Thesis advisor: Shih-Yuan Liu / Described herein is the development of a method to directly borylate the C5-position of monocyclic 1,2-azaborines without the use of a metal catalyst, kinetic resolution or directing group. This method tolerates different substitution on the boron as well as at the C3-position of the azaborine. A new BN-isostere of the drug molecule, felbinac, was synthesized to demonstrate the application of this method. / Thesis (MS) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Boron reagents are known to be valuable in the field of organic chemistry due to their abilities to undergo a variety of transformations, resulting in useful pharmaceuticals and synthetic intermediates. It has also been shown that diboron reagents can act as reaction mediators due to the unique properties of the boron atom. To that end, this dissertation discloses three novel methods of employing boron reagents. Chapter 1 describes a method of utilizing a diboron reagent mediator in the palladium-catalyzed hydrogenation of allenes. In the presence of a palladium catalyst, tetrahydroxydiboron and stoichiometric water, allene semireduction proceeds in good yield. This semireduction is regioselective for the terminal alkene and results in the selective formation of Z-alkenes when used with unsymmetrical allenes (>80:20 Z:E). It is also compatible with more sterically hindered 1,1-diarylallenes, resulting in tri-substituted alkenes in good yields (63-88%). A borylation, defluorination of alpha-trifluoromethyl-alpha,beta-unsaturated esters is described in Chapter 2. The borylation is copper-catalyzed (10 mol %) and proceeds in the presence of stoichiometric bis(pinacolato)diboron and sodium tert-butoxide. The reaction affords compounds that contain two potentially useful functional handles: boronic esters and gem-difluoroalkenes. The products are obtained in moderate to good yield (up to 75%) with a large substrate scope including compounds with electron-donating, electron-withdrawing, heteroatom, and aryl substituents. In addition, the utility of the products in further transformation is demonstrated. A proposed reaction mechanism that provides rationale for the formation of products is described along with experimental evidence. Finally, Chapter 3 describes a transition-metal-free trans hydroboration of alkynoate esters and amides. The reaction is phosphine-catalyzed and proceeds with pinacolborane to afford (E)-beta-borylacrylates and (E)-beta-borylacrylamides in good to excellent yields. The reaction products are converted into novel oxaboroles through reduction with sodium borohydride. Theoretical calculations provide mechanistic insight for the transformation. The formation of a key phosphonocyclobutene intermediate is responsible for the observed stereoselectivity. / Doctor of Philosophy / Boron reagents are valuable in the field of organic chemistry due to their abilities to undergo and to facilitate a wide variety of chemical transformations. In some of these reactions, boron is transferred onto the final molecules. Compounds containing boron are valued both as pharmaceuticals and as intermediates toward the synthesis of other products. In other transformations, the diboron reagents act as reaction mediators. Often, incorporating diboron reagent mediators allows for replacement of less favorable reactants. This dissertation describes three novel uses for diboron reagents in the field of organic chemistry. The first method employs a diboron reagent mediator—replacing flammable hydrogen gas—in the hydrogenation of allenes. The second two methods are novel borylation reactions where boron is incorporated in the final molecules. These compounds are potentially useful in pharmaceuticals and organic synthesis.

A catalytic (in Brønsted superacid) and a stoichiometric process were developed to synthesise aryl boronic esters with boron cations via electrophilic arene borylation. The treatment of CatBX (Cat = catecholate; X = Cl, Br) with the triethyl salt [Et3Si][closo-CB11H6Br6] in arene solvent gave a transient boron electrophile that reacted as a synthetic equivalent of [CatB]+ in intermolecular electrophilic aromatic borylation at 25 °C. The by-product of the reaction was a strong Brønsted acid that was able to catalyse arene borylation using CatBH at high temperature. This catalytic process furnished aryl boronic esters in high yield with H2 as the only by-product. The use of the robust and weakly coordinating anion [closo-CB11H6Br6]- and the electrophile-resistant catecholborane were crucial for the catalytic process. The reaction mixture of R2BCl (R2 = Cat, Cl4Cat, Cl2), aprotic amine and AlCl3 mainly gave a borenium salt [R2B(amine)][AlCl4] which was in equilibrium with neutral species as revealed by NMR spectroscopy and reactivity studies. This reaction mixture was effective for the regioselective borylation, by electrophilic aromatic substitution, of a range of N-heterocycles, thiophenes and anilines at room temperature. The transterification in situ provided the synthetically useful and more stable pinacol boronate esters in excellent isolated yield. This process displayed remarkable functional-group tolerance for a boron based strong Lewis acid with weak bases (for example -NMe2), ether, and halogen groups all compatible. This process represents a new and inexpensive one-pot direct arene borylation methodology for producing pinacol boronate esters.

