Alkyl-arenes are important industry feedstock chemicals that are used as solvents, pharmaceutical precursors, and polymer monomer units. One alkyl-arene, ethylbenzene, is the main focus of this dissertation, and is produced in the million ton a year scale. As alkyl-arenes are important commodity chemicals, catalytic olefin hydroarylation is a lucrative alternative for their production rather than Friedel-Crafts alkylation or various coupling reactions that have lower atom economy, require strong acids, or are energetically demanding. Currently catalytic olefin hydroarylation still suffers from decomposition pathways of the active catalytic complexes, side reactions that lead to waste products, and unfavorable activation barriers, which represent high temperature and pressure. Modifications to the catalytically active system bipyridine platinum(II) (bpyPtII), through computational methods, are explored herein. The work presented here investigates catalytic olefin hydroarylation in order to mitigate the aforementioned difficulties. Included in this study are changes to the electronic profile of the supporting ligand, bpy, through the addition of electron withdrawing or electron donating R groups (methoxy, nitro), definite ligand replacements such as bpy to hydridotris(pyrazolyl)borate (Tp), changes in metal oxidation (II to IV), and replacing the metal center from Pt to Ni. Nickel was selected as a possible alternative to platinum as it is more Earth abundant reducing the monetary requirement for the catalyst. In addition to having a different catalytic energetic profile from platinum. Ni as expected could only facilitate single step hydrogen atom transfers due to its inability to access higher oxidations states.

Thesis advisor: Marc L. Snapper / A catalyst of notoriety Decomposes with great variety. Transformations after metathesis Facilitate tandem catalysis. This reaction has a proclivity For new regioselectivity With methanolic modification: Tandem enyne hydrovinylation. From a diene protonation event, Unexpected reaction with solvent, During catalyst optimization: One-pot enyne hydroarylation. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The diversity of transition metal complexes allows for a wide range of chemical processes to be mediated by the metal, from catalysis to surface chemistry. Investigations into the structure and electronic configuration of transition metal complexes allow for tuning of desired species by modifications to the ligands and/or metals to achieve more efficient thermodynamics and kinetics for the process of interest. Transition metals, often used in catalysts for a number of important processes, require detailed descriptions of intermediates, transition states and products to fully characterize a reaction mechanism(s) in order to design more active and efficient catalysts. Computational investigations into inorganic catalysts are explored with the aim of understanding the activity of each species and how modifications of supporting ligands, co-ligands and metals vary the interaction along the reaction pathway. Reported results give important insight into the development of the most active complexes in addition to determining the least active complexes to aid experimental development. This report first investigates the mechanisms of two unique transfer reactions: 1) formation of low coordinate nickel-nitrene ((P~P)Ni=NR; P~P = 1,2-bis(dihydrophosphino)-ethane or 1,2-bis(difluoromethylphosphino)-ethane) complexes as catalysts for nitrogen atom transfer and 2) oxidation of a triphosphorus niobium complex, [(η2-P3SnPh3)Nb(OMe)3], for the transfer of the phosphorus synthon, Ph3SnP3. These reactions have utility in the synthesis of nitrogen and phosphorus containing molecules, respectively, and the results presented provide mechanistic insight into the synthesis of the organometallic intermediates. Additionally, a computational approach towards rational catalyst design was performed on the ruthenium based hydroarylation catalyst TpRu(CO)(Ph) [Tp = hydrido-tris(pyrazolyl)borate]. Targeted modifications at the Tp, metal and co-ligand (CO) sites were studied in order to tune the electronics and sterics of the catalyst. Modifications, through computational methods, provided a more cost- and time-efficient way to study the impact of modifications, which provided direct input into attractive synthetic targets. The research described heir in highlights the use of computational chemistry methodologies, specifically DFT, in collaboration with experimental results, for the accurate description of reaction geometries and factors influencing the thermodynamics and kinetics of the systems. Valuable insight is gained by treating inorganic complexes with theoretical methods and additionally provides a fast, cheap way to predict and understand the chemistry of such complex systems.

