Publicação
PHOTOCATALYTIC METHODS FOR THE SYNTHESIS OF INDOLE DERIVATIVES
| Resumo: | The indole moiety is one of the most extensively studied heterocycles in organic chem- istry due to its prevalence in natural products, pharmaceuticals, agrochemicals, and a wide range of bioactive compounds. Despite this, traditional methods for the synthesis of indoles, such as the Fischer, Bartoli, and Leimgruber-Batcho reactions as well as many other estab- lished approaches, suffer from major drawbacks, including the need for harsh conditions, the use of expensive, toxic, and difficult-to-handle reagents, and limited functional group toler- ance. Therefore, the development of more sustainable, efficient, and versatile methodologies for the preparation of these scaffolds remains a key objective in synthetic chemistry. In this work, a novel visible light-mediated strategy was developed for the synthesis of 1,2,3,4-tetrahydrocyclopent[b]indoles starting from furfural, a widely available and easily pro- duced industrial chemical. Furfural can be directly obtained from biomass waste, and its con- version into value-added products has been extensively investigated by our research group. The synthetic route begins with the conversion of furfural into trans-4,5-diamino-cyclo- pent-2-enones (DCPs) via a Nazarov-type electrocyclization. Subsequent catalytic hydrogena- tion and β-amine elimination afford α-enaminones, which serve as key intermediates for the photochemical step. Unpon blue light irradiation and in the presence of 3DPAFIPN photocata- lyst, these α-enaminones undergo oxidative photocyclization, yielding the indole derivatives. The scope study shows consistent isolated yields around 38–53% across diverse substit- uents, while strong electron-withdrawing groups (–CF₃, –CN) give lower yields (20% and 27%) with incomplete conversion. Enaminones with secondary amines did not work under these conditions and attempts to use protection or alkylation to broaden the scope were also unsuc- cessful. Optimization studies evaluated the impact of photocatalyst type, solvent, atmospheric conditions, reaction concentration, and the presence of different additives on reaction perfor- mance. The reaction required molecular oxygen for efficient conversion, as yields decreased significantly under inert atmospheres. Preliminary mechanistic studies combined cyclic voltammetry data with literature elec- tronic potentials, pointing toward energy transfer (EnT) as the most likely pathway. |
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| Autores principais: | Vilela, Gonçalo Higino |
| Assunto: | Indole derivatives Blue light irradiation Furfural Photocatalysis Photocyclization 3DPAFIPN |
| Ano: | 2025 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | The indole moiety is one of the most extensively studied heterocycles in organic chem- istry due to its prevalence in natural products, pharmaceuticals, agrochemicals, and a wide range of bioactive compounds. Despite this, traditional methods for the synthesis of indoles, such as the Fischer, Bartoli, and Leimgruber-Batcho reactions as well as many other estab- lished approaches, suffer from major drawbacks, including the need for harsh conditions, the use of expensive, toxic, and difficult-to-handle reagents, and limited functional group toler- ance. Therefore, the development of more sustainable, efficient, and versatile methodologies for the preparation of these scaffolds remains a key objective in synthetic chemistry. In this work, a novel visible light-mediated strategy was developed for the synthesis of 1,2,3,4-tetrahydrocyclopent[b]indoles starting from furfural, a widely available and easily pro- duced industrial chemical. Furfural can be directly obtained from biomass waste, and its con- version into value-added products has been extensively investigated by our research group. The synthetic route begins with the conversion of furfural into trans-4,5-diamino-cyclo- pent-2-enones (DCPs) via a Nazarov-type electrocyclization. Subsequent catalytic hydrogena- tion and β-amine elimination afford α-enaminones, which serve as key intermediates for the photochemical step. Unpon blue light irradiation and in the presence of 3DPAFIPN photocata- lyst, these α-enaminones undergo oxidative photocyclization, yielding the indole derivatives. The scope study shows consistent isolated yields around 38–53% across diverse substit- uents, while strong electron-withdrawing groups (–CF₃, –CN) give lower yields (20% and 27%) with incomplete conversion. Enaminones with secondary amines did not work under these conditions and attempts to use protection or alkylation to broaden the scope were also unsuc- cessful. Optimization studies evaluated the impact of photocatalyst type, solvent, atmospheric conditions, reaction concentration, and the presence of different additives on reaction perfor- mance. The reaction required molecular oxygen for efficient conversion, as yields decreased significantly under inert atmospheres. Preliminary mechanistic studies combined cyclic voltammetry data with literature elec- tronic potentials, pointing toward energy transfer (EnT) as the most likely pathway. |
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