5	100	200	10	97

aThe mixture of 5a (2.0 mmol), 6a (1.0 mmol), piperidine (2.0 mmol) and 3a (3.5 equiv) in water (10.0 ml) was sonicated at 40°C.

aThe mixture of 5a (2.0 mmol), n class="Chemical">6a (1.0 mmol), piperidine (2.0 mmol) and 3a (3.5 equiv) in water (10.0 ml) was sonicated at 40°C.

According to the above experiments (tables 1–5), sonication (80%) of 5a (2.0 mmol), n class="Chemical">6a (1.0 mmol), piperidine (2.0 mmol) and bis-DIL (3a, 3.5 equiv) in water (10.0 ml) at 40°C for 10 min was specified as the optimum reaction condition in which derivative 7a was isolated in 99% yield. Having successfully established an optimized strategy for the model reaction, we next embarked on the reaction scope and generality of the substrates. In the current investigation, a diverse range of functionalized dialdehydes (6a–g) underwent catalytic Knoevenagel condensation reaction expeditiously with rhodanine (5a) and piperidine to furnish the respective hitherto unreported bis-2-(piperidin-1-yl)thiazol-4(5H)-ones (7a, 7e–j) in almost quantitative yields (up to 99%, scheme 3). It was noted that the steric and electronic nature of substituents linked to the dialdehyde cores has a minor impact on the reaction efficiency. Impressively, the reaction was amenable to both the electron-donating group substituent on the dialdehyde counterpart, such as p-methyl (7a, 99%), and electron withdrawing groups like p-carboxylic (7f, 95%) and p-bromo (7e, 95%). Switching to sterically electron withdrawing partners, namely, 6d and 6e, also afforded the required products (7g and 7h) in comparable yields (96% and 95%, respectively). Gratifyingly, 1H-pyrazole-3,5-dicarbaldehyde (6f) and 5,5′-methylenebis(2-hydroxybenzaldehyde) (6g) also underwent an efficient and smooth reaction with rhodanine to provide the condensed derivatives 7i and 7j in 96% and 97% yields, respectively. Furthermore, the generality of the thiazolidin-4-one moiety was also tolerated in the present reaction. The reaction smoothly proceeded with both 2-thioxothiazolidin-4-one (5a) and thiazolidine-2,4-dione (5b) as active methylene compounds. It was noted that rhodanine (5a) afforded slightly better yields of the corresponding products in comparison to derivative 5b.

Scheme 3.

Ultrasound-assisted one-pot protocol for the preparation of bis-arylidenethiazolidinones 7a and 7e–j.

Furthermore, it is worth noting that both the reaction rate and yield were slightly affected by the steric nature of the dialdehydes. For example, n class="Chemical">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 n class="Chemical">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).

Table 6.

Preparation of 2-amino-5-arylidenethiazol-4-ones 9a–m.a

entry	R1	R2	R3	yield (%)	time (min)	mp (°C)	ref.
1	H	H	H	99 (83)	15 (20)	215–216 (213–215)	[6]
2	H	H	Cl	99 (89)	15 (100)	206–208 (207–209)	[13]
3	H	H	CH3	98 (89)	15 (109)	154–156 (152–154)	[12]
4	H	H	OCH3	99 (88)	15 (12 h)	200–201 (197–199)	[5]
5	Br	H	H	97 (89)	20 (100)	165–168 (162–164)	[13]
6	H	H	CN	98 (64)	15 (20)	193–195 (192)	[6]
7	–O–CH2–O–		H	98 (80)	20 (12 h)	185–186 (184)	[5]
8	H	OCH3	OCH3	97 (79)	15 (122)	198–199 (198–200)	[12]
9	H	H	NH2	96 (88)	15 (104)	213–215 (212–214)	[12]
10	H	OCH3	OH	98 (83)	15 (139)	193–195 (192–194)	[12]
11	iso-Nicotinaldehyde			98 (96)	10 (112)	171–173 (172–174)	[12]
12	Thiophene-2-carbaldehyde			96 (53)	15 (20)	203–205 (203)	[6]
13	1H-Indole-3-carbaldehyde			98 (90)	10 (20)	244–246 (245)	[6]

a5a (1.0 mmol), 8 (1.0 mmol), piperidine (1.0 mmol) and 3a (2.0 equiv) in water (10.0 ml) at 40°C.

a5a (1.0 mmol), 8 (1.0 mmol), n class="Chemical">piperidine (1.0 mmol) and 3a (2.0 equiv) in water (10.0 ml) at 40°C.

