A facile and efficient synthesis of 1,8-dioxodecahydroacridines derivatives catalyzed by cobalt–alanine metal complex under aqueous ethanol media

A facile and convenient method for the synthesis of acridines and its derivatives was developed through one-pot, three-component condensation reaction of aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexanedione, aryl amines or ammonium acetates in the presence of a catalytic amount of cobalt–alanine metal complex using aqueous ethanol as a reaction medium is reported. The present described novel methodology offers several advantages over the traditional methods reported in the literature, such as mild reaction conditions, inexpensive catalyst, short reaction times, excellent yields of products, simplicity and easy workup are the advantages of this procedure.


Introduction
Multi-component reactions (MCRs) have been paid much attention by synthetic organic chemists worldwide due to the effectiveness of multiple component reactions at building functionalized, novel drug discovery procedures and allow the fast, automated and highthroughput generation of organic compounds [1]. Thus we believe that discovering and developing new and novel bond formation of C-N, C-O and C-S bonds by MCRs is usual in numerous heterocyclic compounds is an important pursuit in pharmaceutical, biological and material science [2]. Consequently, the development of new multicomponent reactions towards biomedical and industrial scaffolds is inevitable at the present time. Therefore, in the last decade research in academia and industry has increasingly emphasized on the use of MCRs [3][4][5][6][7][8][9][10][11].
However, some of these reported methods for the synthesis of 1,8-dioxodecahydroacridine have limitations such as low yields, unpleasant experimental procedure, reagents are expensive or the use of an excess of catalyst, generation of polluting effluents and prolonged reaction times. Therefore, there is scope for further innovation of methods with milder reaction conditions, short reaction times, increase in variation of the substituents in the components and better yields for the synthesis of 1,8-dioxodecahydroacridine, the discovery of new methodologies using new and efficient catalyst is highly desirable.
In continuation to our effort in developing novel transition metal complexes with amino acids for various organic transformations [56][57][58], herein we would like to report an efficient method for the synthesis of 1,8-dioxodecahydroacridine derivatives through onepot three component cyclisation reaction catalyzed by cobalt-alanine complex under an aqueous ethanol solvent system.

Results and discussions
Initially, we studied the one-pot three component condensation reaction of benzaldehyde (1 mmol), dimedone (2 mmol) and aniline (1 mmol) as a model reaction in the presence of cobalt-alanine complex (5 mol%) as a catalyst in aqueous ethanol solvent system and the product was obtained in excellent yield (Scheme 1).
After successful of the model reaction, we studied for the optimization of the reaction conditions with respect to temperature, time, solvent and molar ratio of the catalyst. It was observed that 5 mol% of catalyst was enough to complete the reaction and the desired 1,8-dioxodecahydroacridines products were obtained in high yield. The results are summarized in Table 1.
Further, we performed a screening of various solvents such as acetonitrile, DCM, DMF, EtOH and without solvent system for this reaction ( Table 2, entries 1-5). we found ethanol (Table 2, entry 4) was the best solvent to afford the desired products in higher yield in shorter reaction time.
To evaluate the scope and the generality of this new protocol for various aldehydes and amines under optimized conditions. A series of aromatic aldehydes bearing either electron-donating or electron-withdrawing substituents reacted successfully with dimedone and aromatic amines or ammonium acetate to afford a wide range of substituted 1,8-dioxodecahydroacridines  products in high yields in a shorter reaction time and the results are summarized in Table 3. We explored further the electronic effect of various substituents present on the aldehyde component. We noticed that a wide range of aldehydes having both electron-donating and electron-withdrawing substituents are equally facile for the reaction, and gave the corresponding 1,8-dioxodecahydroacridine derivatives in very good yields. We have observed most of the electron-donating aldehydes reacted in a shorter reaction time and gave the corresponding 1,8-dioxodecahydroacridine derivatives in good yields than electron-withdrawing aldehydes.
The physical and spectral data of synthesized compounds were (4a-4v) found to be in agreement with the reported data.
A plausible mechanism for the formation of the 1,8-dioxodecahydroacridine products using cobaltalanine metal complex as a catalyst has presented in Scheme 2.

Conclusion
In conclusion, we have developed a facile and an efficient protocol for the synthesis of 1,8-dioxodecahydroacridines using cobalt-alanine metal complex as a catalyst in aqueous ethanol as solvent via one-pot three-component condensation of aromatic aldehydes, dimedone, aniline or ammonium acetate. Significant advantages of this study are reasonably simple experimental workup procedure and catalyst preparation, ease of product isolation, high to excellent yields, short reaction time and using catalytic amount of cobalt-alanine metal complex, are notable advantages of the present methodology.

