One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using In Situ Generated Superoxide Ion: A Rapid Synthesis of Structurally Diverse Drug-Like Complex Heterocycles

A novel, convenient one-pot multicomponent synthesis of tetraheterocy-clicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives has been reported in the presence of tetraethylammonium superoxide under non-aqueous condition. The superoxide induced three-component reaction of various aromatic aldehydes, 2-aminobenzimadazole/2-aminobenzothiazole and dimedone/1,3- cyclohexane-dione produced tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives at room temperature under the mild reaction conditions. The tetraethylammonium superoxide has been generated by phase transfer reaction of potassium superoxide and tetraethylammonium bromide in dry DMF at room temperature. The present study extended the applicability of tetraethylammonium bromide as a phase transfer catalyst for the efficient use of superoxide ion in multi-component synthesis of structurally diverse drug-like complex heterocycles (quinazolines). role of O 2 • − in living cells. Since the investigation has been performed at an ambient temperature in the presence of in situ generated O 2• − , the results may be easily correlated with those occurring at physiological temperatures in more complex biological counterparts. A novel synthetic route has been developed for the synthesis of tetraheterocyclic benzimidazolo/benzothiazolo quinazolin-1-one ring systems using tetraethylammonium superoxide under non aqueous condition at room temperature (mild reaction condition) within 6 h. The yield of the products was obtained up to 88% without using any tedious purification process. The applicability of tetraethylammonium bromide as an inexpensive alternative to 18-crown-6 for superoxide ion generation has been extended in present report.


Introduction
The importance of oxygen in sustaining life is unquestionable but the aerobic life-style is fraught with danger. However, some recent reports about oxygen toxicity have caused much concern among the whole scientific community. The oxygen toxicity is due to various reactive oxygen species (ROS) such as hydroxyl radical (HO • ), superoxide anion radical O 2 • − , and perhydroxyl radical. Hypochlorous acid (HOCl), hydrogen peroxide (H 2 O 2 ), singlet oxygen and ozone are also included in this category, although they are not free radicals but can lead to free radical reaction. Out of all the reactive oxygen species, superoxide anion radical is probably the most important ROS, which has come to the forefront of current chemical and

Results and discussion
In continuation of our ongoing program on superoxide research and the synthesis of biologically active compounds, it is our current endeavor to extent the applicability of Et 4 NO 2 for the synthesis of tetraheterocyclicBenzimidazolo/ benzothiazolo quinazolin-1-one ring systems 4 by a one-pot three-component condensation reaction of various aromatic aldehydes 2 and 1,3-diketones 3 with 2-aminobenzimidazole/2-aminobenzothiazole 1 using tetraethylammonium superoxide under non aqueous conditions (Scheme 1).
In order to achieve the optimum yield of the product, the effect of various parameters such as effect of solvents (DMF, DMSO, and CH 3 CN) and molar proportion of the reactants were investigated in detail using benzaldehyde 2, dimedone 3 with 2-aminobenzimidazole 1 as a model reaction.
To investigate the effect of solvents, the model reaction was carried out in different aprotic solvents. The results obtained clearly indicate that DMF was the best solvent among all investigated solvents in terms of product yield and the reaction time ( Table 1). DOI: http://dx.doi.org /10.5772/intechopen.81146 In order to establish the reactants molar ratio on the yield of product the model reaction was carried out in different concentration of reactants ( Table 2).
A perusal of the table clearly indicates the profound effect of the concentration of KO 2 and Et 4 NBr on the yield of the product 4a. As regards the ratio of KO 2 and Et 4 NBr, it is evident from the entries 1, 2 and 3 that with the diminution of the concentration of Et 4 NBr, the yield of product 4a decreases. But as may be seen only a little difference in the yield of the product in the case of entries 1 and 2, the ratio of KO 2 and Et 4 NBr was further kept to be 2:1. Therefore, in subsequent studies, the concentration of KO 2 has been increased manifold but the ratio of KO 2 and Et 4 NBr was all along maintained to be 2:1. Furthermore, in case of entries 5 and 6, there is just a 2% increase in the yield of the product and for that 2% increase, the concentration of KO 2    substantially (6 fold and 3 fold respectively). As a result, considering the high cost of KO 2 and Et 4 NBr, the entry 5, with the reactants ratio 1:1:1:4:2, has been selected as the optimum ratio. The scope and limitations of this reaction were fully illustrated with various ortho-, meta-and para-substituted benzaldehydes in the presence of 2-aminobenzimidazole and 2-aminobenzothiazole.
As indicated in Table 3, the reaction proceeded efficiently with both electron-withdrawing and electron releasing ortho-, meta-and para-substituted benzaldehydes.
The products were identified by their physical and spectral data, which were in full agreement with the reported values.

Mechanism for the synthesis of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones
The proposed mechanism for the formation of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones ring system is given in Scheme 2. The reaction was initiated by the abstraction of proton from 1,3-diketones 3 by tetraethylammonium superoxide which was in situ generated by the phase transfer reaction of potassium superoxide with tetraethylammonium bromide. Now, Knoevenagel condensation takes place between benzaldehyde 2 and subsequently, by dehydration, olefin 3-benzylidene-2,4-hexanedione 5 is produced. Then 2-aminobenzimidazole/2-ami-nobenzothiazole1 is reacted with compound 5 through a Michael addition to produce a product of type 6 and after cyclisation to afford tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-one ring systems 4.
Potassium superoxide (1.42 g, 0.02 mol) and tetraethylammonium bromide (2.10 g, 0.01 mol) were weighed under nitrogen atmosphere using an atmosbag and were transferred into a three-necked R. B. flask, dry DMF (20 mL) was added to it and the mixture was agitated magnetically for 15 min to facilitate the formation of tetraethylammoniumsuperoxide. To the stirred reaction mixture, dimedone (0.70 g, 0.005 mol) 3 were added. After 10 min, benzaldehyde (0.53 g, 0.005 mol) 2 and 2-aminobenzimidazole (0.665 g, 0.005 mmol) 1 were introduced, and the stirring was continued 6 h. After the reaction was over as indicated by TLC, mixture was treated with cold brine solution (2 mL) followed by saturated sodium hydrogen carbonate solution (2 mL) to decompose the unreacted KO 2 . The mixture was then extracted with dichloromethane (3 × 15 mL) and the combined organic phase was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to give the products 4a, which were purified by column chromatography.

Conclusion
In conclusion, the reaction of in situ generated O 2 •− with imidazoles is able to mimic the in vivo biochemical reactions involved and corroborate the role of O 2 •− in living cells. Since the investigation has been performed at an ambient temperature in the presence of in situ generated O 2 •− , the results may be easily correlated with those occurring at physiological temperatures in more complex biological counterparts.
A novel synthetic route has been developed for the synthesis of tetraheterocyclic benzimidazolo/benzothiazolo quinazolin-1-one ring systems using tetraethylammonium superoxide under non aqueous condition at room temperature (mild reaction condition) within 6 h. The yield of the products was obtained up to 88% without using any tedious purification process. The applicability of tetraethylammonium bromide as an inexpensive alternative to 18-crown-6 for superoxide ion generation has been extended in present report.