Asymmetric conjugate addition of bis(pinacolato)diboron followed by aldol cyclisation of enone diones under the action of a chiral copper catalyst has been developed. This enantioselective process, using a chiral bisphosphine as ligand, allows the formation of bicyclic alcohols with four contiguous stereocentres in high diastero- and enantioselectivity. This catalytic system has been applied to the parallel kinetic resolution of a racemic β- ketoamide. Further functionalization of the bicyclic alcohols synthesised was also possible. A domino addition of arylboronic acids and cyclisation of alkynones via an undescribed iridium 1-4-migration process has been developed. A range of tricyclic compounds using a variety of arylboronic acids have been synthesised in good yields and high diasteroselectivity. The use of chiral bisphosphine ligand together with an iridium salt allows the formation of enantioenriched compounds in moderate yield.

Thesis advisor: Marc L. Snapper / Chapter 1 Bisphosphine monoxides have unique coordinating capabilities with transition metals. Several research groups have independently reported transition metal-catalyzed highly stereoselective reactions by using chiral bisphosphine monoxides as the ligands. A review of recent works in this field is provided in this chapter to showcase the features of this class of ligand. Chapter 2 We have developed a copper-catalyzed borylation method to synthesize α-aminoboronic esters, which are biologically interesting molecules in enzyme inhibitions. Employment of hemiaminal ethers as substrates to in situ generate the corresponding aldimines obviated purification of the unstable aldimines and potential imine-enamine tautomerization. By using a chiral bisphosphine monoxide ligand in our copper-catalyzed borylation conditions, we successfully synthesized a variety of enantioenriched alkyl-substituted α-aminoboronic esters in good yields and with good enantioselectivity. Chapter 3 A ruthenium-catalyzed three-step tandem sequence was established to prepare nitrogen-protected 2,3-dihydroxypyrrolidines and 2,3-dihydroxypiperidines. This tandem sequence includes ring-closing metathesis, olefin isomerization and olefin dihydroxylation, and utilizes the second-generation Grubbs’ catalyst as the initial ruthenium precatalyst. Readily accessible nitrogen-tethered dienes were used as the substrates to prepare the heterocyclic compounds in an efficient fashion. Through optimization, we discovered the optimal conditions for ruthenium-catalyzed dihydroxylation of ene-carbamates and ene-sulfonamides, which were the challenging substrates in the previous methods. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Organoboron compounds are viewed as a crucial intermediate for a wide variety of reactions. The most notorious reaction that exemplifies the capability of organoboron reagents is the Suzuki-Miyaura cross-coupling reaction, which is used to generate carbon-carbon bonds under mild conditions. Because of the versatility of organoboron reagents, methods to selectively install boron remains crucial. Boron containing compounds have recently garnered significant interest in the medicinal chemistry field. Boron's unique properties allows the development of potential new boron-based drugs targeting novel signaling pathways with great efficacy. This dissertation describes the use of a diboron reagent to install boron on the electron withdrawing allenoate scaffold as well as on disubstituted 1,3-diynes. Lastly, this dissertation will cover the preliminary anti-fungal activity of a novel oxaborole scaffold. We investigated the borylation of the electron withdrawing allenoate scaffold. Reports in the literature were scarce and limited in the scope of the work or required the use of less available diboron reagents. We developed a method for the addition of the diboron reagent B2pin2 and a copper chloride catalyst at 60 °C to generate the (Z)-β-borylen-oate in an 18 – 81% yield. A diverse substrate scope was produced, with the reaction being very tolerable with both electron donating and electron withdrawing functional groups attached to the phenyl ring with yields ranging from 29 – 81%. To our delight as well, straight alkyl chains maintained the respective Z stereoselectivity while having yields range from 46 – 60%. During the reaction, activation of the diboron reagent using the copper catalyst in methanol then undergoes boryl-cupration that can subsequently be protonated