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Projeto de investigação
1Pot2Cat: One-pot bimetallic catalyzed synthesis of challenging N-heterocycles
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Advances in green catalysis for the synthesis of medicinally relevant N-heterocycles
Publication . Santos, Ana Sofia; Raydan, Daniel; Cunha, José C.; Viduedo, Nuno; Silva, Artur M. S.; Marques, M. Manuel B.; LAQV@REQUIMTE; DQ - Departamento de Química; MDPI - Multidisciplinary Digital Publishing Institute
N-heterocycles, both saturated and unsaturated, are ubiquitous biologically active molecules that are extremely appealing scaffolds in drug discovery programs. Although classical synthetic methods have been developed to access many relevant N-heterocyclic scaffolds, representing well-established and reliable routes, some do not meet the needs of sustainability. In this context, several advances have been made towards the sustainable synthesis of N-heterocycles. This review focuses on the most recent examples from the last five years of catalytic synthesis of several heterocyclic compounds of medicinal relevance. Thus, the synthesis of isoindoloquinazolines, quinazolines and azaindoles, among others, are covered. The synthetic methods selected include the use of homo-geneous and heterogeneous catalysts and the use of alternative and sustainable methods such as, for example, metal-catalyzed acceptorless coupling and one-pot reactions. The green aspects of the individual synthetic approaches are highlighted, and the scope of each methodology is described.
Sustainable and Efficient Manganese-Catalyzed Imine Formation: a Step Further to One-Pot Bimetallic Synthesis of N-Heterocycles
Publication . Viduedo, Nuno André dos Santos; Marques, Maria Manuel; Royo, Beatriz
Imine derivatives have long been described as exceptionally useful compounds in organic chemistry, being mostly recognized as key intermediates in the synthesis of nitrogen heterocycles, such as indoles and azaindoles. In fact, these two similar N-heterocyclic scaffolds are widely present in biologically active compounds, thus considered privileged nucleus in medicinal chemistry. Therefore, there is a great interest of the scientific community in developing new synthetic methodologies to efficiently obtain both imines and the corresponding heterocyclic structures.
Recently, imine synthesis has been explored by acceptorless dehydrogenative coupling (ADC) of aromatic amines and primary alcohols, via manganese-catalyzed processes. In this thesis, several phosphine-free manganese(I) tricarbonyl complexes, bearing different bidentate ligands, were employed in order to find the most efficient ones for the ADC reaction of aniline and aminopyridine systems. In this context, manganese complexes bearing chelating di-triazole-based ligands proved to be the most appropriate. Additionally, reaction conditions were optimized to maximize imine formation. Interestingly, it was found that ADC reactions were efficiently catalyzed using 3 mol% of Mn-based catalyst loading, in the presence of potassium tert-butoxide and molecular sieves, achieving high yields (up to 99%) of a large variety of imines (more than 25), starting from aniline and aminopyridine derivatives.
Next, imine synthesis from aromatic amines and secondary alcohols, mediated by Mn-catalysts, was explored, while we were getting closer to the creation of N-heterocycles synthetic routes. Reaction conditions were separately optimized for secondary alcohol oxidation and ketimine formation, yielding the desired products in 91% and 95%, respectively. Lastly, a bimetallic route, involving manganese and palladium catalysis, to achieve indoles and azaindoles, from simple and commercially available aromatic amines and alcohols, were established. This one-pot procedure, concerning 3 reaction steps, allowed the obtention of indole scaffold in a promising 30% yield. On the other hand, although only trace amounts of azaindoles were found, the studies performed led to interesting discoveries that could be very useful in the near future.
