Synthesis of benzoimidazoquinazolinone and indolylxanthenone derivatives using Keggin-type heteropoly-11-molybdo-1-vanadophosphoric acid supported on Montmorillonite K-10 clay as catalyst: a green approach

Biologically as well as medicinally important two different organic scaffolds, viz. benzimidazole and quinazoline, are present in the class of heterocyclic compounds called benzimidazoquinazolinone. Similarly, indolylxanthenones are the compounds containing two important organic moieties such as indole and xanthene. In this work, a new green protocol for the synthesis of benzoimidazoquinazolinone and indolylxanthenone derivatives was attained under environmental-friendly solvent-free condition through a simple one-pot three-component condensation reaction. This condensation was achieved by using 10% heteropoly-11-molybdo-1-vanadophosphoric acid (H4[PVMo11O40])-loaded Montmorillonite K-10 clay material (PVMoK-10) as an efficient heterogeneous catalyst. The identification and characterization of the derivatives were done by physical as well as spectral techniques. Synthesis of ten derivatives of benzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one and two derivatives of 9-(1H-indol-3-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-one was successfully achieved using this protocol. A tentative reaction mechanism has also been proposed for the synthetic plans.


Introduction
Heterocyclic compounds are renowned for their diversified and potential biological activity essential for everyday life [1][2][3][4][5][6]. More specifically, the nitrogen-containing heterocyclic moieties are more active in the biological and the pharmacological areas [7][8][9] because of their resemblance of structure with some naturally existing organic molecules, which shows familiar biological activity [4]. Furthermore, the review of literature reveals that polyheterocyclic molecular entity enhances the biological versatility of the natural product [10]. This part of the work dealt with the synthesis of two such types of polyheterocyclic compounds, viz. benzoimidazoquinazolinones and indolylxanthenones.
Benzoimidazoquinazolinone has been attracted extensively by synthetic organic as well as medicinal chemists, due to their diversified applications in the multitude of areas [5,[11][12][13]. On the other hand, the chromene part of xanthene present in indolylxanthenones is one of the more privileged scaffolds in natural products [14]. They are found to be a valuable precedence motif for designing pharmacophore in the area of medicinal chemistry for the development of drugs [15][16][17]. Organic chemists are more concerned with devising synthetic strategies for the synthesis of such biologically active organic molecules. In this regard, multi-component reactions (MCRs) become an appropriate method for the synthesis of variety of medicinally and biologically important heterocyclic organic compounds. MCR involves the selective production of desired complex organic compound in high yield at short reaction time by taking two or more number of readily available starting materials called the synthetic organic precursors in a single pot. MCR becomes a powerful tool for the synthesis of complex organic compounds that are used as drugs through convergent synthetic approach. MCR enables the production of a variety of poly-functionalized organic heterocyclic drug-like compounds. Hence, in contemporary times evolution of new MCR procedures using different types of catalysts has received much attention in synthetic organic chemistry. MCRs diligently have been admired due to their powerful upshot on drug innovation for their sharp focus in shortening the synthetic pathway of drugs and their derivative products [18][19][20][21][22][23][24][25]. Polyoxometalates (POMs) a class of oligomeric aggregates of metal cations bridged by oxide anions capable of existing as free solid acid materials, heteropoly acids (HPAs) attract recent attention in the field of solid acid catalysis. HPAs have an ability to act as proton donor and thereby activate many organic transformations. The main disadvantage of HPA is its low surface area and separation problem from reaction mixture due to very high solubility of HPA in the reaction medium. In order to overcome these problems, HPAs supported on several solid supports and variety of organic transformations have been carried out using these catalytic materials. Tayebee et al. [26][27][28][29][30][31][32][33][34][35][36] have successfully attempted many novel protocols to synthesize biologically active organic molecules using heteropolyoxometalate-supported catalysts through MCRs. Mohammad Nikpassand et al. evolved the usage of modified zeolite solid acid catalysis for the synthesis of variety of organic compounds using MCR protocols [37][38][39][40][41][42][43][44]. This research work is one such attempt to develop a new synthetic protocol for the synthesis of Benzoimidazoquinazolinone and indolylxanthenones using heteropolyoxometalate-supported Montmorillonite K-10 clay catalyst under environmentally benign reaction conditions. A review of the literature finds that a few synthetic approaches have been reported for the synthesis of benzimidazoquinazolines including its synthesis through a threecomponent condensation of 2-aminobenzimidazole, 1,3-cyclohexadione and substituted aromatic aldehydes in the presence of catalyst silica gel under solvent-free condition [45]. Ali Maleki et al. [46] reported the synthesis of benzimidazolo [2,3b]quinazolinone derivatives through a one-pot multi-component reaction promoted by a chitosan-based composite magnetic nanocatalyst. Ziarani et al. [47] proposed a synthetic route for the synthesis of benzimidazoquinazolinones using nanoporous Santa Barbara Amorphous-15 silica (SBA-15).