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 [39-41]. As shown in table 7, compound 9a was obtained in a shorter time and higher yield when n class="Chemical">bis-DIL (3a) was used, clarifying its applicability as an adequate IL for the promotion of these MCRs.

Table 7.

Comparison of reaction conditions, times, yields and yield economies for the preparation of derivative 9a using several ILs.a

entry	IL	time (min)b	yield (%)	yield economy (%)
1	[C1C4im]Brc	38	92	2.42
2	[C1C4im]PF6c	25	96	3.84
3	[C1C4im]OAcc	30	89	2.96
4	[C1C1im]Me2PO4d	25	97	3.88
5	[C1C4pyrr]OTfe	30	87	2.90
6	[HOC2NH3]HCO2f	55	91	1.65
7	bis-DIL (3a, this work)	15	99	6.60

aThe mixture of 5a (1.0 mmol), 8a (1.0 mmol), piperidine (1.0 mmol) and IL (2.0 equiv) in water (10.0 ml) was sonicated at 40°C.

bOptimum time.

c[C1C4im] = 1-butyl-3-methylimidazolium.

d[C1C1im] = 1,3-dimethylimidazolium.

e[C1C4pyrr] = 1-butyl-1-methylpyrrolidinium.

f2-Hydroxyethylammonium formate.

aThe mixture of 5a (1.0 mmol), 8a (1.0 mmol), n class="Chemical">piperidine (1.0 mmol) and IL (2.0 equiv) in water (10.0 ml) was sonicated at 40°C.

c[C1C4im] = n class="Chemical">1-butyl-3-methylimidazolium.

d[C1C1im] = n class="Chemical">1,3-dimethylimidazolium.

e[C1C4pyrr] = n class="Chemical">1-butyl-1-methylpyrrolidinium.

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, 1H NMR spectra displayed only one type of n class="Chemical">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 n class="Chemical">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 addition to high values of YE, CE, AE and RME confirmed the eco-friendly methodology of the developed protocol.

Scheme 6.

Scaled-up preparation of derivative 7a.

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 n class="Chemical">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 H2O 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 1H NMR spectroscopy, which was the same as that of the original one.

Figure 2.

The evaluation of the reusability of the IL (3a) for the preparation of 7a.

Conclusion

In a promising approach, new n class="Chemical">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 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. n class="Chemical">1H, 19F and 13C 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 the catalysts bis-DIL (3a,b)

A mixture of DABCO (0.224 g, 2.0 mmol) and n class="Chemical">2,3-dichloro-1-propanol (0.129 g, 1.0 mmol) in EtOH (15.0 ml) was sonicated for 1 h (TLC). The solvent was removed under reduced pressure to give derivative (2). Then, NaBF4 (0.22 g, 2.0 mmol) or NaOAc (0.164 g, 2.0 mmol) was added to the residue of 2 in EtOH (15.0 ml). The formed solution was sonicated for 40 min, after which the solvent was removed under reduced pressure to give the corresponding ILs (3a,b) in almost quantitative yield.

Bis-DIL 3a

Yield 99%; colourless liquid; n class="Chemical">1H NMR (400 MHz, CDCl3): δ 3.93 (br, 1H, OH), 3.65 (br, 2H, CH2), 3.54–3.51 (m, 6H, 3CH2), 3.35–3.30 (m, 8H, 4CH2), 3.20–3.13 (m, 13H, 6CH2 + CH), 1.92 (s, 6H, 2CH3); 13C NMR (101 MHz, CDCl3): δ 175.0 (C=O), 69.9, 67.2, 64.5, 62.6, 61.9, 53.1, 52.9, 25.0 ppm (CH3); IR (KBr, cm−1): νmax 3421 (br), 2923, 2880, 1638, 1115, 1053, 961; HRMS: m/z [M]+ calcd: 400.2685, found 400.2688; Anal. Calc. for C19H36N4O5: C, 56.98%; H, 9.06%; N, 13.99%. Found: C, 57.03%; H, 9.00%; N, 13.93%.