to form the Z-product. The steric effect of the activated boron complex and the allenoate drives the stereoselectivity of the reaction. To continue the borylation of unique scaffolds, we developed a selective cis phosphinoboration of 1,3-diynes. In this reaction, a catalytic amount of tributyl phosphine and a diphenyl(4,4,5,5-tetramethyl-1-3-2-dioxaborolan-2-yl)phosphane is used to generate the corresponding cis 1,2-phosphinoboronate in yields ranging from 18 – 75%. The reaction is performed in dichloromethane at 40 °C. Substrates bearing an electron donating group on the phenyl ring resulted in the need for a longer reaction time and decreased yields (18 – 39%), while substrates bearing an electron withdrawing groups resulted in increased yields (55 – 72%). The phosphinoboration reaction was also tolerable towards heterocycles (64%) and alkyl groups (34 – 53%). This reaction is able to attach both boron and phosphorous simultaneously without the use of a transition metal. Mild oxidation using iodine resulted in oxidation of the phosphorous. The resulting product interestingly generated a B-O-P heterocycle. In medicinal chemistry, new boron containing scaffolds have shown promising preliminary anti-fungal activity. The oxaborole scaffold is widely seen as a privileged scaffold due to the unique ability of boron to behave as a pharmacophore. The five-membered ring in the oxaborole scaffold also enhances the Lewis acidity of the boron. Our group has previously identified a synthetic route in obtaining a novel 3-monosubstituted oxaborole scaffold. Herein, we have developed a small library of compounds that were tested against a variety of fungal strains. Assaying the library at 25 μg/mL identified multiple hits that allowed the development of a preliminary structure activity relationship profile. Compounds containing electron withdrawing groups on the phenyl ring demonstrated higher anti-fungal activity. This phenomenon is explained due to the change in Lewis acidity of the compound. Incorporating electron withdrawing groups increases the overall Lewis acidity of the oxaborole scaffold, and therefore allowing for stronger covalent interactions in the active site. Increasing the length of the scaffold resulted in a drastic loss in activity, suggesting a smaller scaffold is a necessity. Compounds containing a 4-fluoro, 4-chloro, 4-trifluoromethoxy, and 4-tetrafluoromethoxy were all compounds that consistently observed below 30% cell survival in the candida albicans, aspergillus niger, metarhizium anisopliiae, aspergillus flavus, penicillum chrysogenum, and saccharomyces cerevisiae fungal assays. To further explore the promising potential of the new scaffold, minimum inhibitory concentrations for our lead compounds will be conducted in the future. / Doctor of Philosophy / Boron-containing compounds are prevalent in a multitude of chemical reactions. Due to the versatility of organoborons in chemical transformations, the development for new chemical reactions that install boron is vital. Of great importance in the installation is the ability to perform the reactions under mild conditions and low cost under environmentally friendly fashion. Boron-containing drugs are also a unique scaffold due to the ability boron has in its ability to act as a drug. Boron is able to covalently bind to molecules in the active site, creating an "anchor" that can then therefore deliver the respective therapeutic effect. This dissertation discusses two reactions that install boron in a selective fashion on challenging substrates. The first chapter discusses the installation of boron on a challenging allene scaffold. The focus of the installation is to maintain selectivity of where the boron ends up on the resulting product which we were successful in. The following chapter discusses the installation of both boron and phosphorous in a one-step fashion. Previous methods would require more steps, harsher conditions, and lower overall yields while we can now circumnavigate these challenges in our new method. The third part of my dissertation will discuss the discovery of a novel boron-containing drug scaffold that has promising anti-fungal activity. Anti-fungal drugs are usually difficult to come by, allowing for our scaffold to shine in a challenging field. We have identified multiple hits in our preliminary assays and we can show that manipulating the potential reactivity of the boron can result in greater or lesser anti-fungal activity.

