Introduction, 

Quinoline compounds perform a wide range of functions and play a major part in various pharmaceutical, veterinary medicines, fertilizers, and insecticides [1]. They are also used as optical clarifiers, anti-corrosion, and anti-oxidants, and are important intermediates in organic synthesis [2]. Quinolines are an important class of heterocyclic compounds with a range of medicinal properties. In recent years, the preparation of polyhydroquinolines (1,4-dihydropyridines) has been attempted by many chemists due to their biological and physiological importance [3]. Some quinoline derivatives further show antifungal, anti-tumor, anti-arthritis, vasodilator, and anti-diabetic properties [4,5]. 

Polyhydroquinolinesare of great significance in the fields of organic chemistry and pharmaceutical medicine, since they show valuable properties. [6,7]. The therapeutic success of these compounds is attributed to their ability to bind to calcium channels, and thus reduce the passage of calcium flow affecting the calcium balance of cardiovascular tissues, ultimately dilating them, and reducing the blood pressure [8]. Recent studies indicate that 1,4-dihydropyridines can further display antibacterial, anti-tuberculosis, and anti-inflammatory properties, and are also effective in reducing the symptoms of Alzheimer's disease [9-11]. Drugs including nicardipine (Figure 1), lacidipine (Figure 2), nimodipine (Figure 3), and amLodipine (Figure 4) which are used as vascular agents in the treatment of hypertension are feature 1,4-dihydropyridine scaffold.

Figure 1.Nicardipine

Figure 2.Lacidipine

Figure 3.Nimodipine

Figure 4.Amlodipine

Nanoparticles are utilized in the medical and pharmaceutical industries. Nanoparticles have the ability to bind to nanometer-sized drugs and be specifically absorbed by cancer cells. In this way, healthy cells are not exposed to the drug, and the adverse side effects of the drug are reduced. Other applications of nanoparticles are the production of self-cleaning, or fast-cleaning pavement, and concrete. In addition, they are used in the production of waterproof glass and are economical. We used nano particle on CeO₂/ZnO as a catalyst for the synthesis of Polyhydroquinolines.

Polyhydroquinolines and their derivatives are very crucial heterocyclic compounds that function in biological processes and have attracted a lot of attention due to their abundant biological and medicinal activities. Due to the valuable properties of polyhydroquinolines and their derivatives, methods for preparing these important heterocycles have been developed, some of which have already been mentioned.

As a part of our ongoing interest in the nano-cerium (IV) oxide/zinc oxide catalyzed 

reactions to carry out various organic transformations, we further explored their catalytic activity towards the synthesis of polyhydroquinolines via a four-component reaction of an aromatic aldehyde, ethyl acetoacetate, ammonium acetate, and dimedone in the presence of nano CeO₂-ZnO (Scheme 1).

Scheme 1. Synthesis of polyhdroquinoline using nano CeO₂/ZnO

Optimization of reaction conditions

In order to increase the efficiency of the conditions for preparing polyhydroquinoline derivatives, the reaction of trachemibenzaldehyde, dimedone, ethyl acetoacetate, and ammonium acetate was selected as the model reaction. To obtain the best results, three important parameters of catalyst value, solvent, and temperature were investigated for this reaction.

Choice of solvent

The reaction was performed in different solvents. Obviously, the highest yield was observed while using ethanol as a solvent. The results are indicated in Table 1.

Table 1. Synthesis of 5a in the presence of different solvents using nano-CeO₂/ZnO as a catalyst

^aYields were analyzed by GC

Reusability of nano CeO₂/ZnO

10 mL of ethyl acetate was added to the catalyst separated from the reaction mixture by filtration. The mixture was stirred at room temperature for 5 minutes using a magnetic stirrer. The reaction mixture was filtered, and the catalyst remained on filter paper due to its insolubility in ethyl acetate solvent. Then, to reuse the catalyst, the filter material was washed several times with acetone. After drying, the reaction was repeated to check the potency of the catalyst (Table 2).

Effect of temperature change on model reaction

In this study, various amounts of catalyst were tested at different temperatures to obtain the maximum efficiency. As indicated, the highest efficiency was observed in reflux conditions (Table 3).

Comparison of nano CeO₂/ZnO performance with a number of different catalysts in the synthesis of polyhydroquinoline derivatives

By comparing the reaction results with other methods, we found that the nano CeO₂/ZnO 

performed the reaction in a shorter time and with a higher efficiency (Table 4).

To optimize the amount of catalyst, various amounts (0.01, 0.02, 0.03, 0.05, and 0.08 g) of nano CeO₂/ZnO were used. Table 5 represents the test results performed to optimize the amount of catalyst in the presence of different amounts of nano CeO₂/ZnO. The results presented in the table reveal that the amount of 0.05 g of cerium oxide/aluminum oxide nano-catalyst had the best efficiency.

