Publicação
Sustainable synthesis with the diazo insertion reactions
| Resumo: | Diazo chemistry and its use of carbene reactivity has shaped current organic synthesis, providing a versatile method for synthesizing complex molecules. A broad range of nucleophiles can be introduced using rare-earth metal catalysis with rhodium or copper. More recently, Feᶦᶦ catalysts were found to provide similar reactivity at a fraction of the cost. Still, these catalyst’s low stability and complex ligand design disfavoured their use. Here, FeCH(pz)₃Cl₂ was explored as the first bench-stable Feᶦᶦ catalyst for the reaction between ethyl α-aryl-α-diazoacetates and substituted anilines. The amine products were obtained in good yields with reagents bearing both EDG and EWGs. A DFT study of the reaction mechanism is consistent with forming a metal carbene intermediate. Next, the reaction between ethyl diazoacetate and aniline derivatives, catalysed by Fe(TpFPP)Cl, was improved upon to reduce its environmental impact. The standard chlorinated solvent was substituted by a deep eutectic solvent (DES) - N[₄,₄,₄,₄]Cl:1,2-propanediol. This new solvent system gave comparable yields while allowing the recovery and reuse of the DES+catalyst system through selective extraction. Finally, a set of novel 2-(α-diazo)benzyl-4H-chromen-4-ones were synthesized and characterized. Its reaction with distinct nucleophiles allowed the synthesis of novel chromone derivatives bearing amine, imine, cyclopropane, thiol and azine groups. The unusual reactivity of these diazo compounds with amines, namely through double insertion, was also discussed. The compound library thus obtained was evaluated as potential AChE and MAO-A/MAO-B inhibitors for the treatment of Alzheimer’s disease and Parkinson’s disease, respectively. Several derivatives presented promising biological activities, with IC₅₀s in the low micromolar range. This endeavour into diazo chemistry contributed significantly to the field of diazo chemistry by exploring alternative catalysts and sustainable solvents and introducing a new class of complex diazo substrates. |
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| Autores principais: | Batista, Vasco Figueiredo |
| Assunto: | Diazo Scorpionates Iron catalysts Iron porphyrins Deep eutectic solvents Chromones Acetylcholinesterase Monoamine oxidase |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| Resumo: | Diazo chemistry and its use of carbene reactivity has shaped current organic synthesis, providing a versatile method for synthesizing complex molecules. A broad range of nucleophiles can be introduced using rare-earth metal catalysis with rhodium or copper. More recently, Feᶦᶦ catalysts were found to provide similar reactivity at a fraction of the cost. Still, these catalyst’s low stability and complex ligand design disfavoured their use. Here, FeCH(pz)₃Cl₂ was explored as the first bench-stable Feᶦᶦ catalyst for the reaction between ethyl α-aryl-α-diazoacetates and substituted anilines. The amine products were obtained in good yields with reagents bearing both EDG and EWGs. A DFT study of the reaction mechanism is consistent with forming a metal carbene intermediate. Next, the reaction between ethyl diazoacetate and aniline derivatives, catalysed by Fe(TpFPP)Cl, was improved upon to reduce its environmental impact. The standard chlorinated solvent was substituted by a deep eutectic solvent (DES) - N[₄,₄,₄,₄]Cl:1,2-propanediol. This new solvent system gave comparable yields while allowing the recovery and reuse of the DES+catalyst system through selective extraction. Finally, a set of novel 2-(α-diazo)benzyl-4H-chromen-4-ones were synthesized and characterized. Its reaction with distinct nucleophiles allowed the synthesis of novel chromone derivatives bearing amine, imine, cyclopropane, thiol and azine groups. The unusual reactivity of these diazo compounds with amines, namely through double insertion, was also discussed. The compound library thus obtained was evaluated as potential AChE and MAO-A/MAO-B inhibitors for the treatment of Alzheimer’s disease and Parkinson’s disease, respectively. Several derivatives presented promising biological activities, with IC₅₀s in the low micromolar range. This endeavour into diazo chemistry contributed significantly to the field of diazo chemistry by exploring alternative catalysts and sustainable solvents and introducing a new class of complex diazo substrates. |
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