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Pd-catalyzed C–H functionalization reactions of non-directed substrates have recently emerged as an attractive alternative to the use of directing groups. Key to the success of these transformations has been the discovery of new ligands capable of increasing both the reactivity of the inert C–H bond and the selectivity of the process. Among them, a new type of S,O-ligand has been shown to be highly efficient in promoting a variety of Pd-catalyzed C–H olefination reactions of non-directed arenes. Despite the success of this type of S,O-ligand, its role in the C–H functionalization processes is unknown. Herein, we describe a detailed mechanistic study focused on elucidating the role of the S,O- ligand in the Pd-catalyzed C–H olefination of non-directed arenes. For this purpose, several mechanistic tools, including isolation and characterization of reactive intermediates, NMR and kinetic studies, isotope effects and DFT calculations have been employed. The data from these experiments suggest that the C–H activation is the rate-determining step in both cases with and without the S,O-ligand. Furthermore, the results indicate that the S,O-ligand triggers the formation of more reactive Pd cationic species, which explains the observed acceleration of the reaction. Together, these studies shed light on the role of the S,O-ligand in promoting Pd-catalyzed C–H functionalization reactions

The Cp*Co(III) C−H allylation of (hetero)arenes with allyl aryl ethers has been developed using an amide as directing group (24 examples). DFT calculations have shed light on the mechanistic course and reactivity pattern, showing that strong electron releasing groups favour the reaction by reducing the activation barrier of the rate-determining C−H activation step. However, the steric strain can increase the energy of the migratory insertion step to the point of completely preventing the reaction, as in the case of the 3,5-dimethylbenzamide. The obtained allylated compounds have been transformed into a variety of interesting heterocyclic and carbocyclic structures, such as isoquinolones and isochromanones.

A dual catalytic manifold that enables site-selective functionalization of unactivated sp(3) C-O bonds in cyclic acetals with aryl and alkyl halides is reported. The reaction is triggered by an appropriate sigma*-p orbital overlap prior to sp(3) C-O cleavage, thus highlighting the importance of conformational flexibility in both reactivity and site selectivity. The protocol is characterized by its excellent chemoselectivity profile, thus offering new vistas for activating strong sigma sp(3) C-O linkages.

A highly efficient enantioselective alpha-nitrogenation method of alpha,alpha-disubstituted aldehydes with azodicarboxylates promoted by a chiral carbamate-monoprotected cyclohexa-1,2diamine as organocatalyst has been developed. The process was carried out without any solvent, and the corresponding alpha,alpha- disubstituted alpha-nitrogenated aldehydes were obtained with excellent yields and enantioselectivities up to 99% ee. The sustainability of the procedure was established through the calculation of green metrics, such as EcoScale and E-factor. In addition, theoretical calculations have been used to justify the obtained enantioselectivity sense.

En los proyectos de investigación dirigidos a la búsqueda de compuestos con actividad biológica, es una práctica habitual sintetizar análogos donde se mantiene siempre intacto el núcleo estructural (en este caso, un pirazol, heterociclo que ha sido empleados en campos de estudios farmacéuticos) y únicamente se modifican los grupos funcionales de las cadenas laterales de la estructura general. En este proyecto de grado, se ha trabajado la síntesis orientada a la diversificación. Se han creado, por tanto, múltiples compuestos análogos que posteriormente han sido estudiados en el campo de la actividad herbicida. Aunque todas las moléculas sean estructuralmente muy similares, al diferir en uno o varios grupos funcionales, sus propiedades biológicas son completamente diferentes e impredecibles. Todos estos análogos han sido recogidos en rutas sintéticas lineales formadas por reacciones de acoplamiento como Suzuki y Sonogashira y otras reacciones orgánicas como clorinaciones, saponificaciones, esterificaciones, etc.