<p><p>The wide-spread occurrence of biologically active nitrogen-containing heterocycles and allylic amines inspired us to develop atom-economical methods for their syntheses.</p></p><p><p>A cationic gold(I) <italic>N</italic>-heterocyclic carbene complex catalyzed the intermolecular hydroarylation of allenes with indoles to form (<italic>E</italic>)-allylic indoles in modest to good yield at room temperature. The protocol was effective for monosubstituted, 1,3-disubstituted, and tetrasubstituted allenes and various indoles.</p> </p><p><p>Platinum(II) bis(phosphine) complexes catalyzed the intermolecular hydroamination of monosubstituted allenes with secondary alkylamines in good yield with selective formation of (<italic>E</italic>)-allylic amines. The scope of the protocol included aryl and alkyl monosubstituted allenes as well as a variety of both cyclic and acyclic secondary alkylamines.</p></p><p><p>The scope of gold(I)-catalyzed intermolecular hydroamination of 1-alkenes with 1-methyl-2-imidazolidinone was expanded to include additional 1-alkenes functionalized with carboxylic acid derivatives. However, a nucleophile screen failed to identify nucleophiles other than cyclic ureas and 2-oxazolidinone that efficiently undergo hydroamination with 1-alkenes. Various carbamates, arylamines, amide derivatives, sulfur-containing amide derivatives, and &alpha;-heteroatom compounds failed to react with 1-octene under gold(I)-catalyzed conditions.</p></p><p><p>A chiral bis(gold) phosphine complex catalyzed the stereoconvergent, intermolecular enantioselective hydroamination of chiral, racemic 1,3-disubstituted allenes with carbamates to form <italic>N</italic>-allylic carbamates in good to high yield with up to 92% <italic>ee</italic>. In addition, enantiopurity experiments suggested the nature of the catalytically active species changes with increasing concentration of <italic>N</italic>-allylic carbamate.</p></p> / Dissertation

Le diazonamide A, molécule naturelle extraite d’une ascidie marine, présente une activité antitumorale très importante (IC₅₀ < 5 nM) selon un mode d’action tout à fait original. Des études ont en effet prouvé que cette molécule inhibait une enzyme, l’Ornithine-d-aminotransferase, intervenant dans la réplication cellulaire des cellules cancéreuses faisant d’elle un poison du fuseau mitotique très sélectif. Cette molécule présente en son sein un cœur benzofuroindoline qui serait issu, d’un point de vue biogénétique, d’un couplage oxydant entre un noyau indole et un noyau phénol. Afin de développer une méthode générale de synthèse d’analogues simplifiés du diazonamide A, nous avons mis au point une voie d’accès efficace et simple au noyau benzofuroindoline. Ce projet nous a permis de mettre en place une stratégie en 3 étapes à partir d’indoles acétylés et de phénols qui permettent l’obtention de benzofuroindolines. La première étape est une réaction d’hydroarylation sur la double liaison C₂-C₃ de l’indole médiée par le trichlorure de fer. Cette première étape met en avant une réactivité tout à fait inhabituelle du noyau indole en rendant la position 3 de cet hétérocycle, électrophile. Grâce à cette stratégie, nous avons pu obtenir une librairie importante de benzofuroindolines dont certaines présentent une activité biologique encourageante. La seconde partie de ces travaux de thèse ont porté sur une étude plus approfondie de la réaction d’hydroarylation de l’indole. Une étude intensive du champ d’application de cette réaction ont permis de mettre en avant une haute tolérance de groupements fonctionnels. De plus l’étude des nucléophiles aromatiques tels que des polyaromatiques ou des hétérocycles ont permis d’obtenir un grand nombre de 3-arylindolines avec une diversité structurale très importante. Ces travaux ayant porté sur l’umpolung de l’indole, des études mécanistiques ont finalement été menées afin d’expliquer cette réactivité. Des études de marquage isotopique, d’infra-rouge in-situ ainsi que l’établissement d’une relation de Hammett ont permis de proposer un mécanisme réactionnel plausible. / The benzofuroindoline core is a unique motif found in the natural products diazonamide A bipleiophylline and azonazine. From a biosynthetic point of view, we can assume that the benzofuroindoline skeleton arises from the oxidative coupling of an indole and a phenol.The benzofuroindoline motif represents an opportunity for the discovery of new antitumor agents. Diazonamide A is a very potent anticancer agent that has received considerable attention owing to its high antitumor activity (IC₅₀ < 5nm) and its