Expanding the Reactivity of Hypervalent Iodine Reagents

• Autor(a) principal: Dedeiras, Beatriz Isabel Filipe
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/159463
• topic: Electrophilic Amination; Hypervalent Iodine Reagents; Umpolung; Sulfonamides; Hydroamination; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

The transfer of primary amines using hypervalent iodine reagents with umpolung reactivity is a highly promising and innovative method that has the potential to redesign the synthesis of complex and valuable nitrogenous compounds, along with the development of more sustainable synthetic procedures. The main objective of this master thesis was to deepen our understanding of the reactivity of benziodoxolone derivatives containing an amine moiety, as well as their applicability to various substrates, while also attempting to develop novel derivatives of this amine transfer method in order to generate benziodoxolones capable of transferring several benzylamines and amino acids. The work initiated with the improvement of the benzylamine benziodoxolone (BBX) preparation process resulting in a simpler and safer benzylamine silylation protocol with a yield up to 61%, followed by its application to various benzylamines with substituents in the para- and meta- positions of the ring (with yields between 27 and 70%, depending on the electronic character of the groups present in the ring). Considering the success of the silylations per-formed using the novel approach, the technique was applied to the amino acids phenylglycine, phenylalanine, and glycine, yielding 45, 85, and 70%, respectively. The methodology previously published by our research group was applied to the preparation of hypervalent iodine(III) rea-gents bearing an amine moiety, and all six corresponding derivatives were synthesized with exceptionally high yields (all above 90%). The same methodology was used for the three silylated amino acids, along with the exploration of different conditions, including adding a proton source and peptide coupling agent (HBTU) to facilitate the amino acid's incorporation into the intended position. However, only trace amounts were detected, and further investigation is required. Considering the previously synthesized BBXs, their reactivities were subsequently studied in S-N bond formation, by reaction with in situ generated sulfinate salts. Under the studied conditions, sulfonamide formation was observed. Following numerous efforts to optimize the reaction conditions, the scope of sulfonamides was expanded. A closer analysis of all the data obtained enabled the proposal of a mechanism for this reaction. Parallel investigations were also undertaken to evaluate electrophilic amination reactions of unsaturated bonds using the primary amine transfer reagent, BBX, to generate N-alkyl benzylamines from styrene and BBX reagents. The reaction conditions were tested, and the first experiments involved the use of Ni(acac)2 and Cu(OAc)2 catalysts, different solvents, silane reducing agents, and reagents order of addition. In these preliminary experiments, it was possible to detect the formation of the desired amine (although only 10%), proving that BBX is capable of transferring the amine to an olefin. Despite this progress, further optimization is still required in the future.