144 p., The presen thesis describes computational and experimental studies used to drive the reactivity o allylic and enol subtrates towards new transformations. These synthetic methods give access to a number of organic molecules that may serve as important moieties in synthetic organic chemistry. Additionally, this thesis describes the synthesis of Metal-Organic Frameworks (MOFs) and their use in catalytic organic reactions. The introductory chapter gives an overview of the concept of catalysis emphasizing those that have been used in the thesis. Moreover, synthetic procedures for the formation of MOFs and their use in catalysis. The importance and reactivity of allylic substrates are also presented. A short introduction to hypervalent iodine and their reactivity. Finally, a brief description of computational studies. Chapter 2, an umpolung protocol for the cross-nucleophile coupling of silyl enol ethers with heteronucleophiles mediated by a benzodioxole. The mechanistic study of the reaction has been carried out employing DFT calculations and kinetic investigations. Paper ITotgether with deuterium labelling studies and kinetic simulations, DFT calculations have been used in Chapter 3 for the examination of the base-catalyzed [1.n]-proton shift in conjugated polyenyl ethers. Paper IIChapter 4, describes the synthesis of the family MIL-101(Cr) and MIL-101-NH2(Cr) employing microwave-assisted methods. The method has been compared to the common solvothermal synthetic pathways using common characterization techniques for heterogeneous materials. Paper IIIFinally, Chapter 5 of this thesis describes the synthesis of a UiO-67 MOF containing a iminophosphorane superbase to study the effect of spatial confinement within a MOF on the stereospecific isomerization of allylic systems. Paper IV, Supporting Information.

[SPA] El objetivo de este trabajo es sintetizar cantidades considerablemente grandes de tres metabolitos derivados del insecticida spidoxamato para su posterior uso en estudios ecotoxicológicos y de evaluación de riesgos medioambiantales. Dichos estudios son necesarios en el proceso de desarrollo de este nuevo ingrediente activo. Para ello, se ha trabajado en el diseño de protocolos sintéticos para la preparación de estas moléculas de una manera rápida y efectiva. El primer metabolito sintetizado en este trabajo, spidoxamato-desciclohexilcetona, ha sido preparado mediante la condensación de una amida con oxalato de dietilo para la formación del anillo de maleimida presente en la molécula. Por otro lado, la cantidad requerida del segundo metabolito, spidoxamato-desclorohidroxi, también ha sido obtenida gracias a la optimización de las condiciones necesarias para la hidroxilación del insecticida spidoxamato catalizada por paladio. Finalmente, se ha abordado la síntesis del tercer metabolito, spidoxamato-ciclohidroxi-bencilalcohol (cis), para el cual se ha diseñado un procedimiento algo más largo debido a su complejidad estructural. Este incluye una condensación de Dieckmann para formar el anillo de ácido tetrámico que constituye la molécula y su posterior desmetilación para dar el producto. Este procedimiento ha resultado no ser lo suficientemente selectivo para sintetizar la cantidad deseada del metabolito. Sin embargo, se han propuesto rutas alternativas que podrían ser útiles en futuros intentos de sintetizar esta molécula., [ENG] The main goal of this work is to synthesize considerably big amounts of three metabolites derived from spidoxamat insecticide for their subsequent use in ecotoxicology studies and environmental risk evaluation. These studies are necessary in the development process of this new active ingredient. For that purpose, synthetic protocols have been designed for the fast and efficient preparation of the desired molecules. The first metabolite synthesized in this work, spidoxamat-decyclohexylketone, has been prepared through the condensation of an amide with diethyl oxalate which leads to the formation of the maleimide ring present in the molecule. On the other hand, the required amount of the second metabolite, spidoxamat-dechlorohydroxy, has also been obtained thanks to the optimization of the necessary conditions for the palladium-mediated hydroxylation reaction of spidoxamat insecticide to form the product. Finally, the synthesis of spidoxamat-cyclohydroxy-benzylalcohol (cis) metabolite has been tackled. A longer pathway has been designed in this case due to the structural complexity of the metabolite, which includes a Dieckmann cyclization to form the tetramic-acid core of the molecule followed by its demethylation to give the product. This procedure has not been selective enough to prepare the desired amount of the metabolite. Nevertheless, alternative pathways have been proposed that could be helpful in future attempts to synthesize the molecule.

