This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is categorized according to the cyclization reaction and mechanisms are detailed. Nitrobenzene reduction, cyclization of aryl amidines, lactams and isothiocyanates are described. Protocols include condensation, cross-dehydrogenative coupling with transition metal catalysis, annulation onto benzimidazole, often using CuI-catalysis, and radical cyclization with homolytic aromatic substitution. Many oxidative transformations are under metal-free conditions, including using thermal, photochemical, and electrochemical methods. Syntheses of diazole analogues of mitomycin C derivatives are described. Traditional oxidations of o-(cycloamino)anilines using peroxides in acid via the t-amino effect remain popular.

3,6-Dimethoxy-2-(cycloamino)anilines undergo 4- or 6-electron oxidations to afford novel ring-fused halogenated benzimidazoles or benzimidazolequinones using H2O2/HCl or H2O2/HBr. Cl2 and Br2 are capable of the same oxidative transformation to the benzimidazolequinones. Labeling experiments indicate that water is necessary for oxidation of the para-dimethoxybenzenes to the corresponding quinones.

1-Fluoro-2,5-dimethoxy-4-nitrobenzene was synthesized in 90% yield by the reaction of commercial 2-fluoro-1,4-dimethoxybenzene with nitric acid. The structure was confirmed by X-ray crystallography. The new title compound was characterized by 1H and 13C-NMR, elemental analysis, EI-MS and FT-IR.

Cell viability studies for benzo[1,2,4]triazin-7-ones and 1,2,4-benzotriazinyl (Blatter-type) radical precursors are described with comparisons made with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). All of the stable free radicals were several orders of magnitude less cytotoxic than the benzo[1,2,4]triazin-7-ones. The synthesis and evaluation of two new pyrid-2-yl benzo[1,2,4]triazin-7-ones are described, where altering the 1,3-substitution from phenyl to pyrid-2-yl increased cytotoxicity against most cancer cell lines, as indicated using National Cancer Institute (NCI) one-dose testing. COMPARE analysis of five-dose testing data from the NCI showed very strong correlations to the naturally occurring anti-cancer compound pleurotin. COMPARE is program, which analyzes similarities in cytotoxicity data of compounds, and enables quantitative expression as Pearson correlation coefficients. Compounds were also evaluated using the independent MTT assay, which was compared with SRB assay data generated at the NCI.

Environmentally-friendly and cost effective hydrogen peroxide in ethyl acetate was used to prepare in high yields pyrrolo[1,2-a]benzimidazoles from commercial o-(pyrrolidin-1-yl)anilines without the requirement for organic-aqueous extraction and chromatography. Six, seven and eight membered ring fused analogues were similarly obtained in high yields with methanesulfonic acid required for the pyrido[1,2-a]benzimidazole. Anti-tumour benzimidazolequinone derivatives were obtained in high yield via the cyclization of 3,6-dimethoxy-2-(cycloamino)anilines. (C) 2017 Elsevier Ltd. All rights reserved.

The thioredoxin (Trx)-thioredoxin reductase (TrxR) system plays a key role in maintaining the cellular redox balance with Trx being over-expressed in a number of cancers. Inhibition of TrxR is an important strategy for anti-cancer drug discovery. The natural product pleurotin is a well-known irreversible inhibitor of TrxR. The cytotoxicity data for benzo[1,2,4]triazin-7-ones showed very strong correlation (Pearson correlation coefficients ∼0.8) to pleurotin using National Cancer Institute COMPARE analysis. A new 3-CF3 substituted benzo[1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo[1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo[1,2,4]triazin-7-ones exhibited different types of reversible inhibition of TrxR, and cyclic voltammetry showed characteristic quasi-reversible redox processes. Cell viability studies indicated strong dependence of cytotoxicity on substitution at the 6-position of the 1,3-diphenylbenzo[1,2,4]triazin-7-one ring.

ChemInformVolume 46, Issue 43 Preparative Organic Chemistry ChemInform Abstract: One-Pot Hydrogen Peroxide and Hydrohalic Acid Induced Ring Closure and Selective Aromatic Halogenation to Give New Ring-Fused Benzimidazoles. Michael Gurry, Michael Gurry Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this authorMartin Sweeney, Martin Sweeney Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this authorPatrick McArdle, Patrick McArdle Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this authorFawaz Aldabbagh, Fawaz Aldabbagh Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this author Michael Gurry, Michael Gurry Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this authorMartin Sweeney, Martin Sweeney Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this authorPatrick McArdle, Patrick McArdle Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this authorFawaz Aldabbagh, Fawaz Aldabbagh Sch. Chem., Natl. Univ. Ire., Galway, Ire.Search for more papers by this author First published: 08 October 2015 https://doi.org/10.1002/chin.201543046Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume46, Issue43October, 2015 RelatedInformation

A new series of selectively dichlorinated and dibrominated five- to eight-membered-ring [1,2-a]-fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of >80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl can also be used for a one-pot ring closure and chlorination.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.