HETEROCYCLES

Communication | Regular issue | Vol. 78, No. 4, 2009, pp. 905-909
Received, 29th October, 2008, Accepted, 18th December, 2008, Published online, 19th December, 2008.
DOI: 10.3987/COM-08-11588

■ Silica Gel Catalyzed Synthesis of Quinoxaline 1,4-Dioxides under Solvent-Free Conditions Using Microwave Irradiation

Yusuke Sumiyoshi, Hiroaki Saito, Shinichi Miyairi, and Tohru Takabatake*

College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan

Abstract

We report on the simple and quick synthesis of quinoxaline 1,4-dioxides in solvent-free conditions under microwave irradiation. Heating of various benzofuroxans and β-ketoesters or 1,3-diketones adsorbed on silica gel in a microwave oven for two minutes affords diverse biologically attractive quinoxaline 1,4-dioxides in high to excellent yields. Silica gel functions not only as support using microwave but also as catalyst and dehydration reagent.

Benzofuroxan (benzofurazan N-oxide) has been shown to have numerous pharmacological and industrial applications.1a-d As a part of benzofurazan chemistry, reactions of various benzofuroxans with active methylene compounds catalyzed by silica gel or molecular sieves yield the corresponding quinoxaline 1,4-dioxides, and the antibacterial activity of quinoxaline 1,4-dioxides has been reported.2a-d Pyrido[2,3-b]pyrazine 1,4-dioxides have been obtained from a reaction of pyrido[2,3-c]furoxan with active methylene compounds catalyzed by treatment with silica gel, alumina, or molecular sieves and the antibacterial activity of pyrido[2,3-b]pyrazine 1,4-dioxides has been reported.3a-b Reactions of benzofuroxan with various phenolic compounds catalyzed by silica gel, alumina, or molecular sieves provide the corresponding phenazine 5,10-dioxide derivatives and the antibacterial activity of phenazine 5,10-dioxide derivatives has been reported.4a-b The toxicity of benzofurazans in Escherichia coli has been reported to be caused by an increase in intracellular flux of superoxide on aerobic incubation. 5a　 The superoxide production was confirmed using the cytochrome c reduction method and ESR spectra.5b 4,7-Dimethylbenzofurazan was transformed by 1O2 into 4,7-dimethylbenzofurazan 4,7-endoperoxide, in excellent yields.6
Microwave-assisted organic synthesis is a new and rapidly developing area in synthetic organic chemistry because it is an environmentally benign reaction.7 In order to overcome a serious risk of fire or explosion due to sparking, several solvent-free procedures were developed.8 Herein, we report not only increased in the chemical yield, but also dramatic acceleration of the reaction rate in solvent-free conditions under microwave irradiation using silica gel as support. We investigated the scope of this process with respect to the substituents on the benzene ring of benzofuroxans (Table 1). 9 Both the short reaction time and high yield were maintained with either electron-withdrawing (-F, -Cl) or electron-donating (-CH3, -OCH3) groups on the 5, 6-positions of benzofuroxans. The benzofuroxans that having electron-withdrawing groups at position 5 and 6 (1a, b) gave the purpose products around 90% yield using only 1.1 equivalents of diketone 2 (Entries 1, 2).

Next we explored the effects of the diketones. We used 5,6-dichlorobenzofuroxan as a substrate for the reaction. The dramatic acceleration of the reaction rate was achieved without affecting the chemical yields (Table 2). The method is also applicable to aliphatic diketone 2d (Entry 3).

It was suggested that one of the reasons for the acceleration under microwave irradiation could be due to specific microwave effects.7b The effects act stronger to more polar molecules in the course of the reaction. 　　　　　　
Reaction of various β-ketoesters and 1,3-diketones 2d-g with compound 1e was examined (Table 3).　Compound 2e failed to react with compound 1e and unreacted 2e was almost completely recovered. The enol form of carbonyl compounds was previously shown to be necessary for the formation of quinoxalines, whose yields depended on the enol content in compound 2d-g.10　Silica gel may serve to enhance the stability of the enol form of carbonyl compounds (Scheme 1).

And, effect of dehydration activity of silica gel was examined. For example, Synthesis of 2g in the presence of H2O yield is 13 %. Dryness of silica gel shown to be necessary for the formation of quinoxalines, whose yields decreased with an increase of H2O adsorbed on silica gel. The dehydration capacity of silica gel must significantly determine the possibility of synthesis of quinoxaline 1,4-dioxides.

In conclusion, we have developed a new procedure for the preparation of quinoxaline 1,4-dioxides under microwave irradiation. Silica gel functions not only as support using microwave but also as catalyst and dehydration reagent. This method offers several advantages including an easier experimental procedure than previously described methods, shorter reaction times and excellent yields.

ACKNOWLEDGEMENTS
This research was supported by A Grant from “Academic Frontier” Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology) 2002-2006.

References

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9. All experiments were carried out by using a RE-T13 domestic oven manufactured by SHARP Inc. Silica gel (Wakogel® C-200, Wako Pure Chemical Industries, Ltd) was dried by heating at 110 °C for 1 h.　A typical experimental procedure for synthesizing quinoxaline 1,4-dioxide is as follows (Table 1): In a round bottom flask, silica gel (6 g) was impregnated with a solution of benzofuroxan 1e (27 mg, 0.2 mmol) and dibenzoylmethane 2a (49.5 mg, 0.22mmol) in CH2Cl2 (8 mL). The solvent was evaporated on a rotatory evaporator followed by standing under microwave irradiation (700 W) for 1 min without stirring. For stirring, the reaction mixture was stirred by hand and standing at room temperature for 30 sec. It was re-irradiated in a microwave oven for 1 min. The crude solid was extracted with EtOAc (50 mL) and evaporated in vacuo, which was purified by column chromatography (silica gel, 30:1 CH2Cl2 /MeOH) to provide quinoxaline 1,4-dioxide 3e in 65 % yield .
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