[EUS] Gradu Amaierako Lan honetan, interes handiko konposatuak diren fluorenonen sintesia burutu egin da. Molekula hauek sintetizatzeko metodo aunitz egon arren, ikertu den metodoa, Pd bidez katalizatutako C-H azilazio intramolekular bat da, substratu bezala azido [1,1 ́-bifenil] karboxilioaren ester aktibatuak, Pd(OAc)2 aurrekatalizatzaile bezala eta PCy3·HBF4 ligando moduan erabiliz. Transformazio intramolekular hau burutu ahal izateko, lehenik eta behin, talde ateragarri ezberdinak dituzten ester aktibatu batzuk prestatu egin dira, aurretik aipatutako erreakzioarekiko beraien erreaktibitatea ikertu nahian. Horrela, fluorenonak sintetizatzeko substratu egokienak zeintzuk diren aztertu da. Behin talde ateragarri optimoa zein den ikusita, substratuaren eraztun aromatikoetan ordezkatzaile ezberdinak jartzeak ziklazio erreakzioan izan ditzakeen efektuak aztertu dira, [ENG] In this Final Degree Project, the synthesis of fluorenones has been carried out. Although there are many methods to synthesize these interesting molecules, the method herein studied consists of a Pd-catalyzed intramolecular C-H acylation, using activated esters derivated from [1,1 ́-biphenyl] carboxyl acid as a substrate, Pd(OAc)2 as a precatalyst and PCy3·HBF4 as a ligand. In order to achieve this intramolecular transformation, firstly the synthesis of some activated esters has been acomplished, bearing different leaving groups, with the aim of studying their reactivity. Thus, the most suitable substrates for the synthesis of fluorenone have been tested. Once the optimal leaving group has been determined, the possible effects of placing different substitutes on the aromatic rings of the substrate in the cyclization reaction have been studied.

[EN] In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3-dicarbonyl compounds with a large range of heteroatom nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO2. The scope of the reaction also extends to carbon-based nucleophiles. The reaction relies on the use of 1-bromo-3,3-dimethyl-1,3-dihydro-1 lambda(3)[d][1,2]iodaoxole, which provides a key alpha-brominated carbonyl intermediate. The reaction mechanism has been studied experimentally and by DFT, and we propose formation of an unusual enolonium intermediate with a halogen-bonded bromide.

[EN]Here, we present a new stereoselective alkylation of titanium(IV) enolates of chiral N-acyl oxazolidinones with tert-butyl peresters from Calpha-branched aliphatic carboxylic acids, which proceeds through the decarboxylation of the peresters and the subsequent formation of alkyl radicals to produce the alkylated adducts with an excellent diastereoselectivity. Theoretical calculations account for the observed reactivity and the outstanding stereocontrol. Importantly, the resultant compounds can be easily converted into ligands for asymmetric and catalytic transformations.

193 p., In this thesis, Density Functional Theory (DFT) methods have been applied to study the mechanisms of three different multicomponent organic reactions. Also, a new synthetic procedure for the preparation of quinolinium salts is presented, and its mechanism also studied by DFT calculations. The thesis summarizes the work realized in two universities, and is divided in the following way: The first part of the thesis concerns the development of an experimentally simple, but mechanistically complex, reaction for the formation of quaternary quinolinium salts catalyzed by palladium salts. This multicomponent process uses readily available propylamine and its derivatives as starting materials. Through DFT studies a mechanism through the activation of two aliphatic C¿H bonds is proposed. The second part focuses on the mechanistic investigation of a three-components reaction, namely terminal alkynes, CO2 and allylic chlorides, mediated by an N-heterocyclic carbene catalyst that yields propargylic esters. By DFT calculations, the rate-limiting step was identified to be the reaction between the carboxylated catalyst and the allylic chloride. Through DFT, we were also able to understand the limitations of this reaction. The mechanism of a multicomponent reaction in which allylic alcohols are transformed into ¿-functionalized carbonyls was also investigated. The reaction relies on an umpolung strategy that enables to react enol intermediates with different nucleophiles. By DFT studies, a mechanism via enolonium intermediates is proposed, which provides an understanding of the selectivity of the reaction. The final chapter of the thesis deals with another multicomponent solvent-free reaction for synthesizing propargylamines catalyzed by manganese via a KA2 coupling. DFT studies were undertaken and a mechanism via manganese phenylacetylide species is proposed. 193 p.

