Effect of solvents on the yield of the product 4a.
A novel, convenient one-pot multicomponent synthesis of tetraheterocyclicbenzimidazolo/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- cyclohexanedione 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).
- superoxide ion
- multicomponent reaction
- Tetraethylammonium bromide
- phase transfer catalyst
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 O2• −, and perhydroxyl radical. Hypochlorous acid (HOCl), hydrogen peroxide (H2O2), 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 biochemical research for the two reasons [1, 2, 3, 4]. First superoxide ion as a biochemical species which causes many diseases such as cancer, ageing, inflammation, heart attack and lung injury, etc. More recently, it has been implicated to play a key role in both aging and cancer. Second superoxide ion as a novel reagent. Further from its elementary reactivity pattern, this anion radical has been recognized as a multipotent reagent, which acts as a base, nucleophile, oxidant and reductant. In view of these two points, superoxide research has become an area of interdisciplinary investigation [5, 6, 7, 8, 9, 10, 11, 12, 13].
Multi-component reactions (MCRs), in which multiple reactions are combined into one synthetic operation, have been used extensively to form carbon-carbon bonds in synthetic chemistry. Such reactions offer greater possibilities for molecular diversity per step with minimum reaction time, labor, cost, and waste production. The rapid assembly of molecular diversity utilizing MCRs has gained a great deal of attention, most notably for the construction of ‘drug-like’ libraries [14, 15, 16, 17, 18, 19, 20].
Quinazolines are very interesting heterocycles [21, 22, 23, 24, 25] as they serve as building blocks in numerous natural and synthetic products . They exhibit a wide spectrum of biological and pharmacological activities such as propyl hydroxylase inhibitor , antidiabetics , anti-inflammatory , antiviral , antimicrobial , antineoplastic  and potent immunosuppressive agents . Moreover, benzimidazolo quinazolines have also been an important class of heterocyclic compounds in drug research, as they are formed from both biodynamic heterosystems, benzimidazole and quinazoline, which have shown significant anticancer activities. Many useful methods, have been reported for synthesis of tetrahydrobenzoimidazo [2,1-b] quinazolin-1(2H)-ones ring system skeletons, such as the condensation of aminoazoles with benzylidene compounds, or three-component condensation of 2-aminobenzothiazole or 2-aminobenzimidazole and an aldehyde with cyclic 1,3-diketone.These reported methodologies produce good results in many cases [34, 35]. However, some of them suffer with certain limitations such as expensive catalysts, low yields of products, long reaction times, tedious procedures for preparations of catalysts, and tedious workup conditions [36, 37, 38, 39, 40]. Thus, there is enough room for further investigation in this direction. With a view to investigate the behavior of the superoxide ion in multicomponent organic synthesis, which is of importance in itself and further to assess its synthetic scope, the reaction of this novel reagent was studied.
2. 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 Et4NO2 for the synthesis of tetraheterocyclicBenzimidazolo/benzothiazolo quinazolin-1-one ring systems
In order to achieve the optimum yield of the product, the effect of various parameters such as effect of solvents (DMF, DMSO, and CH3CN) and molar proportion of the reactants were investigated in detail using benzaldehyde
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).
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).
|Entry||Reactants molar ratio||Product yield* (%)|
A perusal of the table clearly indicates the profound effect of the concentration of KO2 and Et4NBr on the yield of the product
The scope and limitations of this reaction were fully illustrated with various
As indicated in Table 3, the reaction proceeded efficiently with both electron-withdrawing and electron releasing
The products were identified by their physical and spectral data, which were in full agreement with the reported values.
2.1 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 Figure 2. The reaction was initiated by the abstraction of proton from 1,3-diketones
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)
All the products were characterized by IR and 1H NMR (because of low solubility of compounds
M.p. = 203–205°C. 1H NMR (500 MHz, DMSO–
In conclusion, the reaction of
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.
The authors are thankful to IIT(BHU),Varanasi for financial support.
Conflict of interest
No conflict of interest.