Elsevier

Tetrahedron

Volume 69, Issue 4, 28 January 2013, Pages 1403-1416
Tetrahedron

A new facile, efficient synthesis and structure peculiarity of quinoxaline derivatives with two benzimidazole fragments

https://doi.org/10.1016/j.tet.2012.10.045Get rights and content

Abstract

A highly efficient and versatile method for the synthesis of quinoxaline derivatives with two benzimidazole fragments have been developed on the basis of the ring contraction of 3-(benzimidazo-2-yl)quinoxalin-2(1H)-one with 1,2-diaminobenzene and its various types of substituted and condensed derivatives. Owing to the inter- and intramolecular processes, involving self association, proton exchange, conformational, and/or tautomeric exchanges between several forms for most of the bis-benzimidazolylquinoxalines signals of bridged and neighboring carbon atoms and the hydrogen atoms of the neighboring carbon atoms of benzimidazole fragments in the NMR spectra are broadened. The conjugation between the benzimidazole fragments and the quinoxaline core of the molecules is increased from the quinoxaline derivative (10c) to its thiadiazol[f]- (17) and pyrrolo[a]-(19) annulated derivatives, resulting in a greater planarity of the molecule as a whole.

Introduction

The benzimidazole skeleton has attracted, and still attracts, much attention from medicinal chemists because of its structural resemblance to various moieties present in the fundamental constituents of proteins and nucleic acids. Benzimidazoles are also well known for their broad spectrum of anti-parasitic properties. For example, thiabendazole is used primarily to control mold, blight, and other fungi in fruits and vegetables.1 Thiabendazole, ciclobendazole, mebendazole, flubendazole, fenbendazole, and albendazole are prescribed to eliminate gastrointestinal parasites and worms in wild and domestic animals, livestock, as well as humans.2 Albendazole is also used for the treatment of lymphatic filariasis and giardiasis in some parts of the world.3 Bis-benzimidazoles are an established class of small molecules having the unusual property of selectively recognizing the minor groove of DNA,4 which makes them potential candidates for the synthetic regulation of gene expression. This site directed specificity has been linked to their promising DNA-topoisomerase I inhibiting5 and anti-tumor properties.6 During the last decade some bis-benzimidazoles have been screened for inhibition of hepatitis C virus serine proteases7 (e.g., 1, Fig. 1), and anti-cancer drug leads6(a), 8 (e.g., 2). In addition, structurally related congeners of 2 (e.g., 3) and other bis-benzimidazoles (e.g., 4) have been evaluated as anti-microbial, anti-fungal, and anti-parasitic agents.9

New insights have recently been found in the sequential binding of bis-benzimidazoles by incorporating an amidine moiety.10 Therefore to have a better understanding of structure–activity relationships a rapid synthesis of structurally diverse bis-benzimidazoles11 is of vital importance.

An analysis of literature data showed that among the drugs and biologically active compounds, there is not a single compound, in which any heterocyclic system contains two directly connected benzimidazole fragments in its composition.

Classically, benzimidazoles are prepared from 1,2-dianilines by acid-promoted dehydrative cyclocondensation with a carbonyl derivative, often at elevated temperatures.12 The requisite 1,2-dianilines are most often produced by the reduction of the corresponding 2-nitroaniline compounds. This common sequence of events suggests that these transformations could be conveniently combined into a one-pot process. Indeed, there have recently appeared reported methods for preparing benzimidazoles directly from 2-nitroanilines.13 However, these methods involve stoichiometric amounts of toxic metals or require harsh conditions, such as strong protic acids and/or elevated temperatures.

Obviously, it is not a simple task to obtain good results in the synthesis of heterocyclic systems with two directly connected benzimidazole fragments with the known methods (by Phillips–Ladenburg14 and Weidenhagen12(b), 14(d), 15(b), 15(c), 15(d), 15, 15(a) reactions). At least twice as many labor-consuming classical methods for the synthesis of benzimidazoles are involved.

