Ionic liquids have green properties such as non- flammability, chemical and thermal stability, extended solvation properties, and negligible vapor pressure ^[1]. Task-specific ionic liquids (TSILs) have been used as valuable substitutes for volatile organic solvents and are environmentally benign catalysts and reagents in chemical procedures ^[2]. Brönsted acidic ionic liquids were synthesized to replace mineral liquid acids like sulfuric acid and hydrochloric acid in academic and industrial chemistry ^{[3, 4, 5]}. The introduction of functional groups such as SO₃H and SO₄H into the cations or anions of ionic liquids obviously changes their acidity and water solubility ^{[6, 7, 8]}, and also makes them useful for use under solvent-free conditions. TSILs can be recycled and they facilitate the isolation of product when the TSIL and product are present in two different phases.

The use of an ionic liquid as a catalyst under solvent-free conditions has been demonstrated in the four-component Hantzsch reaction for the synthesis of polyhydroquinoline derivatives. The four-component Hantzsch reaction in the presence of an ionic liquid [HMIm]BF₄ without a solvent shortened the reaction time to a few minutes at 90 °C and increased the yield up to 96% ^[9]. Some physicochemical properties depend on the halide content of the ionic liquid ^[10]. Typical ionic liquids consist of halogen-containing anions, which limit their ‘‘greenness’’, and the toxic effects of the anion have been studied ^{[11, 12, 13, 14, 15, 16, 17, 18, 19]}. Therefore, ionic liquids with halogen-free anions such as the phosphate or sulfate anion have been developed.

Nitrogen-containing heterocycles have received much attention in chemistry due to their wide spectrum of pharmacological and biological activities as antiasthmatic, anti- inflammatory, antimalarial, anticancer, and anthelmintic agents ^{[20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]}. They are useful dyes and intermediates in organic synthesis ^{[31, 32, 33, 34, 35, 36, 37, 38]}. These compounds also are used as a ligand for the preparation of OLED phosphorescent complexes ^[39] and for the preparation of nano and mesostructures with enhanced electronic and photonic properties ^{[40, 41, 42, 43]}.

4-Substituted-1,4-dihydropyridine (1,4-DHP) derivatives are used in pharmacological species such as amlodipine, felodipine, isradipine, lacidipine, nifedipine, and nicardipine ^{[44, 45, 46, 47, 48]}. They also have other therapeutic applications that include neuroprotectant, platelet antiaggregatory activity, and cerebral anti-ischemic activity in the treatment of Alzheimer’s disease, and as a chemo-sensitizer in tumor therapy ^{[49, 50]}. Different procedures and various catalysts have been reported for the preparation of 1,4-DHPs ^{[51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61]}.

Recently, the halogen-free acidic ionic liquid 3-methyl-1- sulfonic acid imidazolium hydrogen sulfate ((MSAIm)HSO₄) that bears a sulfonic acid group in an imidazolium cation and hydrogen sulfate as the anion was synthesized, and its applications in the promotion of the protection of hydroxyl groups ^[62] and the synthesis of coumarins by the Pechmann reaction ^[63] were investigated. Also, binuclear Brönsted acidic ionic liquids were prepared and their catalytic activity was shown in esterification reactions ^[64]. Here in a continuation of these studies, the preparation of a binuclear Brönsted acidic ionic liquid, namely, 1,1'-butylenebispyridinium hydrogen sulfate (Bbpy)(HSO₄)₂, and its application in the synthesis of ethyl-4- aryl-hexahydro-trimehtyl-5-oxoquinoline-3-carboxylate derivatives under mild reaction conditions is presented.