Bis-DIL 3b

Yield 99%; colourless liquid; n class="Chemical">1H NMR (400 MHz, CDCl3): δ 3.93–3.92 (br, 1H, OH), 3.80–3.78 (br, 2H, CH2), 3.68–3.59 (m, 6H, 3CH2), 3.48–3.36 (m, 8H, 4CH2), 3.25–3.01 (m, 13H, 6CH2 + CH); 13C NMR (101 MHz, CDCl3): δ 70.0, 66.8, 64.2, 61.98, 61.90, 53.0, 52.9 ppm; 19F NMR (377 MHz, CDCl3): δ –148.61 ppm; IR (KBr, cm−1): νmax 3402 (br), 2952, 2876, 1626, 1114, 1059, 960; HRMS: m/z [M]+ calcd: 456.2470, found 456.2477; Anal. Calc. for C15H30B2F8N4O: C, 39.51%; H, 6.63%; N, 12.29%. Found: C, 39.56%; H, 6.58%; N, 12.24%.

Synthesis of derivatives 7a–j

A 25.0 ml round flask was charged with dialdehydes, n class="Chemical">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 H2O, 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, 1H NMR spectra and HRMS (see electronic supplementary material, S31-S36).

(5Z,5′Z)-5,5′-((2-hydroxy-5-methyl-1,3-phenylene)bis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7a

Yield 99%; yellow solid; mp = 287–290°C; 1H NMR (400 MHz, DMSO-d6): δ 11.50 (s, n class="Chemical">1H, OH), 7.98 (s, 2H, =CH), 7.42 (s, 2H, Ar-H), 3.82–3.79 (m, 4H, piperidine-H), 3.72–3.71 (m, 4H, piperidine-H), 2.39 (s, 3H, CH3), 1.70–1.65 (m, 6H, piperidine-H), 1.60–1.59 ppm (m, 6H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 180.4 (C=O), 173.9 (N=C), 153.3 (=CH), 132.8 (thiazole-C5), 148.4, 128.6, 128.0, 124.1 (Ar-C), 50.0, 49.4, 26.0, 25.3, 23.9 (piperidine-C), 21.3 ppm (CH3); IR (KBr, cm−1): νmax 3421–2988 (OH), 1694 (C=O), 1604 (C=N), 1597 (C=C); HRMS: m/z [M−H]+ calcd: 495.1526, found 495.1523; Anal. Calc. for C25H28N4O3S2: C, 60.46%; H, 5.68%; N, 11.28%. Found: C, 60.42%; H, 5.71%; N, 11.23%.

(5Z,5′Z)-5,5′-((2-hydroxy-5-methyl-1,3-phenylene)bis(methanylylidene))bis(2-morpholinothiazol-4(5H)-one) 7b

Yield 93%; yellow solid; mp = 214–217°C; 1H NMR (400 MHz, DMSO-d): δ 11.49 (s, n class="Chemical">1H, OH), 7.98 (s, 2H, =CH), 7.44 (s, 2H, Ar-H), 4.07–4.02 (m, 4H, morpholine-H), 3.88–3.80 (m, 8H, morpholine-H), 3.70–3.64 (m, 4H, morpholine-H), 2.40 ppm (s, 3H, CH3); IR (KBr, cm−1): νmax 3346–3129 (OH), 1686 (C=O), 1611 (C=N), 1589 (C=C); HRMS: m/z [M−H]+ calcd: 499.1090, found 499.1110; Anal. Calc. for C23H24N4O5S2: C, 55.19%; H, 4.83%; N, 11.19%. Found: C, 55.22%; H, 4.79%; N, 11.09%.

(5Z,5′Z)-5,5′-((2-hydroxy-5-methyl-1,3-phenylene)bis(methanylylidene))bis(2-(pyrrolidin-1-yl)thiazol-4(5H)-one) 7c

Yield 92%; yellowish white solid; mp = 243–245°C; 1H NMR (400 MHz, DMSO-d): δ 11.29 (s, n class="Chemical">1H, OH), 7.96 (s, 2H, =CH), 7.40 (s, 2H, Ar-H), 3.80–3.79 (t, J = 6.7 Hz, 4H, pyrrolidine-H), 3.51–3.50 (t, J = 6.4 Hz, 4H, pyrrolidine-H), 2.30 (s, 3H, CH3), 2.06–2.01 ppm (m, 8H, pyrrolidine-H); IR (KBr, cm−1): νmax 3312–3151 (OH), 1698 (C=O), 1617 (C=N), 1576 (C=C); HRMS: m/z [M−H]+ calcd: 467.1211, found 467.1219; Anal. Calc. for C23H24N4O3S2: C, 58.95%; H, 5.16%; N, 11.96%. Found: C, 58.90%; H, 5.21%; N, 11.89%.

