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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/220600
Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
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[eng] Radical reactions have been proven valuable tools in C-C bond generation because the initial radical can evolve to form additional C-C bonds until the new radical species is trapped. With the careful design of the substrates and the control of the reaction conditions, tandem radical reactions can be developed that allow the construction of complex structures starting from simple starting materials. Metal-catalyzed hydrogen atom transfer (MHAT) reactions are radical-based reactions that allow mild and non-toxic conditions, with high chemo- and site-selectivity and a wide functional group tolerance. Our group has developed several MHAT C-C bond-forming reactions of non-activated alkenes with a wide variety of acceptor groups such as aldehydes, ketones, Cbz hydrazones, and tosylhydrazones. Despite the many advantages presented by MHATbased radical reactions and their potential for developing new tandem reactions, few examples have yet been reported in the literature. In the present thesis, the aim was to expand the scope of radical acceptors that can be used in MHAT reactions as well as develop novel tandem reaction processes. First, isocyanides have been studied as radical acceptors to carry out a tandem reaction to obtain functionalized nitrogen heterocycles, highly valued compounds in medical chemistry (Scheme 2). The reaction uses MHAT conditions to generate a radical on an alkene that carries out a first radical addition step on the isocyanide, followed by subsequent intramolecular cyclization to give rise to the functionalized heterocycle. A wide range of different nitrogen-containing heterocycles can be synthesized using this methodology. In cases where the alkene substitution made it more challenging, combining HAT-Minisci conditions made the coupling possible. The reductive cyclization of these isocyanides has also been shown to be effective, in the absence of alkene, to give rise to the corresponding unfunctionalized heterocycles. Secondly, a cross-dehydrogenative coupling reaction has been developed from the initial serendipitously observed side reaction. Using conditions derived from MHAT and Minisci, it has been possible to generate radicals through C-H activation on the - position of ethers, amides, and alkanes to carry out the radical coupling on activated heterorenes. This reaction has the potential to be applied in medicinal chemistry for latestage functionalization under mild conditions. Thirdly, the use of tosylhydrazones as acceptor groups in MHAT reactions has been studied to carry out a tandem reaction that begins with intramolecular cyclization followed by in situ fragmentation of the tosylhydrazine and subsequent intermolecular trapping of the generated tertiary radical with a Michael acceptor in a Giese-type addition. This reaction allows the generation of two adjacent quaternary centers in a single reaction via the formation of two geminal C-C bonds. This methodology has been used to prepare functionalized derivatives of adamantane, a very interesting scaffold from the point of view of medicinal chemistry and other fields, using different Michael acceptors. Further transformations also allowed the preparation of adamantanesubstituted heterocycles.
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PUIG BOSCH, Jordi. Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors. [consulta: 3 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/220600]