General reaction procedure for the synthesis of benzo[4,5]imidazo[2,1-b] quinazolin-1(2H)-one derivatives (R1)
Benzo [4,5] imidazo[2,1-b]quinazolin-1(2H)-one derivatives were prepared as per the procedure adopted in the literature [48,68]. A mixture of one millimole each of 2-aminobenzimidazole, 1,3-cyclohexadione, substituted aromatic aldehyde and 0.05 g of the catalyst 10% PVMoK-10 were heated at 100 °C for 1 h in oil bath. TLC method using petroleum ether-ethyl acetate solvent mixture in the ratio of 7:3 was used to follow the proceeding of the conversion. After the completion of the reaction was ascertained through TLC, 5 mL of ethanol was added to the reaction mixture and the mixture was heated. The organic product thus formed was soluble in ethanol. The solid catalyst from the reaction mixture was removed by filtration. The filtrate was then poured into crushed ice pieces, and the solid product isolated was filtered out. The product formed was washed thoroughly with water and dried and recrystallized from ethanol. The recovered catalyst by filtration method was thoroughly washed with water and dried in air oven for about an hour at 100 °C.

General reaction procedure for the synthesis of 9-(1H-indol-3-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-one derivatives (R2)
9-(1H-indol-3-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-one derivatives were prepared as per the procedure reported in the literature [68][69][70]. One millimole each of indole, 1,3-cyclohexadione, salicylaldehyde were mixed with 0.05 g of 10% PVMoK-10 and heated for about 1 h at 100 °C in an oil bath. The completion of the reaction was followed by TLC using the eluent ethyl acetate and n-hexane solvent in the ratio of 7:3. After the reaction is over, 5 mL of ethanol was added in order to dissolve the organic product formed. The solid catalyst from the reaction mixture was filtered out while heating. A solid product was regenerated by pouring the filtrate into water, and the solid separated out was filtered off, washed thoroughly with water, dried well and recrystallized using solvent ethanol. The recovered catalyst by filtration was washed thoroughly with water and dried in air oven at 100 °C for about an hour.
IR Affinity-1 Shimadzu FT-IR spectrophotometer is used for recording Fourier transform infrared (FT-IR) spectra, under atmospheric conditions using KBr pellets. Bruker 400 MHz NMR instrument is utilized for recording proton and 13 C NMR with DMSO-d 6 as solvent and tetramethylsilane as internal standard. Melting points of samples were noted by the electro-thermal melting point apparatus. Elemental analyses were studied using ElementarVario EL III equipment. High-resolution mass spectra (HRMS) were recorded using the maXis Impact 282,001.00081 Mass Spectrometer for the selected products.

Optimization of catalyst
The efficacy of the catalyst was investigated by choosing the condensation reaction of 2-aminobenzimidazole, 1,3-cyclohexadione with benzaldehyde in the presence of catalyst as a model reaction for the preparation of R1 and the condensation of indole, 1,3-cyclohexadione and salicylaldehyde in the presence of catalyst for the preparation of the R2. The reactions were strived with various catalytic materials such as raw Mont K-10, HPAs, viz.  Table 1. Clearly, the results reveal that the performance of 10% catalysts-PVMoK-10 & PV 2 Mo-K10is found to be very high compared to both raw Mont-K10 clay and vanadium-substituted heteropoly acids. Both vanadium (V)-substituted HPA-loaded Mont-K10 clay shows more or less similar catalytic efficacy. Hence, PVMoK-10 has been selected as a catalyst for the current investigation.

