Academic literature on the topic 'Benzimidazoles – Synthesis'

Thesis (M.S.)--Oregon State University, 1993.<br>Description based on title screen as viewed on April 8, 2009. "Completed 13 May 1992, Commencement June 1993." Includes bibliographical references (p. 73-75). Also available in print.

The aim of this programme was to design and synthesize triazinobenzimidazoles that are analogous to the antihypertensive agents, hydralazine and dihydralazine. Retrosynthetic analysis of these analogues showed that the key intermediates in the synthesis were the novel [1,2,4]triazino[4,5-a]benzimidazol-l-ones and the related 1,4-diones. Existing routes to this tricyclic ring system were either limited in scope or needed expensive starting materials. Therefore, a new synthetic route to these compounds was developed using the readily available 2-acylbenzimidazoles as starting materials. These acyl derivatives were converted to hydrazones, ethoxycarbonylhydrazones and benzimidazole-2-carboxylic acid ethoxycarbonylhydrazides. The substituted hydrazines were cyclized to the desired tricyclic lactam intermediates either thermally, or acylatively using ethyl chloroformate in pyridine. The versatility of these cyclization methods has been demonstrated by the synthesis of a variety of novel N-2 substituted [1,2,4]triazino[4,5-a]benzimidazol- 1-ones which may or may not have a substituent at C-4. In addition, it has been shown that these types of cyclizations provide a better route to existing triazinobenzimidazoles. Although attempts to chlorinate or thiate these lactams were unsuccessful, use of the dithio analogue of ethyl carbazate, methyl dithiocarbazate, afforded sulphur-containing hydrazones which were cyclized to the desired [1,2,4]triazino[4,5-a]benzimi dazole-1-thiones. Displacement of the enolized 1-thione by hydrazine produced the desired target molecules, 1-hydrazino- [1,2,4]triazino[4,5-a]benzimidazoles. In preliminary screening, these compounds exhibited in vivo vasodilatory activity. In an attempt to vary the 4-substituent of the tricyclic system further, the synthesis of a variety of modified 2-acylbenzimidazoles was undertaken. In particular, the structure and reactions of one of these modified ketones, 2-bromoacetylbenzimidazole, was investigated in an attempt to explain its bromination pattern. Other workers have suggested that the unusual bromination pattern of 2-acetyl and 2-bromoacetylbenzimidazole may arise from the influence of intramolecular hydrogen bonding between the imine proton and the carbonyl group. However, a computer-aided reinvestigation of this reaction has shown that a more plausible intermediate is an intramolecularly hydrogen bonded enol of the ketone. The synthesis of two novel triazepinobenzimidazole ring systems has been examined. The acylative-cyclization (ethyl chloroformate-pyridine) developed for the preparation of the novel triazines has been extended to the synthesis of the hitherto unknown [1,2,4]triazepino[4,5-a]benzimidazole ring system. A series of new 1,2-diacylbenzimidazoles were prepared as precursors to [1,2,5]triazepino[5,4-a]benzimidazoles. However, attempts to add hydrazine across the dicarbonyl groups gave only novel benzimidazole hydrazine or hydrazide derivatives instead of the desired triazepinobenzimidazoles. Many of the compounds described in this thesis have been screened for possible pharmacological activity.

Thesis (Ph. D.)--West Virginia University, 2008.<br>Title from document title page. Document formatted into pages; contains xi, 179 p. : ill. Includes abstract. Includes bibliographical references (p. 88-94).