The synthesis of 1,1'-butylenebispyridinium hydrogen sulfate (Bbpy)(HSO₄)₂ involved a two-step process (Scheme 1). Two equivalent of pyridinium was alkylated with 1,4- dichlorobutane in acetonitrile under reflux conditions for 24 h in the first step. The resulting quaternary halide 1,1'- butylenebispyridinium dichloride (Bbpy)Cl₂ was transformed into (Bbpy)(HSO₄)₂ by concentrated H₂SO₄ as the anion exchange agent in CH₂Cl₂ under reflux conditions for 48 h. (Bbpy)(HSO₄)₂ was isolated as a viscous liquid. The structure was confirmed by ¹H NMR and ¹³C NMR. The viscosity of (Bbpy)(HSO₄)₂ was 210 and 198 cPa at 28 °C. The water content of (Bbpy)(HSO₄)₂ was determined to be 2.4% by the Karl-Fischer titration method. The binuclear ionic liquid (Bbpy)(HSO₄)₂ was immiscible with EtOAc, n-hexane, and toluene but readily soluble in water, methanol, ethanol, lactic acid, and dichloromethane. So they can be separated conveniently from the product by a simple phase separation. The chloride impurity content in (Bbpy)(HSO₄)₂ was below 168 ppm using a method reported in Ref. ^[65]. These quantities would not be a problem for the catalytic application in the synthesis of unsymmetrical polyhydroquinolines.

Scheme 1. Synthesis of 1,1'-butylenebispyridinium hydrogen sulfate (Bbpy)(HSO4)2.

The condensation reaction of dimedone (1), 4- chlorobenzaldehyde (2c), ethyl acetoacetate (3), and ammonium acetate was selected as the model reaction. Parameters such as the amount of ionic liquid of (Bbpy)(HSO₄)₂ (5, 10, and 20 mg) in different solvents (CH₂Cl₂, CH₃CN, CH₃OH, C₂H₅OH, H₂O, and the absence of solvent) and reaction temperature (room temperature and reflux) were changed and analyzed to optimize the conditions. It was found that the use of 10 mg (2.4 mol%) loading of the catalyst was sufficient to promote the reaction, and more catalyst did not improve the yield. Among the solvents, methanol was found to be the best with the use of reflux for the yield of product (78%) and rate of the reaction (1 h). When the model reaction was carried out in the absence of the ionic liquid (Bbpy)(HSO₄)₂ in methanol under reflux for 1 h, the yield of the product was very low (trace). In order to look at the effect of temperature, the model reaction was performed in methanol as solvent under both room temperature and reflux. Ethyl-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5- oxoquinoline-3-carboxylate (4c) was obtained in 22% yield within 1 h at room temperature. With reflux, 78% yield of (4c) was obtained in the same time. A high temperature accelerated the reaction. When the model reaction was carried out in ethanol under reflux in the presence of 10 mg (Bbpy)(HSO₄)₂, 4c was obtained in 72% yield in 1 h. However, 4c was obtained in 95% yield in the presence of 10 mg (Bbpy)(HSO₄)₂ at room temperature in 7 min under solvent-free conditions (Scheme 2). These data showed that the condensation Hantz sch reaction was facilitated by the absence of solvent. The environment of the solvent-free system was probably different from that in the solutions, and this facilitated the Hantzsch condensation ^[66].

Scheme 2. Synthesis of ethyl-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylate in the presence of (Bbpy)(HSO4)2.

The optimized conditions for the reaction were selected as 10 mg ionic liquid (Bbpy)(HSO₄)₂, room temperature, and absence of solvent. Various aryl/heteryl aldehydes (2) were converted into the corresponding ethyl-4-aryl-1,4,5,6,7,8- hexahydro- 2,7,7- trimethyl-5-oxoquinoline-3-carboxylate derivatives (4a−x) under the optimized conditions (Table 1). The polyhydroquinoline yield and reaction time were dependent on the electronic nature and position of the substituent on the aromatic aldehydes. The reaction time was slightly longer when an aryl aldehyde with an electron-donating substituent was employed (Table 1, entries 7−9, 13, and 16−20). The yield of the 4-HO-C₆H₄CHO reaction (88%) under the optimized conditions after 15 min was less than that of 4-NO₂−C₆H₄CHO (96%) in 5 min (Table 1, entries 8 and 10) because the activity of aldehydes with electron-withdrawing groups (−NO₂ and halogens) was higher than that of aldehydes with electron-donating groups (CH₃O− and HO−). Also, aldehydes with ortho-position substituents offered lower yields than the para-position substituents (Table 1, entries 3, and 11, 10 and 14). When an aliphatic aldehyde was used as the substrate, GC-MS analysis of the reaction mixture showed numerous products. The molecular structure of new products was established from their spectral properties (IR, ¹H NMR, and MS), m.p., and elemental analysis. The known products were characterized by their physical data (m.p., IR, and ¹H NMR) and comparison with standard samples.