(5Z,5′Z)-5,5′-((2-hydroxy-5-methyl-1,3-phenylene)bis(methanylylidene))bis(2-(benzylamino)thiazol-4(5H)-one) 7d

Yield 88%; yellow solid; mp = 267–269°C; 1H NMR (400 MHz, DMSO-d): δ 11.53 (s, n class="Chemical">1H, OH), 10.08 (s, 2H, NH), 7.92 (s, 2H, =CH), 7.38–7.29 (m, 12H, Ar-H), 4.80 (s, 4H, CH2), 2.29 ppm (s, 3H, CH3); IR (KBr, cm−1): νmax 3384–3109 (OH), 1683 (C=O), 1610 (C=N), 1573 (C=C); HRMS: m/z [M]+ calcd: 540.1292, found 540.1288; Anal. Calc. for C29H24N4O3S2: C, 64.43%; H, 4.47%; N, 10.36%. Found: C, 64.47%; H, 4.41%; N, 10.30%.

(5Z,5′Z)-5,5′-((5-bromo-2-hydroxy-1,3-phenylene)bis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7e

Yield 95%; yellow solid; mp = 311–313°C; 1H NMR (400 MHz, DMSO-d): δ 11.56 (s, n class="Chemical">1H, OH), 7.90 (s, 2H, =CH), 7.63 (s, 2H, Ar-H), 3.85–3.80 (m, 4H, piperidine-H), 3.60–3.55 (m, 4H, piperidine-H), 1.99–1.95 (m, 6H, piperidine-H), 1.77–1.71 ppm (m, 6H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 180.0 (C=O), 174.2 (C=N), 152.2 (=CH), 133.2 (thiazole-C5), 154.9, 129.9, 126.5, 124.5 (Ar-C), 50.2, 49.7, 26.1, 25.4, 23.8 ppm (piperidine-C); IR (KBr, cm−1): νmax 3287–3021 (OH), 1684 (C=O), 1619 (C=N), 1612 (C=C); HRMS: m/z [M]+ calcd: 560.0550, found 560.0556; Anal. Calc. for C24H25BrN4O3S2: C, 51.34%; H, 4.49%; N, 9.98%. Found: C, 51.33%; H, 4.45%; N, 9.94%.

4-Hydroxy-3,5-bis((Z)-(4-oxo-2-(piperidin-1-yl)thiazol-5(4H)-ylidene)methyl)benzoic acid 7f

Yield 95%; yellow solid; mp = 307–309°C; 1H NMR (400 MHz, DMSO-d): δ 13.05 (br, 2H, 2OH), 8.10 (s, 2H, =CH), 7.67 (s, 2H, Ar-H), 3.89–3.88 (m, 4H, n class="Chemical">piperidine-H), 3.68–3.67 (m, 4H, piperidine-H), 1.89–1.85 (m, 6H, piperidine-H), 1.68–1.65 ppm (m, 6H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 178.9 (C=O), 173.0 (C=N), 169.5 (C=O), 150.5 (=CH), 133.6 (thiazole-C5), 159.7, 130.6, 129.9, 125.4 (Ar-C), 50.2, 49.8, 25.7, 25.4, 23.4 ppm (piperidine-C); IR (KBr, cm−1): νmax 3390–2875 (OH), 1698, 1679 (C=O), 1605 (C=N), 1603 (C=C); HRMS: m/z [M−H]+ calcd: 525.1267, found 525.1262; Anal. Calc. for C25H26N4O5S2: C, 57.02%; H, 4.98%; N, 10.64%. Found: C, 56.98%; H, 4.99%; N, 10.60%.

