Thesis advisor: Masayuki Wasa / When a catalytic reaction is carried out between two reactants, usually only onereactant is activated by a single catalyst while the other component is pre-activated so that the sluggish reactivity was compensated. In order to broaden the substrate scope, the development of cooperative catalysts that can generate both electrophilic and nucleophilic species in situ represents a compelling research objective. This thesis is focused on the development of cooperative catalyst systems and their applications to α- and β-amino C−H bond functionalization. In the first chapter of this thesis, a brief summary of the present cooperative catalysts will be discussed. In the second chapter, the development of cooperative acid/acid catalysts for the α-alkynylation of N-alkylamines will be discussed. Typically, catalytic α-amino C−H alkynylation process is carried out under oxidative conditions, and enantioselective reactions are confined to tetrahydroisoquinoline derivatives. We disclose a strategy for the union of N-alkylamines and trimethylsilyl alkynes through cooperative actions of two Lewis acids, B(C 6 F 5 ) 3 and a Cu-based complex without the use of oxidants. We proposed that various propargylamines can be synthesized through the reaction between a L n Cu−alkynyl complex and an iminium ion that are generated in situ. Furthermore, the utility of this protocol was demonstrated by applications in late stage α-alkynylation of bioactive amines and stereoselective synthesis of propargylamines. In the third chapter of this thesis, catalytic and regioselective deuteration of β-amino C−H bonds in an array of N-alkylamine-based pharmaceutical compounds will be described. Isotopic labeling of β-amino C−H bond is promoted by the cooperative action of Lewis acidic B(C 6 F 5 ) 3 and Brønsted basic N-alkylamine, converting a bioactive amine first into an iminium ion and then the corresponding enamine. Meanwhile, the acid/base catalysts can also promote the dedeuteration of acetone-d 6 to afford a deuterated ammonium ion and a boron enolate. Ensuing deuteration of the enamine by deuterated ammonium ion followed by borohydride reduction leads to the formation of β-deuterated bioactive amines with up to 99% deuterium incorporation. / Thesis (MS) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Masayuki Wasa / This dissertation describes the development of novel catalyst systems that could promote the regio- and enantioselective transformations of C-H bonds contained in N-alkylamines and ethers through Lewis acid-mediated hydride abstraction processes. The progress made in C-H functionalization of N-alkylamines and ethers that served as the intellectual foundation of this dissertation research are summarized in Chapter 1. Despite notable advances, the development of broadly applicable, enantioselective, and catalytic protocols to functionalize C-H bonds in N-alkylamines and ethers with high regio- and stereo-selectivity was regarded as an unsolved problem when we started this dissertation research. In an effort to overcome these fundamental limitations, we first identified a B(C6F5)3/Cu-PyBOX cooperative catalyst system for the enantioselective conversion of a-amino C-H bonds through the generation of an iminium by (F5C6)3B-catalyzed hydride abstraction process (Chapter 2). We then envisioned that in situ generated iminium ions could be further deprotonated to furnish an enamine intermediate, which may react with electrophilic species for a-amino C-H functionalization. The design and development of such a catalyst system were discussed in Chapter 3. Finally, we disclose enantioselective Cu–BOX-catalyzed hetero Diels-Alder reactions of enol ethers generated through Ph3C+-mediated oxidation of alkyl ethers. (Chapter 4). / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Directing groups (DGs) are moieties installed onto organic molecules to confer regioselectivity in subsequent reactions. DGs have found utility in selective CH activations catalyzed by transition metal (TM) catalysis on starting materials with multiple CH bonds. Despite their utility, DGs are scarcely used in industrial applications due to the generally wasteful nature of conventional DG strategies and their associated increase in step-count. Transient directing groups (TDGs) have been developed to overcome these limitations, with additives reversibly forming adducts with compounds of interest prior to the DG-mediated CH activation, in one-pot processes. However, the use of TDGs still requires harsh conditions to achieve significant yields, hindering broad applications. Chemoenzymatic catalytic cascades have attracted attention due to the mild and environmentally friendly nature of biocatalysis, with the greatest challenge being compatibility issues between biocatalytic and traditional chemical transformations. Here we propose a concurrent chemoenzymatic catalytic cascade that would enable TM-catalyzed DG chemistry via flanking biocatalytic reductive amination to install, and oxidative deamination to remove, a TDG. Preliminary efforts have identified some incompatibilities arising from the biocatalytic portion of the cascade, namely substrate specificity and organic co-solvent tolerance, that need to be addressed to achieve the proposed chemoenzymatic cascade in a one-pot concurrent protocol.