A straightforward, user-friendly, efficient protocol for the one pot, ZnI2-catalyzed allenylation of terminal alkynes with pyrrolidine and ketones, toward trisubstituted allenes, is described. Trisubstituted allenes can be obtained under either conventional heating or microwave irradiation conditions, which significantly reduces the reaction time. A sustainable, widely available, and low-cost metal salt catalyst is employed, and the reactions are carried out under solvent-free conditions. Among others, synthetically valuable allenes bearing functionalities such as amide, hydroxyl, or phthalimide can be efficiently prepared. Mechanistic experiments, including kinetic isotope effect measurements and density functional theory (DFT) calculations, suggest a rate-determining [1,5]hydride transfer during the transformation of the intermediate propargylamine to the final allene.

Carbonylative cross coupling reactions are of high interest in many organic chemistry syntheses, because they cover numerous organic transformations. A huge number of publications have been done in the last years with regard to C-C cross coupling reactions, but not many of them are related to one- pot late stage functionalization. In this thesis a novel methodology for one-pot carbonylative Sonogashira coupling reaction has been established. In this process aryl iodides are used as starting materials and N-formyl saccharin is employed as CO source, in order to avoid CO gas directly. Carbon isotope exchange has also been studied. For that labeled CO source is used; 13C N-Formyl saccharin. The introduction of 14C in this procedure could in one future be used for different analysis of regulative administrations as part of drug discovery and development processes., Akoplamendu gurutzatu karbonilatiboko erreakzioak oso interesgarriak dira kimika organikoaren sintesi askotan, eraldaketa organiko ugari hartzen dituztelako. Azken urteotan, C-C akoplamendu gurutzatuaren erreakzioei buruzko argitalpen ugari egin dira, baina ez dira asko pote batean eta fase berantiar baten funtzionalizazioari buruzkoak. Tesi honetan Sonogashira karbonilazio akoplamenduerreakziorako metodologia berritzaile bat ezarri da, erreakzioa pote batean eginez. Prozesu honetan, ioduro ariloak erabiltzen dira abiapuntuko material bezala, eta N-formilsakarina erabiltzen da karbono monoxidoaren iturri bezala, zuzenean CO gasa erabili beharrean. Karbono-isotopo trukea ere aztertu da. Horretarako 13C N-formilsakarina etiketa-iturria erabili da. 14C etorkizunean prozedura honetan ere erabil liteke administrazio arautzaileen analisi desberdinetarako, sendagaiak aurkitzeko eta garatzeko prozesuen zati gisa.

[Abstract] The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade under mild reaction conditions, using InI₃ (5 mol %) as a catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at alkene (E and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes, a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents were developed. The double cyclization is stereospecific and operates via a biomimetic cascade cation-olefin through 1,5-enyne cyclization (6-endo-dig) and subsequent C–C hydroarylation or C–O phenoxycyclization. Density functional theory (DFT) computational studies on 1,5-enynyl aryl ethers support a two-step mechanism where the first stereoselective 1,5-enyne cyclization produces a nonclassical carbocation intermediate that evolves to the tricyclic reaction product through a SᴇAr mechanism. Using this approach, a variety of tricyclic heterocycles such as benzo[b]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds are efficiently synthesized with high atom economy.

