Thesis advisor: James P. Morken / This dissertation describes three methods towards the stereoselective synthesis of organoboronates, and their application towards pharmacological targets of interest. The first chapter describes the use of alkyl migrating groups and alkyl electrophiles in the synthesis of secondary boronic esters through a highly selective nickel-catalyzed three component conjunctive cross-coupling reaction. Products from this conjunctive cross-coupling reaction are then converted to two alkaloids through boron amination and annulation processes. The second chapter describes the platinum-catalyzed diastereoselective diboration of carbocyclic, heterocyclic, and bicyclic alkenes. This reaction proceeded under air and both a homogeneous and heterogeneous catalyst was employed. Application of this reaction towards synthesis of the nucleoside analog Aristeromycin is also described. The final chapter details the development of an inexpensive and easily synthesized chiral diazaborinine that provides stereoinduction across a wide range of concerted and stepwise cycloaddition processes, affording heterocyclic-boron containing products in high yield and selectivity. Transformations of resulting organoboronates are also described. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Ligand design is important due to a ligand's ability to tune properties of the transition metals, such as catalytic activity and selectivity. Gold(I) catalysts can be directly impacted by ligands electronically as well as with steric bulk when undergoing enantioselective and regioselective reactions. In the dissertation, a series of gold(I) acyclic diaminocarbenes were synthesized and used to explore the 1,6 enyne cyclization/hydroarylation. The use of metal templated synthesis of the gold(I) acyclic diaminocarbenes allowed for the gradual increase in steric bulk of the catalysts. In the end, it was shown that electronics play the major role in the regioselectivity for the 1,6 enyne cyclization/hydroarylation but localized steric bulk can control the catalytic reaction if placed strategically. Cross-coupling reactions used to form carbon-carbon or carbon-heteroatom bonds are important in the production of pharmaceutical chemicals on a large scale. Iron, an extremely cheap and earth abundant first row transition metal, has had some success in cross-coupling reactions. Iron does not go through the same catalytic cycle for cross-coupling as most transition metals, the most common of which is palladium. In the dissertation, a ligand was developed to induce Iron to undergo the same cycle as palladium. In addition, the same ligand was placed on palladium(II) and reduced to try to form and isolate a catalytically active palladium(0) complex.

Thesis advisor: James P. Morken / This dissertation presents the development of catalytic enantioselective synthesis and selective functionalization of geminal or vicinal borylsilanes and bis(boronates). In the first chapter, a modular approach to the catalytic synthesis of enantioenriched anti-1,2-borylsilanes will be described, which is enabled by the stereospecific 1,2-metallate shift that occurs during Pd-catalyzed conjunctive cross-coupling reaction. In the second chapter, the Cu-catalyzed site-selective cross-coupling of vicinal bis(boronates) to an array of electrophiles is developed to provide a new method to construct complex boron-containing products from terminal alkenes. A dramatic rate acceleration in transmetalation to copper is enabled by the neighboring activating boronate group in the substrate. Mechanistic experiments suggest that the formation of a chelated cyclic ate complex may play a role in facilitating the transmetalation. As a follow-up project, the site-selective cross-coupling of vicinal diborylsilanes is also investigated. A Pt-catalyzed enantioselective hydrosilylation of (Z)-1,2-diborylethylene provides access to a vicinal 1,2-diboryl-1-silylalkane that can be used in catalytic cross-coupling reactions. Depending on the catalyst employed and the electrophile class, the coupling reaction can occur at either the α or β carbon relative to the silane center. In the last chapter, a practical method is developed to prepare a TiO2 supported gold nanoparticle catalyst that facilitates the cis-diboration of terminal alkynes. The resulting products can undergo a practical Cu-catalyzed site-selective cross-coupling with proton or other non-aryl/alkenyl electrophiles to yield α-substituted alkenyl boronates with excellent yield and site-selectivity. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Our research seeks new methods for functionalizing organic small molecules using organoboronic derivatives as a versatile handle for late-stage manipulations. Metal-catalyzed formation of new carbon-boron bonds and their subsequent transformations are highlighted. Among the myriad of unsaturated substrates for conducting borylation reactions, allenes have received minimal attention. These substrates are uniquely advantageous given that diboration results in the formation of both allylic and vinylic boronates. Orthogonal reactivity of the sp2 and the sp3 C-B bonds can allow for chemoselective transformations. However, oxidation of the carbon-boron bond is one example in which the conditions are unselective. To address this shortcoming, a platinum catalyst was developed for the diboration of 1,1-diaryl allenes with a differentially protected diboron reagent, pinB-Bdan. The reaction proceeds regioselectively in high yields to furnish olefins bearing a vinylic Bpin and an allylic Bdan moiety. The subsequent chemoselective transformation of each boron center was demonstrated. Methods for preparing 1,8-diaminonaphthalene protected vinylboronates conjugated to carbonyl groups are severely limited. A simple and efficient protocol was developed for carrying out an environmentally friendly copper(II)-catalyzed beta-borylation of alkynoates and alkynamides in water and open-to-air. Following the discriminative activation of the more Lewis acidic pinacol protected boron center in pinB-Bdan, a regio-, stereo- and chemoselective beta-borylation of acetylenic substrates delivers (Z)-beta-boryl enoates and primary, secondary, and tertiary enamides under very mild conditions. As an inexpensive and earth abundant metal, catalysts based on copper are highly desirable. An international collaborative project to develop a copper-catalyzed cross-coupling reaction of beta-boryl carbonyl compounds was explored. Preliminary results found these substrates to be either unstable towards or unreactive under the reactions conditions screened. / Ph. D.