Synthesis of pharmaceutically relevant N-heterocycles via metal-catalysed reactions
Publication . Alexandre Pirvu, Leonardo; Marques, Maria
N-heterocycles are an important class of compounds present in many bioactive mole cules, constituting a valuable source of therapeutic agents in the pharmaceutical industry. Par ticularly, carbolines and quinolines are notable due to their diverse biological properties and structural diversity. In this work different approaches were explored towards the carboline nucleus. The method investigated relied on a palladium-catalysed denitrative C−H amination, as the key step to achieve the saturated carboline scaffold. The first step involved the preparation of an N,N diarylamine via nucleophilic aromatic substitution reaction using the commercially available 3-fluor-2-nitropyridine and p-anisidine, leading to the desired product in 82% yield. After N protection, a palladium-catalysed denitratrive C−H amination led to the formation of the car boline in 27% yield, constituting of a new and promising route. The synthesis of tetrahydrocarbolines was also considered, and two different approaches were investigated. The first consisted of using properly protected L-threonine and aniline to generate a chiral key intermediate, to be further converted into several chiral C1-substituted tetrahydro carbolines, relying on a metal-catalysed reaction. However, this approach did not afford the desired compound. The second approach consisted of using an allylic amine, pre pared via a molybdenum-catalysed amination reaction, to achieve a key intermediate for further reaction with an aromatic amine, followed by palladium-catalysed cyclization. However, the allylic amine underwent an intramolecular cyclization leading to the formation of a quinoline, by C−H activation reaction, along with the acetylated aza-Cope rearrangement product. This fascinating result, lead us to explore this reaction. The reaction was optimized, and different allylic amines were prepared in yields up to 86%. The reaction proved to be wide in scope, and quinolines were obtained in yields up to 59%, via an unprecedented Pd-catalysed C−H activa tion reaction of allylic amines. The reaction is still being investigated, consisting of a promising and simple route towards biologically relevant quinolines.
Temperature-induced formation of Pd nanoparticles in heterogeneous nanobiohybrids
Publication . Losada-Garcia, Noelia; Santos, A. Sofia; Marques, M. Manuel B.; Palomo, Jose M.; LAQV@REQUIMTE; DQ - Departamento de Química; RSC - Royal Society of Chemistry
The effect of the temperature in the synthesis of Pd nanoparticles in the metal-enzyme biohybrids is evaluated. The effect on the formation, size, and morphology of nanoparticles was evaluated using C. antarctica B lipase as the protein scaffold. XRD analyses confirmed the formation of crystalline Pd(0) as the metal species in all cases. TEM analyses revealed spherical crystalline nanoparticles with average diameter size from 2 nm at 4 °C synthesis to 10 nm obtained at 50 °C synthesis. The thermal phenomenon was also critical in the final hybrid formation using more complex enzymes, where the relation of the protein structure and temperature and the influence of the latter has been demonstrated to be critical in the reducing efficiency of the enzyme in the final Pd nanoparticle formation, in the metal species, or even in the final size of the nanoparticles. Different Pd biohybrids were evaluated as catalysts in the C-H activation of protected l-tryptophan under mild conditions. Pd@CALB4 showed the best results, with >99% conversion for C-2 arylation in methanol at room temperature with a TOF value of 64 min−1, being 2 or 4 times higher than that of the other synthesized hybrids. This catalyst showed a very high stability and recyclability, maintaining >95% activity after three cycles of use.
Palladium- and Manganese-catalysed Synthesis of N-heterocycles
Publication . Raydan, Daniel Alejandro; Marques, Maria Manuel; Royo Cantabrana, Beatriz
Access to a wide range of functionalized N-heterocyclic
compounds is essential for efficient drug discovery programs. A key
challenge remains the lack of simple synthetic methods using readily
available starting materials. Metal-catalysed dehydrogenative
coupling has proven particularly effective in providing catalytic
pathways for converting alcohols and amines into valuable products,
particularly in the synthesis of imines, which are crucial intermediates
in the formation of nitrogen-containing compounds. Additionally,
incorporating dehydrogenative coupling into multicatalytic processes
offers a convenient strategy for N-heterocyclic synthesis.
This work explores the development of dehydrogenative
coupling strategies for nitrogen-containing compounds and their
implementation in multicatalytic approaches. Key findings include the
conversion of primary alcohols with aniline and aminopyridines,
achieving up to 99% yield of imines using only 3 mol% of a manganese-
tricarbonyl complex with a bidentate triazole ligand system. For the
more challenging secondary alcohols, a simple method for imine
synthesis is described, utilizing Pd(OAc)₂ as catalyst in an acceptorless
dehydrogenative coupling strategy, without any base additives.
Sequential reactions with Pd(OAc)₂ led to the formation of indoles,
representing a significant advance in the synthesis of N-heterocycles.
Furthermore, by modifying the reaction conditions, this catalytic
system enabled the selective formation of secondary amines through a
borrowing hydrogen strategy. Finally, the thesis explores the
dialkylation of diamines and diols using a Mn(I)-tricarbonyl complex
with bis(1,2,3-triazol-5-ylidene) ligands, achieving yields of up to 99%.
The catalytic activity was further demonstrated in the synthesis of
1,2,3,4-tetrahydroquinoxalines, a class of compounds with significant
pharmacological activity. Additionally, an unprecedented route for the
synthesis of indoline was developed using a bimetallic
manganese/palladium catalytic system combining primary alcohols
and amines.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/QUI-QOR/0712/2020