The use of Acetic Anhydride in Annulations onto Benzimidazoles to give Novel Reducible p-Dione Adducts

Joyce, Eamonn
Chapter 1: Introduction to the reactive intermediates used in this thesis, namely acyl radicals and N-heterocyclic carbenes (NHC) is presented, along with an assessment of the anti-cancer activity of literature bioreductive heterocyclic quinones. Chapter 2: Acyl radicals are shown to undergo photochemical intramolecular homolytic aromatic substitution onto the 2-position of benzimidazoles from readily accessible phenyl selenoesters using chemical initiator-free conditions. The addition of acetic anhydride (Ac2O) can improve the yields of cyclized products by increasing the electrophilicity of the benzimidazole towards the nucleophilic radical. However many p-dione targets are found to absorb UV-light very efficiently leading to extra reactions, which lower yields. Chapter 3: Ac2O behaves as a traceless activating agent allowing thermal intramolecular condensation of (benzimidazol-1-ylmethyl) benzoic and nicotinic acids. Aerial oxidation gives benzimidazo[1,2-b]isoquinoline-6,11-diones and benzimidazo[2,1-g]-1,7-naphthyridine-5,12-diones in a facile one-pot transformation. 1,4-Dimethoxy analogue of the former is converted to benzimidazo[1,2-b]isoquinoline-1,4,6,11-tetrone (1) using cerium(iv) ammonium nitrate (CAN). The 1,7-naphthyridine-5,12-dione system readily ring-opens, and X-ray crystal structure of the MeOH-adduct was obtained. Ac2O mediated thermal condensation of 4-(1H-benzimidazol-1-yl)butanoic acid led to fully aromatic pyrido[1,2-a]benzimidazole, and intermediates in its formation were characterized. Chapter 4: Ac2O mediates a facile and rapid condensation of benzimidazole with aromatic o-diacid dichlorides to precipitate p-dione adducts in excellent yields. Condensation with pyridine-3,4-dicarbonyl dichloride produced a 1:1 mixture of isomeric p-diones. The X-ray crystal structure of one of the latter isomers revealed unusual high density and inter-layer separation similar to graphite. Cyclic voltammetry demonstrated the p-dione is capable of two consecutive one electron reductions with formal potentials influenced by the fused (hetero)aromatic and substituent effects. Cytotoxicity analysis showed benzimidazo[1,2-b]isoquinoline-6,11-dione was more cytotoxic towards the human prostate cancer cells (DU145) than its tetrone derivative 1, with lesser cytotoxicity towards the human normal cancer cells (GM00637). Chapter 5: All experimental detail is described for Chapters 2, 3, and 4.
Publisher DOI
Attribution-NonCommercial-NoDerivs 3.0 Ireland