MICROWAVE-ASSISTED SYNTHESIS OF SOME NITRO-BENZIMIDAZOLES AND THEIR SALICYL AND ISATIN SCHIFF BASES

A series of 5-nitrosubstituted benzimidazole and 6-nitro substituted benzimidazole derivatives were synthesized starting from iminoester hydrochloride and 4-nitro-o-phenylenediamine under microwave irradiation. The structure of newly synthesized compounds was confirmed by IR, H-NMR, C-NMR, LC-MS spectroscopy and elemental analysis.

Schiff bases are aldehyde-or ketone-like compounds in which the carbonyl group is replaced by an imine or azomethine group.They are widely used for industrial purposes and also exhibit a broad range of biological activities.They have been reported in their biological properties, such as, antibacterial, antifungal activities [16][17][18][19].Their metal complexes have been widely studied because they have anticancer and herbicidal applications [20,21].They serve as models for biologically important species.For example, an imine linkage between the aldehyde derived from vitamin A and the protein opsin in the retina of the eye plays an important role in the chemistry of vision.
Salicyl group is an important group, which shows a positive effect on increasing biological activities of compounds.Because of this biological effect, this group has been used as a side group in design of new biological active compounds.In our previous research on this group, we have seen that this group played a positive role on anticonvulsant activity of triazol-3-on compounds [22].
Isatin is an endogenous compound identified in humans that possesses a wide range of biological activities.Isatin has anxiogenic, anticonvulsant activities and acts as a potent antagonist on a trial natriuretic peptide receptors in vitro [23].Recently, a number of researchers have been studying the use of isatin in the fight against phytopathogens and as potential herbicides [24,25].

EXPERIMENTAL
All the chemicals were supplied from Merck, Aldrich and Alfa Aesar.Melting points were determined on capillary tubes on Buchi oil heating melting point apparatus and uncorrected. 1H NMR and 13 C NMR spectra were performed on Varian-Mercury 400 MHz spectrometer in DMSO-d 6 .The elemental compositions were determined on a Carlo Erba 1106 CHN analyser; the experimental values were in agreement (±0.4 %) with calculated ones.All reactions were monitored by TLC using precoated aluminum sheets (silica gel 60 F 2.54 0.2 mm thickness).A mono mode CEM-Discover Microwave was used in the standard configuration as delivered, including proprietary software.All experiments were carried out in microwave process vials (30 mL) with control of the temperature by infrared detection temperature sensor.

Synthesis of compounds 5a-f
Conventional method.A mixture of compounds 4a, b (0.01 mol) and corresponding salicyl aldehyde derivative (0.012 mol) in ethanol (25 mL, containing 0.5 mL of acetic acid) was refluxed for 6 hours.After completion of the reaction (monitored by TLC, ethyl acetate/hexane, 4:1), the mixture was cooled to room temperature and a solid was apperared.This product was filtrated off, dried and recrystallized from ethanol to obtain the pure product.
Microwave method.A mixture of compound 4a, b (0.01 mol) and corresponding salicyl aldehyde derivative (0.012 mol) was prepared in ethanol (10 mL, containing 0.5 mL of acetic acid) in a microwave process vial (30 mL).Then, the mixture was subjected to microwave irradiation at 120 °C for 8 min.After completion of the reaction (monitored by TLC, ethyl acetate/hexane, 4:1), above purification procedures were applied to obtain the product.

Synthesis of compounds 6a-d
Conventional method.A mixture of compounds 4a, b (0.01 mol) and corresponding isatin derivatives (0.011 mol) in ethanol (25 mL, containing 0.5 mL of acetic acid) was refluxed for 8 hours.After completion of the reaction (monitored by TLC, ethyl acetate/hexane, 5:2), the mixture was cooled to room temperature.The appeared solid was filtrated off, washed with hot ethanol and dried to obtain the pure product.
Microwave method.A mixture ofcompound 4a, b (0.01 mol) and corresponding isatin derivative (0.011 mol) was prepared in ethanol (10 mL, containing 0.5 mL of acetic acid) in a microwave process vial (30 mL).Then, the mixture was subjected to microwave irradiation at 130 °C for 10 min.After completion of the reaction (monitored by TLC, ethyl acetate/hexane, 5:2), above purification procedures were applied to obtain the product.

RESULTS AND DISCUSSION
The targeted isatin and salicylschiff bases of 5(6)-nitro benzimidazoles (5a-f and 6a-d) were prepared as shown in Scheme 1. Firstly, 5(6)-nitrobenzimidazoleacetohydrazides (4a,b) were synthesized according to the literature [43].Secondly, various salicyl aldehyde derivatives were reacted with the compound 4a, b in ethanol with catalytic amount of glacial acetic acid to obtain the salicyl Schiff bases of 5(6)-nitrobenzimidazoles (5a-f).The lastly, isatin and 5-nitroisatin, separately, were reacted with compounds 4a, b in the same condition with compounds 5a-f (Scheme 1).The synthesis of these target compounds performed under microwave irradiation and by using conventional heating procedure.The results of these two methods were compared (Table 1).Spectral investigations of newly synthesized compounds are suitable with the proposed structures. 1 H NMR spectra of each compounds showed characteristic signals.N=CH and OH, coming from salicyl moiety, signals were shown at about 8.5 ppm and 10.0 ppm in 1 H NMR spectra of compounds 5a-f.NCH 2 signals were shown at about 5.0 ppm 1 H NMR spectra of compounds 5a-f and 6a-d.NH signal of isatin moiety in compounds 6a-d was shown at about 11.5 ppm.

CN R
Scheme 2. E/Z geometrical isomer and cis/trans amid conformer of compounds 5a-g.When 1 H-NMR spectra of the compounds have been compared, it has been seen that some of the protons have 2 sets of signal at different ppm.This is because of the compounds, which have arylene-hydrazide structure, exist as E/Z geometrical isomer from C=N double bond and cis/trans amide conformer at the CO-NH single bond.According to the literature [11,44,45], compounds which have C=N double bond prefers E geometrical isomer in DMSO-d 6 and Z isomers can be preferred in less polar solvents.N-CH 2 and N-H signals were observed 2 sets of signals because of cis/trans conformer.The ratio in each case has been calculated by using 1 H-NMR data.E/Z and cis/trans geometrical isomers of compounds 5a-f and 6a-d are shown in Scheme 2. The 1 H-NMR spectra of compound 5a is given as an example in Figure 1.
In the 13 C NMR spectrum of 5a-f and 6a-d shows two signals indicated the appearance of C=O groups at about 165 ppm and 160 ppm.N=CH carbon was shown at about 145 ppm.In addition to this, the elemental analysis and mass spectra results of the compounds 5a-f and 6a-d show good agreement with the calculated values.

CONCLUSION
In conclusion, a new series of potentially bioactive benzimidazole derivatives containing salicyl and isatin moieties were synthesized in a short time and good yields by using microwave irradiation technique.These results can be inspired by researchers for the synthesis of new potential bioactive compounds.

Table 1 .
Comparison of yield and reaction time of compounds