Dependency of solvents
The reactions were run in different solvent media such as EtOH, MeOH, H2O, MeCN, DCE, DMF, CHCl 3 , 1,4-dioxane, n-hexane and toluene at elevated temperature (refluxing for an hour). The reaction was also attempted under solventfree reaction condition. The results of the experiments in terms of yield of products R1 and R2 are given in Table 3. The results favor the solvent-free reaction  condition for the present synthetic transformation since the yield of products under this condition is excellent.

Synthesis of benzimidazoquinazolinone derivatives
The optimized reaction procedure has been adapted for the preparation of ten derivatives of R1 (4a-4j) using 2-aminobenzimidazole, 1,3-cyclohexadione and ten structurally diverse aldehydes. The reaction pattern is schematically explained in Scheme 1, and the results are consolidated in Table 4.

Synthesis of indolylxanthenone derivatives
Similarly, the optimized reaction procedure has been adapted for the preparation of two derivatives of R2 (4k and 4l) using 1,3-cyclohexadione, salicylaldehyde and two different indoles. The reaction pattern is schematically explained in Scheme 2, and the results are consolidated in Table 5.
With the help of above procedure, ten different R1 derivatives (4a-4j) and two different R2 derivatives (4k and 4l) have been synthesized through one-pot reaction condition using 10% PVMoK-10 catalyst in solvent-free reaction condition. The details of specific reactants used, products formed (4a-l) and their percentages of yields are collected in Tables 4 and 5.

Tentative mechanism
The tentative mechanism for the synthesis of R1 derivatives using 10% PVMoK-10 catalyst as a promoter has been arrived based on the mechanism reported by Jolodar and Shirini [71] and is shown in Scheme 3. The catalysis involves the following sequence: (i) The nucleophilic attack of enol form of 1,3-cyclohexadione on the carbonyl carbon of aldehyde leads to the formation of intermediate (I) (iv) Dehydration of (IV) leads to the formation of desired product. 10 % loaded solid heteropoly acid, PVMo on Mont K-10 catalytic material, accelerates the organic transformation.
The plausible mechanism for the synthesis of R2 derivatives using 10% PVMoK-10 as a promoter has been arrived as per the mechanisms reported in the literature [57,58] and is shown in Scheme 4. The reaction sequence is given as follows: (i) The nucleophilic attack of enol form of 1,3-cyclohexadione on the carbonyl carbon of salicylaldehyde leads to the formation of intermediate (I).
(ii) The nucleophile indole reacts at the benzylidene double bond of the intermediate (I), which further experiences ring-closure reaction intra-molecularly followed by dehydration and give the desired product.
The primary role of heteropoly acid is a source of proton, which activates the carbonyl group. Scheme 3 Tentative reaction pathway for benzoimidazoquinazolinone synthesis using 10% PVMoK-10 as catalyst 1 3

Recycling of the catalyst
The separation of the catalyst and its reusability are the two most important criteria for the green catalysts.
In the present investigation, the catalyst from the reaction mixture was separated by simply adding excess ethanol with the fused mass produced at the end of the condensation reaction. The product obtained was dissolved in ethanol, whereas the catalyst was separated from the reaction mixture as insoluble residue, filtered off, washed thoroughly with ethanol and dried in hot air oven for an hour at 120 °C. The catalyst thus recovered was reused under the same reaction conditions. It was observed that the reuse of the catalytic material 10% PVMo-K10 showed gradual decrease in its activity. The consecutive performance of the catalyst thus recovered was examined in terms of its % yield of the products and was found to be sustainable for about five times.

Conclusions
An environmentally benign approach has been devised for one-pot three-component synthesis of ten derivatives of benzimidazoquinazolinone and two derivatives of indolylxanthenone with excellent yield of product (85-94%). The synthesis has been achieved under solvent-free reaction medium, using heteropoly-11-molybdo-1-vanadophosphoric acid-supported Montmorillonite K-10 clay material (10%PVMoK-10) as heterogeneous catalyst. Short reaction duration, excellent yield, reusability of the catalytic material, a simple reaction procedure and solvent-free reaction conditions are the advantages of this protocol. A tentative mechanism has been proposed, and Scheme 4 Tentative reaction pathway for synthesis of indolylxanthenone derivatives catalyzed by 10% PVMoK-10 as catalyst experimental evidences for the support of the mechanism are the future scope of the work.