An Easy and Efficient Protocol for the Synthesis of 2,3-Dihydroquinazolinones Using a Low Cost and Reusable Heterogeneous Catalyst

Clays revealed high catalytic activity for the synthesis of a series of substituted 2, 3-dihydro-2-phenylquinazolin-4(1H)-one. The synthesis was carried out by reacting Anthranilamide and various substituted aldehydes in acetonitrile at room temperature in the presence of a small amount of the catalyst. Several solvents were examined for this reaction; however, in terms of reaction yield and time, Acetonitrile was found to be the optimum solvent.


Introduction
The evolution of simp le and efficient synthetic routes to organic compounds from readily availab le and proficient reagents is one of the foremost challenges in organic synthesis. The field of heterogeneous catalysis has captivated the interest of researchers working in the field of catalysis due to increasing necessity for mo re environmentally acceptable processes in the chemical industry focusing largely on chemical y ield, eliminating waste at source and circumventing the use of perilous materials (1). In this sense, clay catalyzed organic reactions have many advantages, such as ease of handling, separation, recycling, environ mentally safe disposal, easy availability and their low cost. In addition to that clay minerals occur abundantly in nature and their high surface area, sorptive and ion-exchange properties have been exploited for catalyt ic applications through decades. Therefore, clay as a substitute of homogeneous catalyst or an expensive heterogeneous catalyst seems highly desirable (2).
2,3-Dihydroquinazo linones are the group of heterocyclic compounds in which different substitutions can be made to show pharmacological, Biological and Medicinal activity e.g. A n t itu mo r , A n t ib io t ic , A n t ip y r et ic , a n a lg es ic , antihypertensive, diu retic, Ant ihistamin ic, antidep ressant, a n d v a s od i la t in g a g e n t ( 3 ) . I n a d d it io n 2, 3d ih y d ro -2-p h en y lq u in azo lin -4( 1 H) -o n es are p o tent tubulin inhib itors with imp ressive antiprolivative activity against several human cancers with IC 50 value in nano molar concentration. It acts analogously to Colchicine (inhibitors of tubulin poly merization) by binding to α, β -tublin (4).The 2,3-disubstituted quinazolones have been predicted to possess antiviral and antihypertensive activities (5). Additionally, these compounds can easily be oxidized to their quinazolin-4(3H)-one analogs, wh ich is defined as a class of molecu les that are capable of binding to mu ltip le receptors with high affinity (6). These compounds also prove prospective antiprotozoal, immunosuppressive, and anticancer activities, the latter of which have been studied most frequently.
Various synthetic methods have been reported to prepare this class of compound using an assortment of catalysts like Iodine in Ion ic Liquids (7), tetra butyl ammoniu m bromide (8), iridiu m (9), ionic liquids (10), iodine (11), ammon iu m ch loride (12),[b mim] HSO4 (13), galliu m trifluoro methane sulfonate (14), some Bronsted acids (15), TiCl / Zn (16), phosphoric acid (17), citric acid (18), copper chloride (19) and some other catalytic systems like low valent titanium (20) etc. Su W has reported a method for synthesis by reductive cyclisation of o-nitrobenzamide or o-azidobenzamide with aldehydes and ketones promoted by metallic samariu m and a catalytic amount of iodine or SmI 2 (21) . Due to some drawbacks of these procedures such as tedious process, long reaction t imes, harsh reaction conditions, poor yields along with the use of non-recyclab le and toxic catalysts sometimes ineffectiveness associated with most of these catalysts demands development of some greener process involving low cost, easily availab le, easy to handle and efficient catalysts. We have developed an environmentally benign, high y ield ing and kinetically fast synthesis of 2, 3-dihydro-2-phenylquinazolin-4(1H)-one by using Anthranilamide with d ifferent substituted benzaldehyde by using clay catalyst. It is inexpensive, non-hazardous, recyclable, efficient and easy to separate fro m the reaction mixture v ia simp le filtration (22). We tried different clays, out of which Montmorilonite KSF shows better activity in terms of high yield with no side products and could be recycled at least six times and the desired product can be isolated in excellent yield in each run .