Please note that the structures do not display correctly in the pdf document. Therefore the original manuscript in MSWord has also been uploaded. Please contact us email if you cannot view these files. / Sonogashira cross-coupling of 2-aryl-4-chloro-3-iodoquinoline derivatives with stoichiometric amount of terminal alkynes in the presence of bis(triphenylphosphine)palladium(II)chloride and copper iodide in triethylamine afforded the 3-(alkynyl)-2-aryl-4-chloroquinoline, exclusively. On the other hand, the 2-aryl-4-chloro-3-iodoquinolines with excess (2.5 equiv.) of terminal alkynes in the presence of PdCl2(PPh3)2-CuI catalyst mixture and NEt3 in dioxane-water (3:1 v/v) afforded the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-step operation. Further transformation of the 2-aryl-3-(alkynyl)-4-chloroquinoline via Suzuki cross-coupling reaction with boronic acid derivatives in the presence of tetrakis(triphenylphosphine)palladium and tricyclohexylphosphine as a ligand in dioxane-water (3:1 v/v) afforded the 2,4-diaryl-3-(alkynyl)quinolines in moderate to high yields. The 2-aryl-3-(alkynyl)-4-chloroquinolines were also transformed to the corresponding 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives using methylamine in ethanol under reflux. / Chemistry / M.Sc.

Please note that the structures do not display correctly in the pdf document. Therefore the original manuscript in MSWord has also been uploaded. Please contact us email if you cannot view these files. / Sonogashira cross-coupling of 2-aryl-4-chloro-3-iodoquinoline derivatives with stoichiometric amount of terminal alkynes in the presence of bis(triphenylphosphine)palladium(II)chloride and copper iodide in triethylamine afforded the 3-(alkynyl)-2-aryl-4-chloroquinoline, exclusively. On the other hand, the 2-aryl-4-chloro-3-iodoquinolines with excess (2.5 equiv.) of terminal alkynes in the presence of PdCl2(PPh3)2-CuI catalyst mixture and NEt3 in dioxane-water (3:1 v/v) afforded the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-step operation. Further transformation of the 2-aryl-3-(alkynyl)-4-chloroquinoline via Suzuki cross-coupling reaction with boronic acid derivatives in the presence of tetrakis(triphenylphosphine)palladium and tricyclohexylphosphine as a ligand in dioxane-water (3:1 v/v) afforded the 2,4-diaryl-3-(alkynyl)quinolines in moderate to high yields. The 2-aryl-3-(alkynyl)-4-chloroquinolines were also transformed to the corresponding 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives using methylamine in ethanol under reflux. / Chemistry / M.Sc.

Transition metal-catalyzed cross-coupling is one of the most dominant fields of modern synthetic organic chemistry. Research is forever ongoing, in which there is constant expansion of the scope of nucleophilic- and electrophilic- coupling partners, and consequently the types of products that can be formed. More specifically, strong bond activation in cross-coupling is an emerging field that can enable late-stage functionalization; by activating inert functional groups that were untouched in earlier synthetic steps, they can be taken advantage of for further derivatization. This thesis will focus on the use of aggressive reagents in the activation of strong C–H and C–O bonds for their use in transition metal-catalyzed cross-coupling. Chapter 1 will involve the use of organometallic superbases in the palladium-catalyzed cross-coupling of sp3-hybridized carbon-centered nucleophiles. Deprotonation and subsequent electrophilic quench can be considered the most classical form of C–H activation. While modern approaches frequently focus on radical mechanisms or directing groups as modes of C–H activation, stoichiometric metalation has been largely overlooked in the context of cross-coupling. By using aggressive organometallic superbases to deprotonate very weakly acidic C–H bonds, the resultant organometallic species can be taken advantage of as cross-coupling nucleophiles. This chapter will investigate the coupling of organolithiums and organozincs generated in situ in the C(sp3)–H arylation of an array of unactivated substrate classes. Chapter 2 will briefly investigate the use of aggressive alkyl metallic additives in the C–O activation of silyl enol ethers as Suzuki-Corriu cross-coupling electrophiles. Converting ketones to substituted olefins using cross-coupling is a common approach in medicinal chemistry for the synthesis of complex bioactive products. While reliable, this chemistry is generally very inefficient due to multi-step synthesis and the instability of activated intermediates. In contrast, applying modern nickel-catalyzed C–O activation to robust silyl enol ethers made in situ could alleviate these limitations. Using triethylborane as an additive, a nickel-catalyzed Suzuki-Corriu cross-coupling of silyl enol ethers was discovered. While ultimately unsuccessful, attempts were also made to optimize, explore the scope, and elucidate the mechanism of this reaction.