Table 1 Synthesis of ethyl-4-aryl/heteryl-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylates in the presence of (Bbpy)(HSO4)2. Entry Substrate (2) Product (4) Time (min) Isolated yield (%) m.p. (°C) Found Reported 1 C6H5−CHO a 8 92 202-204 202-204 [53] 2 4-F−C6H4−CHO b 7 92 182-184 184-186 [53] 3 4-Cl−C6H4−CHO c 7 95 240-242 241-243 [54] 4 4-Br−C6H4−CHO d 7 94 250-252 253-255 [53] 5 4-CH3−C6H4−CHO e 10 92 261-263 260-261 [53] 6 4-(CH3)2C−C6H4−CHO f 10 90 175-177 179-180 [55] 7 4-CH3O−C6H4−CHO g 12 86 255-257 257-259 [53] 8 4-HO−C6H4−CHO h 15 88 230-232 232-234 [53] 9 4-(CH3)2N−C6H4−CHO i 12 87 231-233 229-231 [53] 10 4-NO2−C6H4−CHO j 5 96 240-242 240-242 [9] 11 2-Cl−C6H4−CHO k 10 90 202-204 208-210 [9] 12 2,4-Cl2−C6H3−CHO l 10 92 242-244 241-244 [53] 13 3,4-(CH3O)2−C6H3−CHO m 15 88 196-198 198-200 [56] 14 2-NO2−C6H4−CHO n 7 89 207-209 207-208 [56] 15 3-NO2−C6H4−CHO o 7 95 182-184 182-184 [54] 16 3-CH3O-4-HO−C6H3−CHO p 12 85 215-217 219-221 [55] 17 2-C2H5O-4-HO−C6H3−CHO q 17 83 197-199 — 18 2-HO-5-Br−C6H3−CHO r 15 84 228-230 — 19 2-HO-3,5-Br2−C6H2−CHO s 15 86 280-282 — 20 2-HO-5-Cl−C6H3−CHO t 15 83 210-212 — 21 Cinnamaldehyde x 8 93 200-202 204-206 [53] 22 Furfural u 17 84 242-244 246-248 [53] 23 3-Nicotinaldehyde v 15 82 69-71 66-67 [53] 24 2-Thienylaldehyde w 20 79 236-238 238-240 [53] Reaction conditions: Dimedone 1 mmol, aryl/heteryl aldehyde 1 mmol, ethyl acetoacetate 1 mmol, ammonium acetate 1 mmol, (Bbpy)(HSO4)2 10 mg (2.4 mol%), room temperature, solvent-free.

Table 1 Synthesis of ethyl-4-aryl/heteryl-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-carboxylates in the presence of (Bbpy)(HSO4)2.

The reuse of (Bbpy)(HSO₄)₂ was a prime objective in the present method. Therefore, we performed a set of reactions to explore whether the ionic liquid can be reused (Fig. 1). After completion of the reaction, the ionic liquid was recovered, and the reaction vessel was charged with further portions of the substrate for another run, which afforded the product in 93% yield. This process was repeated four more times, and each run afforded the desired product in excellent yield. The simple experimental and product isolation procedures combined with the ease of recovery and reuse of ionic liquid will contribute to the development of a green strategy for one-pot multicomponent reactions. In addition, the sulfuric acid leakage from the matrix was evaluated under the optimized reaction conditions. No measurable leakage was observed under the optimized conditions. After 8 recycle runs, the catalyst retained 95% of its initial activity (data not shown).

Fig. 1. Recyclability of (Bbpy)(HSO4)2 for the synthesis of ethyl-(4- chlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline- 3- carboxylate (4c).