Los complejos “metalosalen” [salen = N,N’-bis(salicilideno)etilendiamina] han sido objeto de estudio en la catálisis homogénea y últimamente también en la ciencia de materiales y catálisis multimetálica. En cuanto a esto, hemos explorado el potencial de los complejos “salfen” [N,N’-bis(salicilideno) fenilendiamina] centrados en Zn(II) como componente en el desarrollo de nuevos materiales y sistemas multimetálicos. Los primeros capítulos de esta tesis proporcionan una mejor comprensión sobre las propiedades de estos complejos y esto es seguido por aplicación como detector quiral y estudios de comportamiento de autoensamblaje. Los últimos capítulos se centran en sistemas metalosalen multimetálicos mediante enfoques supramolecular y covalente para su aplicación en la catálisis cooperativa. Este tesis demuestra el potencial de los compuestos salen para su aplicación en ciencia de materiales y catálisis cooperativa. / Metallosalen complexes [salen = N,N’-bis(salicylidene)ethylenediamine] have been well-studied in homogeneous catalysis and lately reveive inceasing interest in materials science and multimetallic catalysis. In view of this, we have explored the potential of Zn(II)-centered salphen [N,N’-bis(salicylidene)phenylenediamine] complexes as a building block in the development of new materials and multimetallic systems. The first chapters of this thesis provide a better understanding of the properties of these complexes and this is followed by application as a chiral sensor and studies of their self-assembly behavior. The last chapters focus on multimetallic metallosalen systems for application in cooperative catalysis using supramolecular and covalent approaches. This thesis illustrates the potential of metallosalen complexes for application in materials science and cooperative catalysis

Thesis advisor: Masayuki Wasa / Cooperative catalysis has been developed for transformations where at least two reactants are activated in situ by acid or base sensitive catalysts to form the reactive species and subsequent bond formation leads to desired product. This thesis focuses on the development of ɑ-amino C-H alkynylation and β-amino C-H deuteration through the use of cooperative catalysts. In the alkynylation reaction, N-alkylamines and trimethylsilyl substituted alkynes were used to synthesize propargylamines by the cooperative actions of Lewis acid catalysts, B(C₆F₅)₃ and copper complex. The reaction between in situ generated iminium ion and copper alkyne complex afforded the product. The method is applicable to the late-stage functionalization of bioactive amine drug molecules and has been shown to tolerate different functional groups on trimethylsilyl-substituted alkynes. In addition, an enantioselective and diastereoselective version of the method was also developed through the use of chiral copper complex. In the second part, selective deuteration of β-amino C-H bonds of various acylic and cyclic alkyl amines will be introduced. B(C₆F₅)₃ and Brønsted base work cooperatively to afford enamine and deuterated ammonium ion as reactive intermediate. Deuteration of enamine at the β-position and hydride reduction at the ɑ-position gave the selectively deuterated products. Acetone-d₆ was the found to be the optimal source of deuterium. This method was able to incorporate deuterium atoms up to 99% and can be applied in a gram scale reaction without compromising the yield or d-incorporation level. / Thesis (MS) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Thesis advisor: Shih-Yuan Liu / Thesis advisor: Amir H. Hoveyda / Chapter 1. Senphos–Palladium-Catalyzed cis-Carboboration of Internal 1,3-Enynes with Carbon–Bound Boron Enolates: Reaction Development and Mechanistic Analysis. A new family of carbon-bound boron enolates (C–boron enolates) that are created through a kinetically controlled halogen exchange process between B–chlorocatecholborane and silylketene acetals is presented. These C–boron enolates are demonstrated to activate 1,3-enynes substrates in the presence of a Senphos-Pd complex to achieve carboboration reaction of an alkyne unit. This carboboration reaction produced highly substituted dienyl boron building blocks in high site-, regio-, and diastereoselectivity. A combined experimental and computational study of this carboboration reaction by Density-Functional Theory (DFT) calculations, 31P NMR study, kinetic study, Hammett analysis and Arrhenius/Eyring analysis will also be described. Mechanistic study supports a syn outer-sphere oxidative addition mechanism featuring a Pd-π-allyl intermediate followed by coordination-assisted rearrangement instead of the conventional inner-sphere β-migratory insertion mechanism. Chapter 2. trans-Hydroalkynylation of Internal 1,3-Enynes Enabled by Cooperative Catalysis. A trans-hydroalkynylation reaction of internal 