The importance of multicomponent reactions as an efficient tool in organic synthesis is widely recognized, as the need for sustainable, practical, atom- and step-economic methodologies is becoming a crucial concept in contemporary research. In this context, the synthesis of propargylamines via multicomponent protocols holds great promise, because of their biological action and their potential as synthons. Ketone-derived, tetrasubstituted propargylamines are a relatively unexplored subclass of compounds, while protocols to access them have only been described in the past decade, owing to the challenging nature of ketones as multicomponent coupling partners. Herein, we report a catalytic system based on the earth-abundant manganese for the ketone, amine, alkyne (KA2) reaction. The efficiency of manganese, combined with sustainable reaction conditions, comprise a useful new method for accessing various interesting propargylamines. Additionally, the use of computational methods reveals mechanistic aspects of this reaction, for the first time, raising important points regarding the reactivity of both manganese and ketones.

275 p., The present thesis deals with three different topics that have in common the formation of carbo- and heterocycles. The whole work is organized as a synergy of experimental and computational studies to provide a deep understanding of the systems of interest.The first chapter contains an introduction about computational chemistry with a particular focus on DFT and its application. The second chapter regards asymmetric catalysis and includes two works made in collaboration with the group of Prof. Palomo at the Universidad del País Vasco. Bifunctional catalysts are employed to afford good levels of stereoselectivity in the alpha-functionalization of challenging substrates, as substituted dienolates and trienolates, with olefins. Computational studies were performed mainly to rationalize the role of the catalyst. The third chapter in collaboration with the group of Prof. E. Occhiato at the Universitá degli Studi di Firenze presents two examples of gold catalysis applied to the [3,3]-rearrangement/Nazarov reaction of propargylic esters and the tandem Claisen Rearrangement/Hydroarylation reaction of propargyl vinyl ethers. The mechanism of the reactions were studied computationally, as well as the effect of particular features in the substrates or in the catalysts. The last two chapters concern the synthesis of fluorinated isoquinolines and computational studies on particular issues encountered experimentally. The strategy employed is a two step reaction that includes a Rh-catalyzed CH activation of oximes with difluoroalkenes and an electrocyclisation.

78 p.(parte I); 110 p.(parte II), La presente tesis consiste en una serie de estudios realizados en el marco de la química computacional. La teoría del funcional de la densidad ha sido aplicada para la simulación de diversas reacciones químicas. Mediante la optimización y el cálculo de las energías de sustratos, intermedios, productos y estados de transición, se han elucidado los mecanismos de reacciones pericíclicas y de reacciones catalizadas por metales. Concretamente, se ha examinado la estereoespecificidad de reacciones 6¿-electrocíclicas que utilizan oximas como producto de partida. El mecanismo ha estudiado y clasificado como pseudopericíclico mediante el analisis de la aromaticidad del estado de transición. En cuanto a las reacciones organometálicas, por un lado se ha estudiado una reacción intramolecular de Fujiwara-Moritani para la síntesis de 1,4-dihidroquinolinas, explorando el mecanismo con el objetivo de explicar los diferentes isómeros observados experimentalmente. Por otro lado, se han estudiado una serie de cicloisomerizaciones catalizadas por oro y platino, cuya compleja reactividad ha podido ser racionalizada. Los estudios computacionales han sido llevados a cabo en colaboración con diferentes grupos experimentales, y han dado como resultado tres publicaciones científicas.

[EU]Lan honetan laborategian egin diren diamina kiralez organokatalizatutako enamina eta maleimida molekulen arteko Michael adizio erreakzioaren enantioselektibotasuna ikerketa konputazionalen bidez azaldu da. Azterketan katalizatazaileak erreakzioan duen mekanismoan sakondu da, diamina organokatalizatzailearen talde desberdinen eta disolbatzailearen efektua azalduz purutasun enantiomerikoan., [EN]In this work, Michael addition of enamine and maleimide organocatalyzed by diamine reactions have been explained by a computational study. In the research, the mechanism of the catalyst has been studied in depth, explaining the effect of different groups of the diamine organocatalyst and the solvent.