Expanding the Reactivity of Hypervalent Iodine Reagents
Autor(a) principal: | |
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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 |
Resumo: | 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. |
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Expanding the Reactivity of Hypervalent Iodine ReagentsElectrophilic AminationHypervalent Iodine ReagentsUmpolungSulfonamidesHydroaminationDomínio/Área Científica::Engenharia e Tecnologia::Engenharia QuímicaThe 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.A transferência de aminas primárias recorrendo a reagentes de iodo hipervalente com reatividade umpolung é um método altamente promissor e inovador com o potencial de redesenhar a síntese de compostos nitrogenados complexos e de grande valor, bem como o desenvolvimento de procedimentos sintéticos mais sustentáveis. O principal objetivo desta tese de mestrado foi aprofundar a nossa compreensão acerca da reatividade dos derivados de benziodoxolonas contendo um grupo amina, bem como a sua aplicabilidade a diversos substratos, tentando também desenvolver novos derivados deste método de transferência de amina, a fim de gerar benziodoxolonas capazes de transferir diversas benzilaminas e aminoácidos. O trabalho experimental iniciou-se com a otimização do processo de preparação da benzilamina benziodoxolona (BBX), tendo resultado na obtenção de um protocolo de sililação para a benzilamina mais simples e seguro com rendimentos de até 61%. Este protocolo foi posteriormente aplicado a diversas benzilaminas com substituintes nas posições para- e meta- do anel aromático (nestes casos os rendimentos variaram entre os 27 e 70%, dependendo do caráter eletrónico dos grupos presentes no anel). Considerando o sucesso das reações de sililação realizadas através do novo método, este foi ainda aplicado aos aminoácidos fenilglicina, fenilalanina e glicina, devidamente protegidos, para os quais se obtiveram respetivamente os rendimentos de 45, 85 e 70%. A metodologia previamente publicada pelo nosso grupo de investigação foi aplicada à preparação dos reagentes de iodo(III) contendo a amina, tendo-se sintetizado todos os seis derivados com rendimentos excecionalmente elevados (acima dos 90%). A mesma metodologia foi aplicada aos três diferentes aminoácidos sililados, tendo-se testado também diferentes condições reacionais, incluindo a adição de uma fonte de protões e de um agente de acoplamento de péptidos (HBTU), por forma a facilitar a incorporação do aminoácido na posição pretendida. No entanto, apenas foram detetadas quantidades vestigiais, sendo necessária uma investigação mais aprofundada. Considerando os BBXs previamente sintetizados, as suas reatividades foram posteriormente estudadas na formação de ligações S-N, por reação com sais de sulfenato gerados in situ. Nas condições estudadas, observou-se a formação de sulfonamida. Após várias tentativas de otimização das condições reacionais, o número de sulfonamidas sintetizadas foi alargado. A análise detalhada dos resultados obtidos permitiu ainda propor um mecanismo para esta reação. Paralelamente, foram também realizados alguns estudos para avaliar as reações de aminação eletrofílica de ligações insaturadas utilizando o reagente de transferência de aminas primárias, BBX, com o objetivo de gerar N-alquil benzilaminas a partir do estireno. As condições reacionais foram testadas e os primeiros ensaios envolveram a utilização de catalisadores de Ni(acac)2 e Cu(OAc)2, diferentes solventes, agentes redutores de silano, e modificação da sequência de adição de reagentes. Nestas experiências preliminares, foi possível detetar a formação da amina desejada (embora apenas 10%), provando que o BBX é capaz de transferir a amina para uma olefina. Apesar dos progressos, no futuro será ainda necessária uma maior otimização das condições reacionais.Marques, Maria ManuelRUNDedeiras, Beatriz Isabel Filipe2023-10-172026-09-01T00:00:00Z2023-10-17T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/159463enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:41:52Zoai:run.unl.pt:10362/159463Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:57:33.205790Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Expanding the Reactivity of Hypervalent Iodine Reagents |
title |
Expanding the Reactivity of Hypervalent Iodine Reagents |
spellingShingle |
Expanding the Reactivity of Hypervalent Iodine Reagents Dedeiras, Beatriz Isabel Filipe Electrophilic Amination Hypervalent Iodine Reagents Umpolung Sulfonamides Hydroamination Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química |
title_short |
Expanding the Reactivity of Hypervalent Iodine Reagents |
title_full |
Expanding the Reactivity of Hypervalent Iodine Reagents |
title_fullStr |
Expanding the Reactivity of Hypervalent Iodine Reagents |
title_full_unstemmed |
Expanding the Reactivity of Hypervalent Iodine Reagents |
title_sort |
Expanding the Reactivity of Hypervalent Iodine Reagents |
author |
Dedeiras, Beatriz Isabel Filipe |
author_facet |
Dedeiras, Beatriz Isabel Filipe |
author_role |
author |
dc.contributor.none.fl_str_mv |
Marques, Maria Manuel RUN |
dc.contributor.author.fl_str_mv |
Dedeiras, Beatriz Isabel Filipe |
dc.subject.por.fl_str_mv |
Electrophilic Amination Hypervalent Iodine Reagents Umpolung Sulfonamides Hydroamination Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química |
topic |
Electrophilic Amination Hypervalent Iodine Reagents Umpolung Sulfonamides Hydroamination Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química |
description |
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. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-10-17 2023-10-17T00:00:00Z 2026-09-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/masterThesis |
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masterThesis |
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http://hdl.handle.net/10362/159463 |
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eng |
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eng |
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