Materials and methods
All chemicals were purchased from Sigma Aldrich and used as received without further purification. All chemicals and reagents used in the present study were of analytical grade. The reactions were monitored by TLC using silicagel plates. The FTIR spectra were recorded on a Shimadzu JASCO FTIR-460 plus spectrometer using KBr pellets or neat. The UV-visible spectra of the compounds were recorded on Shimadzu UV-2100 spectrophotometer. The morphology of synthesized complex was characterized by Scanning electron microscopy (SEM) on a JEOL-JSM-6390 LV. 1 H NMR and 13 C NMR spectra were recorded on a Brucker DRX 500 AVANCE (500 MHz) spectrometer using CDCl 3 as solvent and TMS as internal standard. The elemental analysis of the complexes were recorded by using Perkin-Elmer CHN-2400 analyzer their results were found to be good agreement with the calculated values. Photoluminance spectra of the complexes and ligands were recorded on LUMINA fluorescence spectrometer of Thermo Scientific Co. USA. The XRD measurements were performed on Schimadzu DX-6000 using Cu for Kα-particle source.

General procedure for the preparation of cobalt-alanine complex
It is commonly well-known that a metal ion can bind two amino acids to form an amino acid metal complex (Fig. 1). Therefore, amino acid-metal complexes were prepared in hot ethanol solvent by reacting the corresponding metal ion and amino acid in a 1:2 molar ratio.
The synthesis of cobalt-alanine metal complex was achieved in a two steps. In a first step, the CoCl 2 ·6H 2 O (2.4 g) metal salt was dissolved in a hot ethanol solvent and l-alanine (1.8 g) amino acid ligand also dissolved in ethanol separately. In the second step, the resultant solution of ligand was slowly added drop by drop into the metal salt solution under vigorous stirring. Once the addition of ligand solution was completed, then 0.01 M Na 2 CO 3 solution also added slowly to adjust the P H around 6.5 to 8.5 for the formation of Co-alanine metal complex. The reaction mixture was refluxed for 3 h at 80 °C under vigorous stirring (Scheme 3) [56][57][58]. The reaction progress was observed by TLC. The mobile phase condition was n-butanol:acetone:acetic acid:water (7:7:2:4) used as a solvent system. The TLC plate was run in this solvent system and the obtained amino acid metal complex was moved well on the TLC plate and also visualized by using solution of ninhydrin. After completion of the reaction, as indicated by TLC, the mixture was allowed to cooled at room temperature; thus the obtained solid crude product was separated by filtration and the crude product was recrystallized in acetone and diethyl ether solvent system with constant stirring under reflux for a period of time, later it was allowed to cool. The resultant solid product was filtered and dried under vacuum. The obtained pure solid product was in a purple color.
Elemental analysis: C: 30.14%, H: 5.52%, N: 11.82%, Co: 25.24%. The synthesized cobalt-alanine metal complex was characterized by using photoluminescence spectroscopy, which provided an evidence of complexation. The recorded emission spectra showed an interesting evidence for the complex formation. The emissions at λ max 556-566 and 660-730 nm provide evidence that the metal atoms are transferring energy to the ligand (alanine) hence; promoting the photoluminescence to the organic ligand (Fig. 2).
Further evidence to suggest this justification was revealed by the powder XRD analysis of the complex. The obtained new peaks were observed at 30-40 θ which clearly provides the evidence for the formation of complex (Fig. 3).
The final evidence of complex composition was predicted from by SEM analysis. The SEM-micrograph for the cobalt-alanine has shown in Fig. 4. The morphology, texture and shape of the synthesized complex with varying thickness in the range of 5 to 10 µm are seen. The morphology of this complex was seen as rods at different magnifications.

General procedure for the synthesis of 1,8-dioxodecahydroacridines catalyzed by cobalt-alanine metal complex
A mixture of an aromatic aldehyde 1 (1 mmol), 5,5-dimethyl-1,3-cyclohexanedione 2 (2 mmol), aromatic amine or ammonium acetate 3 (1.2 mmol) and cobalt-alanine complex (5 mol%) in ethanol (10 mL) was stirred at reflux. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature and   filtered. The filtrate was concentrated to obtained the crude product. The crude products were purified and recrystallized from EtOH and water mixture to obtain pure products in high yields (Scheme 4).