Ruthenium(II) and rhodium(III)-catalyzed C-H activation: diversifying bioactive and fluorescent compounds via alkenylation, oxygenation and annulation protocols

Abstract

This thesis describes the development of synthetic methodologies, based on C-H bond activation, to perform alkenylation and oxygenation of 1,4-naphthoquinone and annulation of lapimidazole. 1,4-naphthoquinones exhibit low reactivity on the benzenoid ring by conventional arene reactions, resulting in a limited scope of molecules to be applied in Medicinal Chemistry. To overcome this synthetic restriction, in the first part of this thesis, some efforts in the development of C-H activation based on ruthenium catalysis are described. First, several optimization reactions were studied to find the suitable experimental condition to perform the functionalization of the C-H bond of the benzenoid ring of 1,4-naphthoquinones, focused on alkenylation and oxygenation reactions. After completing the optimization of the reaction, several 1,4-naphthoquinoidal compounds bearing electron-donating and withdrawing groups were prepared and subjected to C-H alkenylation and oxygenation protocols developed. The compounds obtained were subjected to biological assays against Trypanosoma cruzi and several of them presented promising biological activity, particularly products bearing halogens. In the second part of this thesis, C-H/N-H annulation reactions on imidazole using diphenyl acetylene are described. Most works in the literature report similar reactions using symmetrical imidazoles, as a strategy to avoid isomers. Thus, aiming to overcome this limitation, optimization studies were conducted using the non-symmetrical lapimidazole. Several lapimidazole derivatives, bearing different groups, were synthesized and subjected to C-H/N-H annulation methodology. In all cases, annulations in the benzene side of lapimidazole were observed in higher yield while the annulations close to the aliphatic side were observed in lower yield. NMR and X-ray crystallography studies enabled the correct distinction of both product and mechanistic investigations were carried out justifying the majority of one isomer. Also, photo-physical studies were accomplished with the products bearing a methoxyl and nitro product as well as the product without substituent. In general, the products exhibited blue or green-yellow fluorescence emission while compounds bearing nitro group displayed orange-red fluorescence emission. In conclusion, C-H alkenylation, oxygenation and annulation developed in this work allowed to obtain diverse products with biological and fluorescent properties.