Novel catalytic approaches for the synthesis of value-added compounds

This thesis explores novel catalytic approaches for the synthesis of value-added compounds, focusing on three research areas that leverage different homogeneous catalysis methods: Palladium/Norbornene cooperative catalysis, photocatalyzed Hydrogen Atom Transfer (HAT), and asymmetric organocatalysis with Chiral Phosphoric Acids (CPAs). Each of these methodologies offers unique features and advantages for generating compounds of synthetic importance. Chapter 1 explores the role of homogeneous catalysis in organic synthesis, emphasizing its contributions to green chemistry, such as waste reduction, selectivity improvement, and energy efficiency. It traces the evolution of catalytic methods, including key innovations like palladium-catalyzed cross-coupling reactions and C‒H activation strategies, notably the Catellani reaction, which enables efficient polycyclic structure formation. The chapter also highlights the impact of photocatalysis, with a focus on photocatalyzed Hydrogen Atom Transfer (HAT) for direct C‒H bond functionalization. Additionally, it discusses the rise of organocatalysis, using small organic molecules for sustainable, metal-free reactions, with advances in chiral catalysts like chiral phosphoric acids driving highly selective transformations. Chapter 2 introduces a new, one-pot Catellani-Heck sequence for synthesizing carboxyl-functionalized biaryls, which are important intermediates in organic synthesis. By combining ortho-substituted aryl iodides, 2-bromobenzoic acids, and palladium/norbornene cooperative catalysis, this method preserves the carboxyl group, offers milder reaction conditions, and achieves high yields (up to 97%) for over 26 compounds. The reaction is simple, compatible with various functional groups, and effective for further transformations, including the synthesis of a phenanthrene derivative and 5- and 7-membered lactones. Aniline, as an additive, is crucial for improving selectivity and reaction yield. This behaviour had been observed not only in this reaction protocol, but also in a different Catellani reaction — a decarboxylative palladium-catalyzed regioselective aromatic extension of internal alkynes — where aniline strongly enhanced the formation of the phenanthrene products. Computational studies will be conducted to investigate the role of aniline. Chapter 3 outlines the development of a novel photocatalyzed hydrogen atom transfer (HAT) strategy aimed at overcoming the key limitations of this process, regioselectivity and inefficiency. The strategy leverages a Traceless Activating Group (TAG) on the H-donor, specifically a formyl group, which is naturally present in common feedstock chemicals like aldehydes. This TAG enhances both selectivity and efficiency in HAT reactions by facilitating a faster hydrogen abstraction from H-donors in stoichiometric amounts (1.2 equivalents rather than a large excess). It promotes C−C bond formation via decarbonylation of the generated acyl radical, guiding regioselectivity to the position previously occupied by the formyl group. The HAcTive strategy, was successfully demonstrated using different aldehydes in a Giese-type radical hydroalkylation reaction with Tetrabutylammonium decatungstate (TBADT) as photocatalyst. Notably, the use of Garner’s Aldehyde (GA) as an H-donor enabled the formal synthesis of a variety of functionalized amino alcohols (21 compounds) through a Giese-type reaction and SOMOphilic alkynylation, achieving high yields. The effectiveness of the strategy was further demonstrated by a synthesis on a 5 mmol scale under continuous-flow conditions, along with the successful opening of the oxazolidine ring to yield the corresponding amino alcohol derivative. In collaboration with our colleagues from University of Pavia, mechanistic studies using Laser-Flash Photolysis (LFP), and computational analysis via Density Functional Theory (DFT) were performed. Chapter 4 introduces a novel approach to the asymmetric, regioselective three-component vinylogous Povarov reaction, using phenolic dienes as dienophiles, catalyzed by chiral phosphoric acids (CPAs). This reaction allows to synthetize tetrahydroquinolines (THQs), which are an essential class of heterocyclic compounds in medicinal chemistry. The study, conducted during my period abroad as visiting PhD student at ICSN-CNRS in the research group of Prof. G. Masson, explores various reaction conditions, such as different CPA catalysts, solvents, and temperatures, to optimize yield and enantioselectivity. A variety of aldehydes and aniline were tested, demonstrating the robustness of the methodology. Ortho-substituted anilines, however, resulted in diminished enantioselectivity due to steric hindrance disrupting catalyst-imine hydrogen bonding. Additionally, the reaction scope was expanded using various phenolic dienes. Notably, electron-rich dienes showed excellent results. The study also revealed the importance of catalyst bifunctionality, with hydrogen bonding playing a crucial role in determining stereochemical outcomes. A stepwise pathway involving a Mannich reaction followed by Friedel-Crafts alkylation, supported by experimental evidence, had been proposed. Moreover, post-reaction modifications demonstrated the synthetic versatility of the transformation.