unique mode of action the inhibition of a newly discovered role for the ornithine-δ-aminotransferase. It is suggested that this natural product may have clinical utility for cancer therapy because it is as active in vitro as widely used antimitotic drugs such as taxanes and vinca alkaloids, but does not have their toxicity in normal dividing tissue. Owing to the high potential of diazonamide A and its scarce availability, it is highly desirable to identify simplified benzofuroindoline analogues as promising as the natural product, but more synthetically accessible.We report herein the C3-regioselective hydroarylation of N-acetyl indoles with phenols mediated by FeCl ₃ featuring a rare example of the electrophilic reactivity of the indole core in a Friedel–Crafts reaction. The indole Umpolung, followed by an oxidation step, allows us direct access to the tetracyclic benzofuroindoline motif found in the natural product diazonamide A.Moreover, this activation of N-acetylindoles with iron(III) chloride allows the C-H addition of other aromatic substrates than phenols to the C ₃ =C₂ double bond of the indole nucleus generating a quaternary center at C ₃ and leading regioselectively to 3-arylated indolines. Optimization, scope, practicability (gram scale, air atmosphere, room temperature) and mechanistic insights of this process are presented in this study.

Cette thèse porte sur la synthèse de composés d'Au(III) et de Cu(III) ainsi que sur l'étude de leur stabilité et de leur réactivité vis-à-vis de substrats p. Une approche conjointe expérimentale et théorique a été exploitée afin d'accéder à des complexes capables d'induire des processus d'insertion migratoire. Le premier chapitre aborde de manière globale la chimie organométallique de l'or et du cuivre sur le plan bibliographique. L'importance du degré d'oxydation +III est mis en évidence par la description des principaux exemples ayant contribué à la compréhension des processus associés à l'accès et la réactivité des complexes d'Au(III) et de Cu(III). Le second chapitre traite de la synthèse de deux complexes p-arènes d'Au(III) par insertion migratoire d'oléfines dans la liaison Au-C(sp)2 d'un composé (P,C) cyclométallé. Les interactions entre les systèmes aromatiques et l'or ont été mises en évidence par RMN, DFT et DRX pour un des complexes. Sur la base de cette réactivité, un processus d'arylation directe de l'éthylène a été mis en évidence. Le chapitre trois a pour objet la mise au point d'une réaction d'hydroarylation intermoléculaire d'alcynes catalysée par des complexes de type [(P,C)Au(III)(OAcF)2]. Ces derniers se sont avérés très actifs et robustes en présence d'acide trifluoroacétique. La réaction a pu être généralisée à un large panel de substrats et une étude comparative, notamment avec des complexes (N,C) cyclométallés, a mis en évidence la supériorité des complexes (P,C) pour l'hydroarylation des alcynes. Le quatrième chapitre expose la stratégie envisagée pour le développer d'un processus d'oligomérisation de l'éthylène catalysé par le cuivre. Une approche prédictive basée sur les calculs DFT a permis de mettre en évidence des insertions migratoires plus aisées dans les liaisons Cu(III)-C que dans les Cu(I)-C. Deux stratégies d'accès aux complexes de Cu(III) par addition oxydante de liaisons C-I sur des précurseurs de Cu(I) ont été évaluées théoriquement. Les calculs les plus favorables ont orienté le choix des modèles de ligands envisagés dans les chapitres cinq et six. Le cinquième chapitre aborde l'étude expérimentale associée à la première stratégie d'accès au Cu(III) : l'addition oxydante intramoléculaire dirigée par des ligands naphthylphosphine et naphthylamine peri-iodées. [...] / The present work deals with the synthesis of Au(III) and Cu(III) compounds and the study of their stability and reactivity toward p substrates. An experimental and theoretical approach has been used in order to access complexes capable of undergoing migratory insertion processes. The first chapter delivers a bibliographic overview of the organometallic chemistry of gold and copper. The importance of the high oxidation state +III is highlighted by the description of important examples having contributed to the understanding of processes associated to the access and reactivity of Au(III) and Cu(III) complexes. The second chapter describes the synthesis of two p-arene Au(III) complexes by migratory insertion of olefins in the Au-C(sp)2 bond of a (P,C) cyclometallated complex. Interactions between the metallic center and the aromatic systems have been characterized by NMR, DFT