From the Ref. ^[54], a possible mechanism for this reaction is shown in Scheme 3. Dimedone (1), aldehyde (2), or ethylacetoacetate (3) was activated by the binuclear Brönsted acidic ionic liquid catalyst. First, dimedone or ethyl acetoacetate was converted to its enol form using the Brönsted acidic ionic liquid, and then Knoevenagel type coupling with the activated aldehyde by (Bbpy)(HSO₄)₂ afforded intermediate I or III. Also, the activatation of ethyl acetoacetate or dimedone by the ionic liquid and ammonium acetate gave enamine II or IV. (Bbpy)(HSO₄)₂ gave a proton to activate carbonyl groups, and then the proton was transferred to the ionic liquid in another step. Subsequent Michael addition of enamine II to intermediate I or enamine IV to intermediate III followed by cyclization and dehydration afforded the polyhydroquinoline product (4). Aromatization by air (O₂) was absent in the present method under the reaction conditions.

Scheme 3. Mechanism for the synthesis of polyhydroquinoline in the presence of (Bbpy)(HSO4)2 under solvent-free conditions.

To show the merits of the present method compared to other reported methods for similar reactions, we tabulated some of the results in Table 2. The Hantzsch reaction carried out in the presence of 10 mol% Guanidine HCl (organocatalyst) in ethanol at room temperature gave compound 4c, 4x, 4u, and 4v in 95%, 90%, 78%, and 75% yields in 3 h, respectively ^[69], and compounds 4c, 4e, and 4i were obtained in the presence of 10 mol% L-proline (organocatalyst) in 91%, 94%, and 96% yields in 30 min, respectively ^[25]. In the present method, these compounds 4c, 4e, 4i, 4x, 4u, and 4v were obtained in 95%, 92%, 87%, 93%, 84%, and 82% yields in 7, 10, 12, 8, 17, and 15 min, respectively.

The synthesis of compound 4c was achieved with 83% yield in the presence of 25 mol% 1-(4-sulfonic acid)butyl-3- methylimidazolium hydrogen sulfate in ethanol under reflux conditions in 1.5 h, and the same reaction carried out in the presence of 10 mol% 1-vinyl-3-ethyl imidazole iodide in ethanol as solvent at 40 °C offered product 4c in 93 % yield in 12 min. On the other hand, product 4c was synthesized in 95% yield in the presence of 2.4 mol% of (Bbpy)(HSO₄)₂ at room temperature under solvent-free conditions in 7 min.

Also, compounds 4c, 4i, 4g, and 4h were obtained in 92%, 95%, 95%, and 94% yield in the presence of 3 mol% of Brönsted acidic ionic liquid [pyridine-SO₃H]Cl at 50 °C in 10, 8, 10, and 8 min, respectively ^[71], and these compounds were obtained in 97%, 98%, 96%, and 95% yield in water using 3 mol% [2-MPyH]OTf at room temperature in 5, 1, 6, and 6 min, respectively ^[77]. In the present method without solvent, products 4c, 4i, 4g, and 4h were obtained in 95%, 87%, 86%, and 88% yields in 7, 12, 12, and 15 min, respectively.

As seen from the results, the rate of reaction and yield of the present method were similar to or higher than those reported in the literature. However, the reported methodologies in the literature suffer from one or more of the following disadvantages: (1) potential health hazard in the preparation of the catalysts, (2) difficulty in handling, (3) high cost of the catalyst, (4) need to use a halogenated solvent, (5) requirement of special efforts to prepare the catalyst, (6) lack of atom economy (use of excess substrate and catalyst), (7) severe reaction conditions and long reaction time (4−24 h), and (8) in some cases, the reported methodology was not suitable for acid-sensitive substrates.

A facile and efficient method for the synthesis of polyhydroquinoline derivatives was developed that has the advantages of simple experimental procedure, solvent-free conditions, good yields, reusability of the catalyst, and ease of product isolation/purification by non-aqueous work-up. Investigations to clarify the mechanism and explore more applications in organic transformations are underway.