(5Z,5′Z)-5,5′-((4-hydroxy-[1,1′-biphenyl]-3,5-diyl)bis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7g

Yield 96%; yellow solid; mp = 354–356°C; 1H NMR (400 MHz, DMSO-d): δ 11.40 (br, n class="Chemical">1H, OH), 8.12 (s, 2H, =CH), 8.01 (s, 2H, Ar-H), 7.71–7.59 (m, 2H, Ar-H), 7.30–7.13 (m, 3H, Ar-H), 3.98–3.80 (m, 8H, piperidine-H), 1.62–1.44 ppm (m, 12H piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 179.5 (C=O), 171.7 (C=N), 151.2 (=CH), 132.9 (thiazole-C5), 163.1, 138.6, 136.2, 133.6, 130.8, 128.3, 126.5, 123.7 (Ar-C), 49.9, 49.1, 25.7, 25.4, 23.5 ppm (piperidine-C); IR (KBr, cm−1): νmax 3223–2998 (OH), 1698 (C=O), 1620 (C=N), 1611 (C=C); HRMS: m/z [M]+ calcd: 558.1761, found 558.1757; Anal. Calc. for C30H30N4O3S2: C, 64.49%; H, 5.41%; N, 10.03%. Found: C, 64.52%; H, 5.39%; N, 9.97%.

(5Z,5′Z)-5,5′-((5-benzyl-2-hydroxy-1,3-phenylene)bis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7h

Yield 95%; yellow solid; mp = 335–338°C; 1H NMR (400 MHz, DMSO-d): δ 11.52 (br, n class="Chemical">1H, OH), 7.91 (s, 2H, =CH), 7.86 (s, 2H, Ar-H), 7.59–7.43 (m, 5H, Ar-H), 4.00 (s, 2H, CH2), 3.10–3.08 (m, 8H, piperidine-H), 1.51–1.50 ppm (m, 12H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 180.1 (C=O), 173.5 (C=N), 152.6 (=CH), 132.3 (thiazole-C5), 162.4, 139.3, 137.4, 133.7, 129.2, 128.7, 126.4, 123.8 (Ar-C), 49.6, 49.1, 25.7, 25.4, 23.5 (piperidine-C), 41.6 ppm (CH2); IR (KBr, cm−1): νmax 3265–3098 (OH), 1689 (C=O), 1623 (C=N), 1617 (C=C); HRMS: m/z [M + Na]+ calcd: 595.1815, found 595.1811; Anal. Calc. for C31H32N4O3S2: C, 65.01%; H, 5.63%; N, 9.78%. Found: C, 65.07%; H, 5.61%; N, 9.75%.

(5Z,5′Z)-5,5′-((1H-pyrazole-3,5-diyl)bis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7i

Yield 96%; yellow solid; mp = 377–381°C; 1H NMR (400 MHz, DMSO-d): δ 14.03 (br, n class="Chemical">1H, NH), 7.94 (s, 2H, =CH), 7.10 (s, 1H, pyrazole-H), 4.00–3.89 (m, 8H, piperidine-H), 1.78–1.69 ppm (m, 12H piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 180.4 (C=O), 174.1 (C=N), 152.9 (=CH), 133.8 (thiazole-C5), 149.7, 109.8 (pyrazole-C), 49.7, 49.4, 25.4, 25.1, 23.7 ppm (piperidine-C); IR (KBr, cm−1): νmax 3245 (NH), 1701 (C=O), 1604 (C=N), 1596 (C=C); HRMS: m/z [M−H]+ calcd: 455.1322, found 455.1326; Anal. Calc. for C21H24N6O2S2: C, 55.24%; H, 5.30%; N, 18.41%. Found: C, 55.21%; H, 5.33%; N, 18.38%.

(5Z,5′Z)-5,5′-((methylenebis(6-hydroxy-3,1-phenylene))bis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7j

Yield 97%; yellow solid; mp = 365–368°C; 1H NMR (400 MHz, DMSO-d): δ 12.77 (br, 2H, 2OH), 7.99 (s, 2H, =CH), 7.30–7.29 (d, J = 7.7 Hz, 2H, Ar-H), 7.20 (s, 2H, Ar-H), 7.09–7.08 (d, J = 7.7 Hz, 2H, Ar-H), 4.10 (s, 2H, CH2), 3.78–3.70 (m, 8H, n class="Chemical">piperidine-H), 1.79–1.59 ppm (m, 12H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 179.7 (C=O), 173.2 (C=N), 153.5 (=CH), 132.3 (thiazole-C5), 161.2, 129.4, 129.0, 127.1, 126.7, 123.8 (Ar-C), 49.9, 49.7, 25.8, 25.5, 23.4 ppm (piperidine-C); IR (KBr, cm−1): νmax 3321–3075 (OH), 1697 (C=O), 1612 (C=N), 1592 (C=C); HRMS: m/z [M−H]+ calcd: 587.1786, found 587.1789; Anal. Calc. for C31H32N4O4S2: C, 63.24%; H, 5.48%; N, 9.52%. Found: C, 63.25%; H, 5.44%; N, 9.48%.

