Transition metal-catalyzed C(sp2)-H acylation and olefination reactions for the functionalization of (Hetero)Arenes

Abstract

The research work collected in this thesis is focused on the development of new methodologies of carbon-carbond bond formation (acylation, aminocarbonylation and olefination) of heteroaromatic rings, such as pyrroles or thiophenes via C-H activation reactions catalyzed by Pd(II) and Co(III). In the first chapter, and to give context to this thesis, the experience of our researching group in the Palladium and Cobalt catalyzed reactions is described. The second chapter is focused, on the one hand, on the development of a methodology of Pd(II)-catalyzed acylation of pyrroles. The optimized reaction conditions have been applied to the synthesis of Celastramycin analogue and Tolmentin. As a secondary objective, anti-leishmanicidal activity against visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis and cytotoxicity of some of the synthesized 2-acylpyrroles have been evaluated through biological assays carried out by Dr. M. A. Dea from University CEU Cardenal Herrera (Valencia). On the other hand, Pd(II)-catalyzed C-3 acylation of thiophenes with aldehydes via C(sp2)-H activation has been developed. To show the synthetic applicability, selected ketones were subjected to further diversifications, including an intramolecular reaction, which involves the directing group. In the third chapter, the attempts to expand the methodology for the acylation of pyrroles to the use of Co(III) catalysis, is described. Furthermore, the nucleophilic addition of thiophene C-H bond to isocyanates catalyzed by Co(III) has been explored. Finally, in the fourth chapter, the research realized in my predoctoral three-month stay in Prof. Manuel Antonio van Gemmeren¿s research group at the Organic Chemistry Institute of the University of Münster is explained, which was focused on the use of dual-ligand-based palladium catalysts for the late-stage olefination of bioactive arenes.