This PhD thesis reports the development of novel C-H activation strategies and aqueous-phase Suzuki-Miyaura cross-coupling reactions for the synthesis of modified deazapurine nucleobases. The methodologies of chemo- and regioselective synthesis of highly functionalized deazapurines have been developed by using modern C-H activation chemistry. Various functional groups such as amino-, imido-, silyl- and phosphonyl- were introduced by C-H activation reactions. Amino deazapurine derivatives were synthesized by developed Pd/Cu-catalyzed direct C-H amination and C-H chloroamination of 6-substituted 7-deazapurines with N-chloro-N- alkyl-arylsulfonamides. C-H imidation reactions of pyrrolopirimidines were performed under ferrocene catalysis with N-succinimido- or N-phtalimidoperesters. In order to obtain silylated derivatives, Ir-catalyzed C-H silylations of phenyldeazapurines with alkyl silanes were designed. Highly interesting deazapurine phosphonates were prepared by using Mn-promoted C-H phosphonation method and were further transformed into the corresponding phosphonic acids. All of the developed direct C-H functionalization reactions proceeded regioselectively at position 8 in deazapurine core, except for C-H silylation where reaction undergoes mainly as directed ortho C-H silylation on phenyl ring,...

La synthèse d’oléfines et plus précisément de vinylchalcogénures di- ou trisubstitués sous contrôle régio- et stéréosélectif constitue l’objectif de ce travail. La stratégie adoptée consiste à utiliser des dérivés acétyléniques comme précurseurs, et des alcénylboranes comme intermédiaires réactionnels. Deux voies synthétiques distinctes ont été sélectionnées : l’hydroboration de 1-chalcogéno-1-alcynes (préparation d’alcénylboranes α-chalcogénés) et le réarrangement de sels d’alcynyltriorganylborates induit par des électrophiles chalcogénés (préparation d’alcénylboranes β-chalcogénés). La cis hydroboration du 1-phénylthio-1-hexyne par le dicyclohexylborane est régiosélective et fixe majoritairement l’entité dicyclohexylboryle en &alpha du soufre, conséquence d’une interaction de type acide-base de Lewis entre les deux hétéroatomes. Les tentatives d’optimisation de la régiosélectivité ([α :β] = [97 :3]) montrent que la modification de la densité électronique autour du soufre (par introduction de substituants électroattracteurs ou -donneurs en para sur le cycle aromatique) ou la présence de substituants (alkyl/aryl)thio à demande stérique plus importante impactent à plusieurs niveaux, mais ne permettent pas d’augmenter le degré de régiosélectivité de l’hydroboration. La fonctionnalisation des vinylboranes α-chalcogénés par transmétalation stœchiométrique (bore-cuivre) suivie de l’alkylation ou par couplage de Suzuki-Miyaura donne accès à des vinylsulfures disubstitués. L’utilisation de fluorure de tétrabutylammonium en solution dans le tétrahydrofurane, à la place d’une solution aqueuse d’hydroxyde de sodium comme base pour le couplage Suzuki, permet l’évitement de la réaction parasite principale, la protodéborylation du vinylborane. Le réarrangement des 1-acynyltriarylborates de lithium induit par les halogénures d’(alkyl/aryl)chalcogényle est totalement stéréosélectif et dispose le groupement migrateur du bore en trans par rapport à l’électrophile entrant. La migration de substituants aromatiques (phényle, thiényle et anisyle) est tout à fait inédite dans le domaine de la préparation d’alcénylboranes chalcogénosubstitués. La conversion de ceux-ci ouvre des perspectives très intéressantes pour la préparation d’arylcétones α-chalcogénées par oxydation, de vinylsulfures disubstitués par traitement à l’acide acétique, ainsi que de vinylsulfures trisubstitués par couplage ou transmétalation stœchiométrique (bore-cuivre ou bore-zinc). Toutes ces transformations sont totalement stéréosélectives. L’utilisation de l’une de ces deux voies synthétiques assure une formidable flexibilité pour l’introduction des divers substituants sur les futurs carbones oléfiniques.