Fawaz Aldabbagh

Bu3SnH mediated oxidative radical cyclisation onto imidazoles and pyrroles

Abstract A new protocol using radical cyclisation has been developed for the synthesis of [1,2-c]-fused imidazoles and [1,2-a]-fused pyrroles. The intermediate nucleophilic N-alkyl radicals, generated using Bu3SnH from N-(ω-bromoalkyl) or N-[ω-(phenylselanyl)alkyl] imidazoles and pyrroles, undergo regio-selective radical cyclisation onto the azole rings followed by oxidative re-aromatisation.

OXIDATIVE RADICAL CYCLISATIONS ONTO IMIDAZOLES AND PYRROLES USING BU3SNH

Oxidative radical cyclisation using Bu3SnH has been used for the synthesis of [1,2-c]-fused imidazoles and [1,2-a]-fused pyrroles from imidazolecarbaldehydes and acylpyrroles respectively. The intermediate nucleophilic N-alkyl radicals cyclise onto imidazole and pyrrole rings followed by oxidative re-aromatisation.

Radical cyclisation onto imidazoles and benzimidazoles

Abstract A new protocol for the synthesis of [1, 2-a]-fused benzimidazoles and imidazoles has been developed using intramolecular homolytic aromatic substitution via ω-alkyl radicals generated from 1-(ω-benzeneselenylalkyl)- 2-(benzenesulfenyl)-benzimidazoles and -2-(p-toluenesulfonyl)imidazoles.

Photochemical intramolecular aromatic substitutions of the imidazol-2-yl radical are superior to those mediated by Bu3SnH

Six-membered photochemical cyclisations of 2-iodo-N-(2-arylethyl)imidazoles proceeded regioselectively in higher yields than the equivalent tin hydride-mediated reactions. The decrease in yield of cyclisation products, 5,6-dihydroimidazo[2,1-a]isoquinolines containing strongly deactivating substituents on the aryl ring confirmed the electrophilic nature of the sigma-imidazol-2-yl radicals. The seven-membered cyclisation was only successful under photochemical conditions, as radical reduction occurred with tin hydride. Nitration of 5,6-dihydroimidazo[2,1-a]isoquinoline with nitric/sulfuric acid occurred at the 2- and 8-positions.

The reactivity of nitroxides towards alkenes

At elevated temperatures, nitroxides (e.g. 1,1,3,3-tetramethyl-2,3-dihydroisoindol-2-yloxyl) undergo a slow addition reaction with acrylonitrile, methyl acrylate and styrene to give the bis-nitroxide adducts. With alkenes containing an allylic hydrogen such as methyl methacrylate and 6-methylene-1,4-oxathiepan-7-one, the major reaction observed was hydrogen abstraction. The resulting hydroxylamines can be trapped as Michael addition products.

Nanomechanical properties of poly(lactic-co-glycolic) acid film during degradation

Despite the potential applications of poly(lactic-co-glycolic) acid (PLGA) coatings in medical devices, the mechanical properties of this material during degradation are poorly understood. In the present work, the nanomechanical properties and degradation of PLGA film were investigated. Hydrolysis of solvent-cast PLGA film was studied in buffer solution at 37 °C. The mass loss, water uptake, molecular weight, crystallinity and surface morphology of the film were tracked during degradation over 20 days. Characterization of the surface hardness and Youngs modulus was performed using the nanoindentation technique for different indentation loads. The initially amorphous films were found to remain amorphous during degradation. The molecular weight of the film decreased quickly during the initial days of degradation. Diffusion of water into the film resulted in a reduction in surface hardness during the first few days, followed by an increase that was due to the surface roughness. There was a significant delay between the decrease in the mechanical properties of the film and the decrease in the molecular weight. A sudden decline in mechanical properties indicated that significant bulk degradation had occurred.