It should be pointed out that there is only one paper16 in which the formation of 2,3-bis(benzimidazol-2-yl)quinoxaline, as a side product in the reaction of tetrachloropyridazine and 1,2-diaminobenzene in N-methylpyrroldone at 115 °C for 17 h is described. The yield of the main product of this reaction 5,6,7,8,13,14-hexaazapentaphene obtained as a free base after treatment of the corresponding hydrochloride with aqueous sodium hydroxide is 15%. The yield of the side product—2,3-bis(benzimidazol-2-yl)quinoxaline has not been given in this paper. Therefore this method can not be used, as preparative process for the synthesis of 2,3-bis(benzimidazol-2-yl)quinoxalines, not to mention the synthesis of other heterocyclic systems with the two benzimidazole fragments.

As part of our ongoing interest in the synthesis and utilization of nitrogen-containing heterocyclic and heteroaromatic compounds,17 we had a cause to explore the chemistry of quinoxalin-2(1H)-ones 5. We recently reported a new method for the synthesis of the 2-(benzimidazol-2-yl)quinoxalines via the reaction of alkanoyl(aroyl)quinoxalin-2(1H)-ones 5 and 1,2-diaminobenzenes 6 (Scheme 1).18 The key step in this transformation involves a novel acid catalyzed rearrangement of an intermediate spiro-quinoxalin-2(1H)-one derivatives with the contraction of the pyrazine ring of the quinoxalin-2(1H)-one fragment.

We also showed that the scope of this rearrangement could be extended to the use of other functionalized quinoxalinones and N-nucleophiles for synthesizing various 2-(hetero)aryl-substituted benzimidazoles.18(f), 19(a), 19(b), 19(c), 19(d), 19(e), 19(f), 19(g) A further exploration of this strategy made us examine how this rearrangement would proceed, if 3-heteroaroylquinoxalin-2(1H)-ones were used instead of alkanoyl- or aroylquinoxalin-2(1H)-ones 5.

Section snippets

Synthesis of 2,3-bis(benzimidazol-2-yl)quinoxalines 10ag, 12

Among heteroaroyl groups we were first of all interested in the benzimidazoyl group, since the successful course of the reactions of the 3-(benzimidazo-2-yl)quinoxalin-2(1H)-one20 with the 1,2-diaminobenzenes on the one hand, opens a new and effective way to the 2,3-bis(benzimidazol-2-yl)quinoxaline derivatives, inaccessible by any known methods of constructing the benzimidazole system. On the other hand this could answer to the question of whether the interaction of

Conclusion

To summarize, we have found that the reactions of 3-benzimidazoylquinoxalin-2(1H)-one 8 with both 1,2-diaminobenzene dihydrochloride and 1,2-diaminobenzene proceed according to the novel quinoxalin-2(1H)-one benzimidazole rearrangement we previously discovered. The formation of 2,3-bis(benzimidazol-2-yl)quinoxaline 10a and not the formation of the benzodiazepine derivative 9 occurs, as was described in literature. We have extended the scope of the rearrangement to other 1,4-di-N-nucleophiles

General methods

NMR spectroscopic investigations were carried out at the NMR Department of the Federal Collective Spectral Analysis Center for physical and chemical investigations of the structure, properties and composition of matter and materials. NMR experiments were carried out with Bruker spectrometers AVANCE-600 (600 MHz (1H), 151 MHz (13C), 61 MHz (15N)) equipped with a pulsed gradient unit capable of producing magnetic field pulse gradients in the z-direction of 53.5 G cm−1. All the spectra were

Acknowledgements

This work was supported by the Russian Foundation for Basic Research (grants No10-03-00413-a, 09-03-00123-a) and Federal Agency of Science and Innovation (the state contract No2012-1.1-12-000-1013-9552), the Program “Research and scientific-pedagogical personnel of innovative Russia” in 2009–2013 years (the state contract No2012-1.1-12-000-1013-007, Agreement number: 8432).

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