Synthesis of biologically important heterocyclic compounds via transition metal-catalyzed and SuFEx click reactions

Heterocyclic compounds are a highly important class of organic compounds due to their large number of applications in pharmaceuticals, biology, agrochemicals, industry, biotechnology, and material chemistry. The synthesis of heterocyclic compounds has always been a fundamental topic for chemistry research. Among them, indoles, benzofurans, quinolines, azepines and triazoles play a major role since they are part of many natural products and biologically active compounds. Indeed, recent studies have confirmed the involvement of molecules containing these structural motifs in a diverse array of biological processes, thereby exerting modulatory effects on various cellular actions. In this context, the primary goal of organic and medicinal chemists is to develop novel synthetic strategies for accessing challenging structures and small heterocycles. Among the many known chemical processes, organometallic catalysis, in particular that mediated by palladium, copper and sulfur-fluorine exchange (SuFEx) reactions occupy a place of absolute importance for the following reasons. Palladium (Pd) catalysis represented a huge leap forward in heterocycle chemistry, paving the way toward a variety of compounds, once inaccessible. CuAAC reaction introduced the regioselective synthesis of 1,4-disubstituted 1,2,3-triazole under mild reaction conditions. SuFEx chemistry enables the efficient and selective formation of S−F bonds under mild conditions, facilitating the synthesis of diverse sulfur-containing compounds with high functional group compatibility. Integrating these synthetic approaches enhances the efficiency and diversity to synthesize biologically relevant compounds. For instance, Pd-catalyzed cross-coupling reactions and C−H or C−X activation can introduce key functional groups, while click chemistry can modularly connect molecular scaffolds. SuFEx chemistry can establish specific functionalities or modify existing groups selectively. Overall, the combination of Pd-catalyzed, click, and SuFEx chemistry provides a powerful toolkit for the synthesis of biologically important moieties, enabling the rapid and efficient generation of diverse chemical libraries for drug discovery and development. This PhD thesis investigates the synthesis of biologically significant heterocycles, focusing on these advanced methodologies as primary strategies. The research aims to elucidate their utility and efficacy in creating heterocyclic compounds with potential biological relevance, contributing to synthetic chemistry's advancement and novel compound development for drug discovery and biomedical applications. Chapter 1 provides an overview of catalytic reactions, including Pd-catalyzed cross-coupling, C−H activation, and CuAAC, introducing SuFEx as an innovative synthetic methodology. Chapter 2 outlines the primary objective of synthesizing biologically significant heterocycles through transition-metal catalyzed reactions, click chemistry, exploring novel SuFEx hubs and their applications. Chapter 3-5 focus on synthesizing heterocyclic fused 1,2,3-triazoles using click chemistry and Pd-catalyzed intramolecular C−H activation, demonstrating efficient methodologies for building these compounds. Chapter 6 presents novel approaches for synthesizing azepine- and oxepine-fused 1,2,3-triazoles via sequential click chemistry and Pd-catalyzed annulation, highlighting high yields and broad functional group tolerance. Chapter 7 provides a gold-catalyzed protocol to obtain functionalized 3H-pyrrolo [1,2,3-de] quinoxalines from suitable substituted N-alkynyl indoles. The mild reaction conditions were revealed to be compatible with different functional groups, including halogen, alkoxyl, cyano, ketone, and ester, allowing the isolation of title compounds with yields from good to high. A reaction mechanism has been proposed, and theoretical calculations have been provided to rationalize the final step of the hypothesized reaction mechanism. Chapter 8 presents a straightforward assembly of polysubstituted 1,2-dihydro-3H-pyrrolo[1,2-a]indol-3-ones through a domino Pd-catalyzed reaction of indol-2-ylmethyl acetates with 1,3-dicarbonyl derivatives. The key role of the features of the 1,3-dicarbonyls on the reaction outcome has been explored. The employment of 2-methylcyclohexan-1,3-dione as the dicarbonyl source could allow further challenging indole nucleus functionalization. Chapter 9 is about the synthesis of silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2-mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces sulfurimidoyl fluorides in high yields. In addition, this workflow is fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials. Chapter 10 presents a new method for the facile preparation of aryl−IF4 compounds using KF and ex situ generated chlorine gas within a two-chamber reactor setup. Notably, the process stands out for its simplicity by omitting the use of specialized equipment and generating less chemical waste than the previously reported works. While demonstrating high efficiency at room temperature, the novel approach provides access to a diverse array of products with moderate to excellent yields.