Ceria-Molybdenum Mix Metal Oxide: A Mild and Efficient Recyclable Catalyst for One-Pot Synthesis of Polyhydroquinoline via Hantzsch Reaction

In laboratory, ceria-molybdenum mix metal oxide catalyst was synthesized by using simple grinding method and characterized by FT-IR, XRD, SEM, and EDX. Catalytic activities of catalyst were testified in Hantzsch condensation reaction for the synthesis of polyhydroquinoline by using dimedone, substituted aryl aldehydes, ethylacetoacetate and ammonium acetate with high percent yield. It is an efficient catalyst for 1,4-dihydropyridines synthesis. Cerium molybdenum mix metal oxide catalyst can be re-covered and re-used.


Introduction
Recently from 2-3 decades, 1,4dihydropyridines/ polyhydroquinoline (PHQ) identified, as a desired structure that is screened synthon / moiety as part of many drug design processes in medicinal chemistry due to their amine group and other functional group increase biological importance of molecules. In between the nitrogen base pair containing heterocyclic designs, small molecule like azoles, Imidazoles, 1, 4-dihydropyridines extremely important component due to their presence in a huge number of biological application such as neuroprotectants [1], geroprotective, cerebral antiischemic agents, bronchodilator [2], antiinflammatory, multidrug resistance (MDR) in cancer [3], antimicrobial [4], antitubercular [5], anti-parkinson, anticancer [6], analgesic and anticonvulsant [7], activities usual products as advantage pharmacophores. Similarly in polyhydroquinoline (PHQ) and its derivatives is impressive significance because of their important roles in biological systems such as anti-malarial activity against plasmodium falciparum, in vitro antibacterial activity against pathogenic strains of bacteria and fungi, moreover their antitubercular activity against Mycobacterium tuberculosis H37Rv strain [8]. Furthermore they have used as calcium channel agonist [9], it is fix the disarranged heart proportion as a chain cutting specialist [10], Cardiovascular agents, nifedipine, nicardipine, hypertension treatment [11], anticancer agents [12], antimicrobial activity [13], antihyperglycemic as well as antidyslipidemic [14], similarly other related derivatives which are effective in the treatment of hypertension [15]. Various methods have been reported for the synthesis of 1,4-Dihydropyridines (DHP) or polyhydroquinoline (PHQ), for the reason lots of biological importance associated with these derivatives. The classical method involves a one pot four-component cyclocondensation of an aryl aldehyde, dimedone, ethylacetoacetate and ammonia in presence of Lewis acid catalyst or acid / acetic acid or reflux in ethanol or other solvent [16]. However, such methods suffer from quite a few disadvantages such as extensive reaction times, use of harmful and volatile as well as excess organic solvents, low product yields and harsh reaction conditions.
Recently, researcher attract to simplify methods for synthesis of highly active compound of polyhydroquinoline such as using both conventional as well as nonconventional method [17]. Large number of mixed metal oxides catalyst utilized as reusable catalysts. It is an attractive class of materials for sustainable development of pharmaceutical industrial products [18]. So many classical methods, for the synthesis of polyhydroquinoline were reported such as acetic acid, PEG-400 reaction medium [19], ionic liquids [20]. Some reaction used as special technique like microwave irradiation and ultrasound [21]. Many more methods are require prolong heating time [22,16], Similarly, some other reported methods are including TMSCl [23], HClO4-SiO4 2- [24], HYzeolite [25], Ionic liquids [26], MCM-41 [10], Mesoporous vanadium ion doped titanic nanoparticles (V-TiO2) [27], Yb(OTf)3, Gadolinium triflate [28], Cu (II) Complex, silica supported sulfuric acid (SSA) [29], this reported method quite efficient for the synthesis of 1,4dihydropyridines or polyhydroquinolines and the development in this field remarkable as well as needs to improvement of the synthesis process.
Herein, we have reported efficient cost effective and reusable ceria-molybdenum mix metal oxide (CMMO) catalyst for one-pot synthesis of polyhydroquinolines (PHQ) by cyclocondensation reactions of substituted aryl aldehydes, dimedone, ethyl acetoacetate, and nitrogen source of ammonium acetate in presence of ceria-molybdenum as a heterogeneous catalyst which was prepared by simple grinding method to gives excellent yield.