General Procedure
Various substituted aldehyde (1 equiv), anthranilamide (1 equiv), catalyst (0.1 equiv) was stirred at roo m temperature in acetonitrile fo r a specified period of t ime. After the complet ition of the reaction, monitered by the TLC, the catalyst was filtered and washed with ethyl acetate and the resulting filterate was dried and concentrated on rotavapour. The product was purified by crystallization technique using Ethyl acetate and Hexane as two solvent to afford the pure 2, 3-dihydroquinazo lin-4(1H)-one. The products thus obtained are characterized by HRMS, NM R. The spectral data were found to be consistent with authentic samples.

Result and Discussion
At the onset of the research, we investigated the model cyclo-condensation reaction between anthranilamdes and 4-chlo robenzaldehyde (Scheme.1) at roo m temperature and under different reaction med ia. After screening a variety of reaction media, Acetonitrile was found to be the most effective mediu m for the generation of the desired product (Table 1, entry 1) with no side products which may be due to the dipole mo ment (3.92 D) of Acetonitrile. The use of other solvents such as DCM and methanol (Table 1, entry 2and 3) was examined which did not imp rove the product yield but produce some unidentified by-products. When the reactions were conducted in water, the expected products were obtained in lower yields and with longer reaction times compared to organic solvents used, but still it was better than those earlier reports. (Table 1, entry 6). The lower yield obtained in water med iu m may be due to the suppression of condensation, following Le-Chatliers princip le. To show the merit o f the present work we further compared the as prepared catalysts with those reported in the literature (23-26) ( Table 2.), for the reaction of anthranilamdes and 4-Ch lorobenzaldehyde to afford 3a (Sheme 1). As shown in Table 2, Mont morilonite KSF can act as an effective catalyst with respect to reaction times and yields of the obtained products. Thus, the present protocol with this catalyst is an alternate route for production of 2, 3-dihydro-2-phenylquinazolin quinazo lin-4(1H)-ones. All the clay catalysts tried show good catalytic activity fo r the reaction discussed above but some unidentified by products were observed along with the required product except when Mont. KSF was used. Furthermo re it can be reused several times without any appreciable loss in activ ity, which clearly proves the recyclability and reusability of the catalyst (Table 2 entry 4). C Catalyst was reused for additional six runs and figures within parentheses indicate the corresponding yield fo r each run.
On the basis of our previous optimized conditions we started our investigations with reaction the Clay (Montmorilonite KSF) mediated catalyzed reaction of 2-aminobenzamide with various aldehydes in good to e xcellent yield as shown in Table 3. The reaction was compatible with variety of electron donating groups such as F, Cl, Br, OH, OMe and electron withdrawing groups such as NO2 without much affect on the product yield. Heteroarylaldehyde (2m) could affo rd the corresponding products (3m) with high yield as well (Table 3, entry 13). The use Vanillin (2n ) also afforded the desired product in good yield (Table 3, entry 14). The results acquired fro m the cyclisation reactions demonstrate that the method can be in general applicable for the preparat ion of the corresponding dihydroquinazolinones. All the products formed are well characterized by NMR and HRMS study.

Conclusions
In conclusion, we developed a simple and environmentally friendly clay catalysed synthesis of a novel class of quinazolinones. This method allows the use of the inexpensive, easy to prepare, efficient , easy to separate from reaction mixture and reusable clay as the catalysts and offers good results for most 2, 3-dihydroquinazolin-4(1 H)-ones. Starting materials are inexpensive and co mmercially available. By the reaction o f a range of anthranilamides and substituted benzaldehyde, novel libraries of 2, 3-dihydroquinazo lin-4(1 H)-ones could be obtained, which would make this method a suitable candidate for combinatorial and parallel synthesis in drug discovery.