Small Molecule Activation for the Formation of Heterocyclic Compounds

Resumen

Lewis acid catalyzed coupling reactions between epoxides and different heterocumulenes can lead to a wide variety of interesting heterocycles. Aluminium triphenolates proved to be a very active catalyst in the formation of cyclic carbonates via oxiranes-CO2 couplings, we decided to prove that this potential was not only limited to this reaction but was a more general catalyst for acid promoted couplings. Aminotriphenolate systems are highly modular, with coordination geometries controlled by the ligand, in particular by the nature of the substituents in ortho position to the phenol, which are able to influence their reactivity and stability. They are tunable and readily synthesized catalysts with great potential in Lewis acid catalysis. Using this acid catalyst with a halide cocatalyst if necessary we have developed simple methodologies for the synthesis of oxazolidinones, cyclic sulfites, and cyclic carbonates with higher substitutions patterns, which have not been as intensively, reported as their monosubstituted cyclic carbonates analogues. As reaction partners we have tried to use waste gases such as SO2 and CO2 whose research is gaining great importance as they represent an important enviromental threat. The methodology used throughout the thesis has consisted in identifying a possible target molecule and studying a pathway for its synthesis. We have used for every project NMR, IR and mass spectrometry techniques. When CO2 was used, high pressure equipment was required. When we had achieved an effective synthetic methodology we then set out to study the mechanisms and associated stereoselective outcomes to try to control them in order to achieve stereoselective synthesis. Some of them were already stereoselective so in this cases the work was simpler. In some cases we could not identify the stereoconfiguration of the products by NMR so we had to crystalize the products and obtain an X Ray. In chapter I we study aluminium amino triphenolates as catalysts in coupling reactions of epoxides and phenyl urethane. We evaluate the potential to create a decent scope of oxazolidinone with the idea that this are precursors to assymetric ureas. Assymetric ureas are valuable organic products which recently have attracted attention for their catalytic activity. We show how this oxazolidinone can be easily ring opened, through an aminolysis reaction with various amines yielding asymmetrically substituted ureas. Therefore, we describe a simple, selective and efficient method for the synthesis of these products. Chapter II we evaluate the catalytic activity of amino triphenolates in another coupling reaction of epoxides. This time we use SO2 as the coupling partner, SO2 is an exhaust gas in fossil fuel combustion processes and an industrial intermediate in sulfuric acid production. We compare the reaction with the known coupling reaction of CO2 and epoxides, differences and similarities are described and noted. The coupling reaction yields cyclic sulfites, the methodology proves to be efficient, selective and have a wide scope. Chapter III describes how the aluminium amino triphenol system is able to catalyze the coupling reaction of CO2 and internal epoxides, in particular we focus on multicyclic scaffolds with different ring sizes, we tune the conditions and catalyst loadings to selectively form cis carbonates. This cis carbonates via basic treatment decompose into the corresponding cis diols. The cyclic carbonate can be therefor considered as a protecting group of cis diols, presenting a greener alternative to osmium based existing methods for the synthesis of these type of scaffolds On chapter IV we present a one pot method to make carbamates from cyclic epoxides, CO2 and amines. We are able to control diastereoselectivity on the product by tuning the conditions to selectively form either the cis or the trans configured carbamate. We do this by tuning the conditions to form a cyclic carbonate or oligocarbonate intermediate which is then attacked by an amine on the electrophilic carbonyl moiety to yield the corresponding carbamate. The intermediate configuration determines the configuration of the final product as cyclic carbonates and oligocarbonates have opposite configurations. We describe how the ring size affects drastically the selectivity, indicating the tendency of different substrates to either polymerize or form cyclic carbonates. In final chapter V we report on the stereoselective preparation of bicyclic trisubstituted carbonates by coupling CO2 to cyclic syn epoxy alcohols. We unveil a new depolimerization pathway which opens the possibility of producing selectively and in high yields these carbonates. Traditional SN2 pathway where CO2 couples to trisubstitued epoxides has proved to be sluggish and low yielding so this represents a useful alternative, where the adyacent alcohol to the epoxide on the substrate acts as a nucleophile in a depolimerization process of an oligomeric species. Syn epoxy alcoholds of different ring sizes were studied to learn about the favoured mechanistic pathway of each structure. Overall, the work described throughout the chapters proves the activity of the aluminium amino triphenol system in a series of Lewis acid catalyzed coupling reactions. The importance and potential of these coupling reactions is demonstrated by then using the obtained products as intermediates in further synthetic reactions. The reactivity of cyclic epoxides in coupling reactions is described, and new synthetic approaches such as using oligo carbonates as intermediates to control the stereoselectivity are proved to be valuable. In a field where there are plenty of catalytic systems which have proved to be active in these reactions we have focused our efforts in going a step further studying how these products could be valuable synthons with applications in organic synthesis. Throughout these research we have achieved the synthesis of different product with stereo, chemo and regioselectivity by studying the mechanistic pathways and trying to use conditions which favor the formation of only one product. The CO2-epoxide coupling is a field which has been extensively studied in the last decade and multiple catalytic systems have been described which catalyze this process. We stopped focusing on the catalyst design to try to investigate alternative approaches to the synthesis of cyclic epoxides and their use as intermediates for other valuable functionalities.