Investigation of the reaction mechanism

The reaction between aromatic aldehyde (1), dimedone (2), ethyl acetoacetate (3), and ammonium acetate (4) is proposed in the presence of the NanoCeO₂/ZnO catalyst in Scheme 2. The catalyst acts as a Lewis acid and attracts electrons of the carbonyl group and activates the carbonyl aldehyde group, which eventually attacks the tautomerizeddimedone and produces intermediate 7. Ethyl acetoacetate is coupled with ammonium acetate and reacts with the intermediate 7, following which the water is removed, and the desired product is obtained (Scheme 2) [20].

Table 2. Reuse of the nano CeO₂/ZnOfor synthesis of (5a)

^aIsolated yields

Table 3. Comparison of various temperatures for the synthesis of 5a

^aIsolated yields

Table 4. Comparison of various catalysts for the synthesis of 5a

^aIsolated yields

Table 5. Comparison of the amount of catalysts for the synthesis of 5a

^aYields were analyzed by GC

Scheme 2. The proposed mechanism for polyhdroquinoline using nano CeO₂/ZnO

Experimental

General

Solvents and chemicals in this research project were purchased from the Merck Company and were used without the need for further purification. The structure of the obtained products has been compared and confirmed with the spectra and physical data from literature.

In this paper, various materials and devices were used that have the following specifications: Electrothermal Bransted-9200 was used to measure melting points. The IR spectra were recorded on an IR Tensor-FT using the KBr tablet. ¹HNMR spectra were recorded in ⁶d-DMSO solvent using TMS as an internal standard on a DRX AvanceBruker-400 MHz spectrometer.

Typical experimental procedure for the synthesis of Hantzschpolyhydroquinoline derivatives

A mixture of aldehyde (1 mmol), dimedon (1 mmol), ethyl acetate (1 mmol), ammonium acetate (2 mmol), and catalyst (0.05 g) in ethanol (5 mL) was refluxed for the indicated time (Table 6). After completing the reaction, as indicated by TLC (in a mixture of ethyl acetate and n-hexane in 3:1 ratio), the reaction solvent was evaporated, and then dried ethyl acetate was added and the catalyst was separated by filtration. The residue solvent was removed under reduced pressure. The pure product was obtained by recrystallization from ethanol. Melting points and IR spectra, ¹HNMR of the obtained crystals were taken and compared with the references.

Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-phenylquinoline-3-carboxylate (5a): ¹H NMRd(ppm):  0.93 (s,3H), 1.05 (s,3H), 1.36 (t, 3H, J=6.9), 2.4-2.39 (m,7H), 3.98 (q,2H,J=6.9), 5.04 (s, 1H), 5.89 (s,1H), and 7.23-7.49 (5H,m).

Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-p-tolylquinoline-3-carboxylate (5b):  0.95 (s,3H), 1.07 (s,3H), 1.29 (t, 3H, J=7.2), 2.13-2.37 (m,7H), 2.38(s,3H), 4.03 (q,2H,J=7.2), 4.67 (s, 1H), 5.53 (S, 1H, NH), and 7.05-7.49 (4H,m).

 Table 6.nanoCeO₂-ZnO catalyzed the synthesis of polyhydroquinolines

Synthesis of nanocerium (IV) oxide-zinc oxide (CeO₂-ZnO)

Preparation of CeO₂-ZnO nanostructures was carried out by magnetic stirring by stirring CeCl₂ (1.04 g), ZnCl₂ (4.09 g), and distilled water (300 mL) continuously at room temperature for 30 minutes in a balloon. By adding a drop of ammonia (NH₄OH) to bring pH to 10.15 and stir at 80 °C for 6 hours. The resulting white precipitate was washed and dried several times at room temperature with water and ethanol and calcined at 400 °C for 5 hours [15].

Figure 5. TEM Spectra of nano CeO₂-ZnO

Figure 6. SEM Spectra of nano CeO₂-ZnO

Conclusion

To sum up, we have found a simple, convenient, straightforward, and practical procedure for the synthesis of polyhydroquinolines derivatives in the presence of nano cerium (IV) oxide/zinc oxide as an efficient catalyst. All starting materials are readily available from commercial sources. The advantages of this reaction include easy separation steps, preparation of products with high efficiency, short reaction time, use of recyclable, and environmentally friendly catalysts. The procedure is very simple and can be used as an alternative to the existing procedures

Orcid

BitaBaghernejad:https://www.orcid.org/0000-0002-1733-0829