1,3-enynes enabled by a cooperative catalysis system that comprises of Senphos–Pd complex, tris(pentafluorophenyl)borane, copper(I) bromide, and 2,2,6,6-tetramethylpiperidine, is described. The tris(pentafluorophenyl)borane as Lewis acid catalyst is shown to promote the reaction involving the emerging outer-sphere oxidative reaction step. This hydroalkynylation reaction affords the cross-conjugated dieneynes that serve as versatile synthons for organic synthesis. The photophysical properties of these cross-conjugated dieneynes depend on the position of electron donor/acceptor substituents along the conjugation path, as characterized by UV–vis absorption and emissions spectroscopy. Chapter 3. Senphos–Palladium/B(C6F5)3-Catalyzed trans-Hydrothiolation of 1,3-Enynes: Reaction Development and Mechanistic Analysis. A trans-hydrothiolation reaction of 1,3-enynes enabled by a cooperative catalysis system that comprises of Senphos–Pd complex and tris(pentafluorophenyl)borane is detailed. The tris(pentafluorophenyl)borane is shown to alter the reaction pathway, leading to a trans-addition product over cis-addition one. Experimental mechanistic study that includes 31P NMR, kinetic study, kinetic isotope effect (KIE) study, Hammett analysis, is consistent with a cooperative activation mechanism that features an outer-sphere protonation step. / Thesis (PhD) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

En raison de leur capacité à intervenir dans les processus rédox, les ligands non-innocents ont depuis longtemps suscité un intérêt chez les spectroscopistes, mais leur potentiel en catalyse n'a été que récemment considéré. Le comportement non-innocent des ligands iminosemiquinonate et de leurs dérivés est bien établi et maîtrisé, et, associés à différents métaux, ces ligands ont démontré leur efficacité dans diverses applications synthétiques, telles que les oxydations et les réactions de couplage. Ce travail de thèse a pour objectif de développer des réactivités induites par des complexes de cuivre et nickel coordinés par des ligands de type iminosemiquinonate. Tout d'abord, la capacité de ces complexes à générer des radicaux CF3 par réduction d'une source électrophile de trifluorométhylation a été démontrée, et les espèces organométalliques résultant de l'oxydation monoélectronique centrée sur le ligand ont été identifiées par spectroscopie UV-visible. Un système catalytique a également été mis au point pour la trifluorométhylation radicalaire d'éthers d'énol silylés, d'hétéroarènes et l'hydrotrifluorométhylation d'alcynes. Les propriétés rédox des ligands iminosemiquinonates ont permis l'accès au premier complexe CuII–CF3 coordiné par des ligands oxydés iminobenzoquinones. L'étude de sa réactivité a mis en évidence le rôle essentiel des ligands oxydés, qui stabilisent le degré d'oxydation +II du cuivre, sans empêcher un comportement de CuIII haute valence. Ces observations ont été attestées par un ensemble de données spectroscopiques et théoriques. Enfin, l'étude de l'influence des ligands iminosemiquinonate sur la structure et la réactivité d'espèces cuivre–nitrène, impliquées dans les réactions de transfert de nitrène catalytique, est au centre d'un projet en cours. / Because of their ability to get involved in redox events, non-innocents ligands have long sparked the interest of spectroscopists, and their potential in catalysis has only later been considered. Iminosemiquinonate radical ligands and their derivatives are well-established non-innocent ligands and have been previously used with several metals, showing their efficiency in specific synthetic applications, such as oxidations and cross-couplings. This thesis work deals with the development of reactivities using iminosemiquinonate copper and nickel complexes. First, the ability of these complexes to induce the controlled generation of CF3 radicals by reduction of a CF3+ source was demonstrated, and key organometallic species resulting from a ligand-centered single electron transfer were identified using UV-vis spectroscopy. Catalytic conditions were developed and applied to the trifluoromethylation of silyl enol ethers, heteroarenes and hydrotrifluoromethylation of alkynes. Then, the synthesis of the first well-defined CuII–CF3 complex bearing fully oxidized iminobenzoquinone ligands was achieved. The study of its reactivity revealed the prominent role of the redox ligands, which stabilize a (+II) oxidation state without preventing its ability to behave as a high-valent CuIII complex. These observations were substantiated by a combination of advanced EPR spectroscopy techniques with DFT calculations. Finally, the influence of iminosemiquinonate ligands on the structure and the reactivity of copper–nitrene species, in catalytic nitrene transfer reactions, is the focus of a last project, which is still in progress.