Synthesis and toxicity towards normal and cancer cell lines of benzimidazolequinones containing fused aromatic rings and 2-aromatic ring substituents

A facile 6-exo-trig cyclization of sigma-aromatic radicals has allowed the synthesis of various aromatic ring fused benzimidazoles and benzimidazolequinones. The most highly conjugated naphthyl fused benzimidazolequinone, (5-methyl-5,6-dihydrobenzimidazo[2,1-a]benzo[f]isoquinoline-8,11-dione) showed the highest specificity towards human cervical (HeLa) and prostate (DU145) cancer cell lines with little toxicity towards a human normal (GM00637) cell line at doses of <1 microM. In contrast, 2-aromatic ring substituted (benzimidazole-4,7-diones) analogues, benzimidazolequinone with a pyridine ring and mitomycin C were more toxic than the highly conjugated naphthyl fused benzimidazolequinone towards the normal cell line.

COMPARE analysis of the toxicity of an iminoquinone derivative of the imidazo[5,4-f]benzimidazoles with NAD(P)H:quinone oxidoreductase 1 (NQO1) activity and computational docking of quinones as NQO1 substrates.

Synthesis and cytotoxicity of imidazo[5,4-f]benzimidazolequinones and iminoquinone derivatives is described, enabling structure-activity relationships to be obtained. The most promising compound (an iminoquinone derivative) has undergone National Cancer Institute (NCI) 60 cell line (single and five dose) screening, and using the NCI COMPARE program, has shown correlation to NQO1 activity and to other NQO1 substrates. Common structural features suggest that the iminoquinone moiety is significant with regard to NQO1 specificity. Computational docking into the active site of NQO1 was performed, and the first comprehensive mitomycin C (MMC)-NQO1 docking study is presented. Small distances for hydride reduction and high binding affinities are characteristic of MMC and of iminoquinones showing correlations with NQO1 via COMPARE analysis. Docking also indicated that the presence of a substituent capable of hydrogen bonding to the His194 residue is important in influencing the orientation of the substrate in the NQO1 active site, leading to more efficient reduction.

The influence of the aziridinyl substituent of benzimidazoles and benzimidazolequinones on toxicity towards normal and Fanconi anaemia cells.

Aziridinyl substituted benzimidazolequinones are more toxic than methoxy analogues towards normal human fibroblast cells (GM00637). The aziridinyl substituent is required for hypersensitive killing of Fanconi anaemia (FA) cells (PD20i) deficient in FANCD2. Despite lacking quinone functionality, 4,7-dimethoxy-N-[(aziridin-2-yl)methyl]benzimidazole also induces hypersensitivity from FA cells, similar to their response towards mitomycin C. Expression of FANCD2 (in PD20:RV) corrects FA cell hypersensitivity supporting cellular response via the FANC pathway.

Aldehydes: Aryl and Heteroaryl Aldehydes

A comprehensive review of aromatic aldehyde preparations, published since 1995, is described. New methods include the introduction of new reducing reagents that convert benzoic acids and benzoyl halides into aldehydes. Alternatives to the use of DIBAL-H for the reduction of aromatic esters, amides, and nitriles into aldehydes are described. The Sommelet reaction, oxidations of benzyl halides, benzylamines, toluenes, oxidative cleavages of aryl ethylenes, and numerous selective oxidations of benzylic alcohols to aldehydes are reviewed. DDQ has been used to selectively oxidize benzyl ethers and carbamates. Pd-catalyzed formylation of aryl halides, and organolithum and Grignard-hydrogen or halogen exchanges followed by quenching of the carbanion with a formylating reagent are described. Electrophilic formylations of arenes include the Duff, Reimer–Tiemann, Vilsmeier–Haack, Gattermann–Koch, and Gattermann reactions. Formylations using dichloromethyl methyl ether, and polyformamides under typical Friedel–Crafts conditions have been shown to be applicable to activated as well as nonactivated arenes. Selective ortho- and para-formylation of phenols and nitrobenzenes respectively is described. Preparations of dicarbaldehydes, polyaromatic, furan, benzofuran, thiophene, benzothiophene, pyrrole, indole, pyridine, quinoline, pyrazole, imidazole, benzimidazole, thiazole and miscellaneous aromatic and heterocyclic carboxaldehydes are included.