and XRD for one of the complexes. Based on this insertion reactivity, a process of direct arylation of ethylene has been evidenced. The third chapter concerns the development of an intermolecular hydroarylation of alkynes process, catalyzed by [(P,C)Au(III)(OAcF)2] complexes. These have shown great activity and robustness in presence of trifluoroacetic acid. The reaction has been generalized to a broad substrate scope and a comparative study has been carried on, especially with (N,C) cyclometallated complexes, showing the superiority of (P,C) complexes for the hydroarylation of alkynes. The fourth chapter presents the envisioned strategy to develop a copper-catalyzed oligomerization of ethylene process. A predictive approach based on DFT calculations permitted to evidence easier migratory insertions in the Cu(III)-C bond than in the Cu(I)-C bond. Two strategies for the access to Cu(III) species have been theoretically evaluated. The most favourable calculations have oriented the choice of ligand models used in chapters five and six. The fifth chapter deals with the experimental study related to the first strategy of access to Cu(III) species: the directed intramolecular oxidative addition by peri-iodo napthylphosphine and naphthylamine ligands. [...]

Le projet de recherche est centré sur le développement de nouvelles transformations catalysées par de l'or en chimie des ions N-acyliminiums. L'objectif de la première partie de ce projet est de développer une séquence 5-exo-dig intramoléculaire hydroalkoxylation/aza-Ferrier-Petasis réarrangement catalysée par l’or. Une deuxième partie du projet est consacrée à l'élaboration de la première alcynylation catalytique d'ions cycliques N-acyliminium utilisant N,O-acétals. Ce type de réaction est potentiellement une transformation importante, donnant naissance à des dérivés d'amines propargyliques. Ces derniers peuvent faire l’objet d’autres réactions conduisant à des produits naturels azotés ainsi qu’à certains analogues. Compte tenu de nos objectifs, l’intérêt principal est l'utilisation d’alkynes TMS en accord avec des complexes d'or qui ont été coordines avec des contre-ions faiblement nucléophiles. Pour élargir le champ de la catalyse basée sur l'or, il est important d'étendre la gamme de substrats et les groupes fonctionnels qui peuvent être activées par des complexes d'or. Une dernière partie est consacrée à la catalyse séquentielle qui favorise des processus catalytiques à plusieurs étapes. De cette manière, deux transformations catalytiques et fondamentalement différentes sont réalisées dans un même récipient. Ce travail nous a permis l’accès rapide et efficace à une famille de composes à structure complexe avec bons rendements. Par conséquent, il s'agit d'un sujet innovant en synthèse organique moderne qui a permis d’ouvrir la voie à de nouveaux projets. / The research project is centred on the development of new gold catalyzed transformations in N-acyliminium ion chemistry. The objective of our first part of the project is to develop an enantioselective gold-catalyzed 5 exo-dig intramolecular hydroalkoxylation/aza-Ferrier-Petasis rearrangement sequence. This sequence could give an asymmetric and atom economic expeditious access to the structure of hydropyrrolizidines, which are known to be potential biologically active compounds. A second part of the project is devoted to the development of the first catalytic alkynylation of cyclic N-acyliminium ions using N,O-acetals. This type of reaction is potentially an important transformation, giving rise to propargylic amine derivatives amenable to further interesting synthetic manipulations en route to nitrogen-containing natural products and some analogs. Considering our objectives, key features is the use of TMS alkynes in conjunction with gold complexes that have been paired with poorly nucleophilic counter-ions. To broaden the scope of catalysis based on gold, it is important to extend the range of substrates and functional groups that can be activated by gold complexes. A final section is devoted to the sequential catalysis which designs the promotion of catalytic multistep processes. In this way, two fundamentally distinct chemical transformations are catalytically promoted in a single flask. This research area allows the rapid and efficient reach of complex molecular frameworks with improved yields and resource efficiency. Therefore, this is an exciting theme in modern organic synthesis that has recently stimulated the report of numerous excellent contributions.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.