Thesis advisor: Lawrence T. Scott / The Scott lab is interested in the functionalization of corannulene as a building block for large polycyclic aromatic hydrocarbons and carbon nanotube end-cap precursors. Toward that end, a new approach to the direct five-fold borylation of corannulene with iridium (I) catalysts via C-H activation has been explored. It has been discovered that the addition of catalytic amounts of base to the reaction mixture promotes the formation of symmetrical penta-borylated corannulene in a good yield on a sizable scale. All byproducts can be easily removed with iterative methanol washes. The present work also provides proof of the reversibility of the direct borylation reaction under the conditions used. Furthermore, modified Suzuki-Miyaura conditions have been employed to synthesize pentakis(2,6-dichlorophenyl)corannulene, a precursor for a [5,5] carbon nanotube end-cap. The reported reactions provide good yields and are scalable. / Thesis (MS) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Projects were undertaken investigating the functionalisation of polyaromatic cores (chrysene, pyrene and perylene) for use in organic electronics and aqueous graphene stabilisation. In each case an iridium-catalysed aromatic C-H borylation formed a key synthetic step, allowing access to unique substitution patterns. The development of strategies for the orthogonal and asymmetric functionalisation of polyaromatic hydrocarbons was explored. In a key synthetic step 4,10-dichlorochrysene was regioselectively borylated in high yields at the 2,8-positions though C-H activation chemistry. The subsequent application of sequential palladium-catalysed Suzuki and Kumada coupling reactions to this intermediate enabled the synthesis of a series of chrysene derivatives with a unique orthogonal "A2B2" 2,8- and 4,10-substitution pattern. In addition the application of a trifluoromethylation at the borylated 2,8-positions enabled the synthesis of a donor-acceptor chrysene derivative. The effect of these substitution patterns on the photophysical and electrochemical properties of these derivatives was investigated and their potential use as organic semiconducting materials evaluated. In particular the synthesised chrysene derivatives displayed broadened UV-vis absorption spectra, redshifted fluorescence spectra, increased HOMO levels and decreased band gaps. In an extension of these aromatic substitution methodologies, pyrene and perylene aromatic cores were functionalised to perform as stabilisers for aqueous graphene dispersions, investigating asymmetric motifs that may maximise performance. A series of amphiphilic pyrene- and perylene-based alkylsulfonic acid salts were synthesised via their intermediate hydroxyalkyl derivatives. In addition the application of the previously explored aromatic C-H borylation allowed access to 7- and 5,8,11- asymmetrically substituted pyrene and perylene derivatives. Through collaboration, initial steps have been undertaken to compare and evaluate these novel stabilisers for their ability exfoliate graphite to graphene in aqueous solution.

La thèse porte sur de nouvelles préparations et utilisations en synthèse du 4,4,6-trimethyl- 1,3,2-dioxaborinane (MPBH) comme agent d'hydroboration d'alcynes et de borylation d'halogénures d'aryle. La préparation de MPBH à partir de diverses sources de borane a été mise au point et la stabilité du réactif confirmée. L'hydroboration d'alcyne terminaux par MPBH, catalysée par le réactif de Schwartz, donne accès à des esters vinylboroniques hautement fonctionnalisés dans des conditions douces. Les produits obtenus sont stables, isolables, stockables. Ces esters vinylboroniques, par transmétallation avec le diméthylzinc et piégeage par une nitrone, conduisent efficacement à des E-allyl-hydroxylamines. Les conditions sont compatibles avec de nombreux groupes fonctionnels. Deux réactions de borylation d'halogénures d'aryle par MPBH ont été ensuite développées. Elles conduisent à d'excellents rendements en esters arylboroniques, stables et faciles à purifier, à partir d'iodures et de bromures. L'efficacité de ces esters boroniques dans des couplages de Suzuki-Miyaura a été vérifiée. Donc, l'utilisation de MPBH donne accès à des esters vinyl- et aryl-boroniques stables, faciles à purifier et à stocker ; ces esters sont des intermédiaires de synthèse très efficaces.

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第17522号 / 工博第3681号 / 新制||工||1560(附属図書館) / 30288 / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 辻 康之, 教授 大江 浩一, 教授 松原 誠二郎 / 学位規則第4条第1項該当