Results and Discussion
Synthesis of heterogeneous catalyst by using green approach with including percent atom economy is an emerging and challenging area of researchers, considering environmental, ecofriendly catalyst and balance reaction side product. Government apply rules and regulation with alteration legislation on the discharge of waste (contaminated water) and cyanogenic emissions having serious implications for the pharmaceutical industry toward the implementation of innovative "clean technology" together with the utilization of different heterogeneous catalyzed chemical processes [30]. Here, we have minimized the reaction byproduct in chemical reaction as well as catalyst synthesis and balance the atom economy in total synthesis. The recently developed family of mix metal oxide of Ceria-Molybdenum catalyst with their present high Lewis and Bronsted acidic sites.

Characterization of the catalyst
The XRD pattern of the Cerium-Molybdenum (CM) catalyst calcined at 500°C for 2 hrs are shown in In organic synthesis, the catalyst was optimized the reaction conditions to investigate the reaction involving p-hydroxyl benzaldehyde, dimedone, ethyl acetoacetate, and ammonium acetate to afford the appropriate (PHQ) product (5e). Reaction optimization results are shown in Table 1  The reactions proceed resourcefully and smoothly at 80 ºC (reflux in oil bath) and were completed within 40 min -60 min. with high percent yield up to 85-94%.

General procedure for the synthesis of Catalyst
The ceria-molybdenum (CM) metal oxide catalyst where prepared by simple grinding method, 0.33 gm of ammonium Ceric nitrate salt ( as a source of Ce) and 0.49 gm of ammonium heptamolybdate salt (as a source of Mo) are well mix with mortal and piston for 20 min to change a colure of mixture to form a catalyst, then mixture was calcined at-500ºC for 02 hr. Prepared ceriamolybdenum (CM) mix metal oxide used as a catalyst in organic transformation such as, in synthesis of polyhydroquinolines (PHQ).

Typical procedure for the synthesis of polyhydroquinoline derivatives 5e:
A mixture of p-hydroxy aldehyde 0.122 mg(1 mmol), dimedone 0.140 mg (1mmol), ethylacetoacetate 0.130 mg (1 mmol), ammonium acetate 0.170 mg (1.5 mmol) and 50 mg ceriamolybdenum (CM) as a catalyst, were the mixture was refluxed up to completion of reaction in presence of ethanol. Reaction was monitored by using TLC (pet ether: ethyl acetate 6: 4, as an eluent). After completions of reaction then add 5ml excess ethanol to reactant disappeared and filtered to separate a catalyst. Then few mL of child water was added drop wise with continuous stirring in the filtrate to obtained crud product of polyhydroquinolines (PHQ) (5e), solid crude product was filtered and recrystallized from ethanol to get a pure product.

Reusability and recycling test
Subsequent to completion of the catalytic reactions, the Lewis acid catalyst ceriamolybdenum (CM) was recollect through filtration for further reuse of next batch reaction. Then they are carefully washed consecutively with acetone or ethyl acetate (2-3 times). Then the recollected catalyst was dried in a furnace at 110ºC for 10 min. The recycling effectiveness of the CM catalyst was tested up to four time reused without loose of catalytic activity. In the synthesis of polyhydroquinoline from dimedone, substituted aryl aldehydes, ethylacetoacetate and ammonium acetateas reactants, subsequent this recycling process, CM catalyst was reused for three consecutive cycles.

Conclusions
In summary, we have developed new methods of one-pot synthesis of polyhydroquinolines(PHQ) using ceria-molybdenum mix metal oxide catalyst to gives excellent yields. Ceria-molybdenum (CM) as a heterogeneous Lewis acid catalyst offers several advantages such as reusability without loss of catalytic activity up to three cycles, easy to separate, easy to handling. In the synthesis of catalyst and organic synthesis milder reaction condition, better yield, simple experimental procedure and easier work-up, is an environmental binge process, eco-friendly, less toxic catalyst as well as less corrosive, over all synthesis become a green synthesis.

Supporting Information
Full experimental detail, 1 H and 13 C NMR, Mass spectra and other information of this material can be found via the "Supplementary Content" section of this article's webpage.