Benzimidazoles are heterocyclic compounds. Symmetrical and unsymmetrical benzimidazoles/oligomers are minor groove DNA sequence selective binding compounds. Distamycin A and netropsin are examples of naturally occurring DNA binders. Hoechst 33258 (Bis–benzimidazole) is a synthetic minor groove A-T sequence selective reagent and has in vivo activity by inhibiting the topoisomerase II enzyme. The targets in this research work were to synthesise extended analogues of Hoechst with structural modifications (amide bond) or amide-linked dimers with a view to identifying new potential ligands. To synthesise a library of novel bis-benzimidazoles (analogues of Hoechst) several methods were used. For C5–C2 direct linkage aldehyde synthesis via ester, Weinreb amide reduction, condensation of acids with diamine by Eaton’s reagent were applied. Cyclization of amide-linked benzimidazoles (amide bond between carboxylic acid of C5 benzimidazole and diamine), an indirect method of bis-benzimidazole synthesis was also used to prepare a library of novel bis-benzimidazoles giving a series of novel intermediates. Higher molecular weight oligomeric structures (Linked by amide bond either between C5-C5 or C5-C2) were prepared by using (EDCI / HOBt) or (HBTU / DIPEA). A library of novel amide-linked, oligomeric analogues of Hoechst were also synthesised by coupling bis-benzimidazole building blocks bearing reactive groups at positions 2 or 5. Amine (by the reduction of a nitro precursor) or carboxylic acid (from ester hydrolysis) was coupled with monomeric amino or carboxylic acid benzimidazole derivatives using different peptide coupling reagents. Further structural modifications were performed either by reduction of an ester on a bis-benzimidazole or by the reaction of hydrazine with the ester or acid to have an additional flexible spacer (amide bond) with reactive amine to address the issue of solubility. SPR (Surface Plasmon Resonance) was employed to evaluate more than 30 different analogues in comparison with Hoechst 33258 in terms of their DNA binding affinity using three different oligonucleotides having A2T2, A3T3, A4T4 sequences. The data revealed that compounds with charged specie at peripheral groups are better binders in the grooves of DNA.

Amido-oligopyrroles/imidazoles and dimeric benzimidazoles are heterocyclic compounds which are nucleic acid minor groove binding agents. The targets for this project were symmetrical and unsymmetrical amide-linked di- and tri- and tetrameric benzimidazoles to evaluate as potential DNA binding agents. Syntheses involved linkage between C2 and C5 positions of 2-carboxy, 5-carboxy or 2,5-dicarboxy and 2-amino, 5-amino or 2,5-diamino-bearing benzimidazoles. This matrix of substrates could be coupled directly C2-C5 by amide linkage, or these same precursors could also be dimerized symmetrically using small bifunctional linkers (diamine or diacid), affording symmetrical C2-C2 or C5-C5 dimer types of orientation, such as head-to- head, and tail-to tail systems. Monomeric building block benzimidazoles were prepared by condensation of o- phenylene diamines with either aldehydes or carboxylic acids affording the corresponding C2 or C5 amino and C5 carboxybenzimidazoles. 2- Carboxybenzimidazoles were however prepared by condensation of o-phenylene diamines with trichloroacetimidate followed by hydrolysis. New different novel symmetrical and unsymmetrical-bis(benzimidazole) libraries (C2-C2, C5-C5 and C5- C2 orientation) were prepared via coupling of different aminobenzimidazoles with different carboxybenzimidazoles from the matrix of available monomers. Novel tris(benzimidazoles) with differently linked orientations were prepared either by coupling one equivalent of 2,5-dicarboxybenzimidazole with two equivalents of aminobenzimidazole or coupling one equivalent of 2,5-diaminobenzimidazole with two equivalents of carboxybenzimidazole. A second set of novel tris(benzimidazoles) was prepared via reduction of a nitro- to amino bearing dimer followed by coupling with another carboxybenzimidazole monomer. Novel symmetrical tetra(benzimidazoles) (C2-C2-C2-C2 and C5-C2-C2-C5 orientation) were synthesized via either coupling one equivalent 2-dicarboxy dimeric benzimidazole with two equivalents of 2 or 5-aminobenzimidazole or via coupling one equivalent of 2-diaminobis(benzimidazole) with two equivalents of 2 or 5- carboxybenzimidazoles. Novel symmetrical bis(benzimidazoles) piperidine derivatives were synthesized via coupling one equivalent of 2-dicarboxy dimericbenzimidazole with two equivalents of piperidine derivatives. Forty oligomeric benzimidazoles were evaluated using Surface Plasmon Resonance (SPR) for binding to a series of three oligonucleotides containing A2T2, or A3T3 or A4T4 sequences. Data are presented showing the identification of four optimum ligands from a screen of 40, primarily 2L2552L2 tetramers but also several 2L5 dimers and dimeric 5,5-units without terminal additional benzimidazoles.