(5Z,5′Z)-5,5′-(1,4-phenylenebis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7k

Yield 98%; yellow solid; mp = 348–350°C; 1H NMR (400 MHz, DMSO-d): δ 7.91 (s, 2H, =CH), 7.21 (s, 4H, Ar-H), 3.65–3.61 (m, 8H, n class="Chemical">piperidine-H), 1.91–1.79 ppm (m, 12H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 180.2 (C=O), 174.7 (C=N), 153.3 (=CH), 132.9 (thiazole-C5), 135.8, 130.2 (Ar-C), 49.9, 49.4, 25.5, 25.2, 23.1 ppm (piperidine-C); IR (KBr, cm-1): νmax 1690 (C=O), 1622 (C=N), 1599 (C=C); HRMS: m/z [M]+ calcd: 466.1498, found 466.1495; Anal. Calc. for C24H26N4O2S2: C, 61.78%; H, 5.62%; N, 12.01%. Found: C, 61.77%; H, 5.65%; N, 11.97%.

(5Z,5′Z)-5,5′-(1,3-phenylenebis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7l

Yield 91%; yellow solid; mp = 359–362°C; 1H NMR (400 MHz, DMSO-d): δ 7.89 (s, 2H, =CH), 7.35–7.34 (d, J = 7.7 Hz, 2H, Ar-H), 7.09–7.06 (t, J = 7.9 Hz, n class="Chemical">1H, Ar-H), 6.70 (s, 1H, Ar-H), 3.92–3.91 (d, J = 5.8 Hz, 5H, piperidine-H), 3.80 (br, 3H, piperidine-H), 1.88–1.72 ppm (m, 12H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 180.0 (C=O), 174.4 (C=N), 153.4 (=CH), 132.5 (thiazole-C5), 135.2, 129.3, 128.8, 128.6, 124.3 (Ar-C), 50.1, 49.7, 25.4, 25.2, 23.2 ppm (piperidine-C); IR (KBr, cm−1): νmax 1699 (C=O), 1611 (C=N), 1589 (C=C); HRMS: m/z [M]+ calcd: 466.1498, found 466.1499; Anal. Calc. for C24H26N4O2S2: C, 61.78%; H, 5.62%; N, 12.01%. Found: C, 61.75%; H, 5.67%; N, 11.96%.

(5Z,5′Z)-5,5′-(1,2-phenylenebis(methanylylidene))bis(2-(piperidin-1-yl)thiazol-4(5H)-one) 7m

Yield 82%; yellow solid; mp = 339–341°C; 1H NMR (400 MHz, DMSO-d): δ 8.10 (s, 2H, =CH), 7.79–7.70 (d, J = 7.9 Hz, 2H, Ar-H), 7.22–7.19 (t, J = 7.8 Hz, 2H, Ar-H), 3.90–3.83 (m, 4H, n class="Chemical">piperidine-H), 3.69–3.60 (m, 4H, piperidine-H), 1.88–1.80 (m, 6H, piperidine-H), 1.53–1.49 ppm (m, 6H, piperidine-H); 13C NMR (101 MHz, DMSO-d): δ 180.3 (C=O), 174.1 (C=N), 153.9 (=CH), 132.7 (thiazole-C5), 135.9, 130.1, 128.5 (Ar-C), 49.6, 49.2, 25.7, 25.3, 23.5 ppm (piperidine-C); IR (KBr, cm−1): νmax 1689 (C=O), 1621 (C=N), 1613 (C=C); HRMS: m/z [M + Na]+ calcd: 489.1396, found 489.1397; Anal. Calc. for C24H26N4O2S2: C, 61.78%; H, 5.62%; N, 12.01%. Found: C, 61.79%; H, 5.60%; N, 11.98%.