Thesis advisor: Shih-Yuan Liu / Thesis advisor: Marc Snapper / Organoboron compounds are widely used in organic synthesis and medicinal chemistry. It has been shown that organoboron compounds can undergo a vast quantity of transformations, especially stereospecific reactions. Boron enolates and their reactivity are less explored in the field of organic chemistry. In enolates, boron can be bound to oxygen or carbon. The boron-carbon enolates are of interest for having the potential to engage in stereospecific organoboron chemistry via the stereospecific carbon connected to the boron atom. Two methods of synthesizing boron-carbon enolates are through quaternized and unquaternized boron centers. While quaternized boron-carbon enolates are more studied, unquaternized boron-enolates represent a gap in the field. To date only four unquaternized boron-carbon enolates have been isolated and characterized with only one of the compounds engaging in organoboron chemistry. Herein I report the synthesis, isolation, and characterization of a boron-carbon enolate containing 1,2-azaborine as the organoboron analog. / Thesis (MS) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Shih-Yuan Liu / Described herein are two distinct research projects focused on the development of metal-catalyzed late-stage functionalization strategies for 1,2-dihydro-1,2-azaborines separated into three chapters. The first chapter discusses the development, synthesis, and recent contributions to the field of azaborine chemistry. The second chapter details the development of rhodium catalyzed B-H bond activation for the synthesis of a new class of BN-stilbenes as well as the discovery of a novel B-H to B-Cl transformation that is successful both with B-H azaborines as well as other B-H containing compounds. The third chapter pertains to the development of a B-H and B-Cl tolerant C(3) functionalization strategy through the use of Negishi cross-coupling. Using this methodology, previously unreported isomers of BN-naphthalene and BN-indenyl have been synthesized and characterized. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Benzene and its derivatives are ubiquitous in chemical research, with applications ranging from material science to biomedical research. 1,2-Dihydro-1,2-azaborine is a benzene mimic which replaces a CC bond with a BN bond. The basic science and applications of 1,2-azaborines is relatively underdeveloped. This thesis expands the fundamental understanding of 1,2-azaborines. Chapter I describes the air and moisture stability of 1,2-azaborines. Chapter II introduces nucleophilic aromatic substitution reactions that the parent 1,2-dihydro-1,2-azaborine will undergo. Chapter III discusses a trimerization reaction that 1,2-dihydro-1,2-azaborine can perform, which is unique from benzene. Chapter IV examines a novel protection free synthesis of 1,2-azaborines, which provides a more direct route to functionalized 1,2-azaborines. Chapter V discusses the novel deprotection of the N-silicon using an amide, giving one of the first 1,2-azaborine pharmaceutical mimics. Finally, chapter VI summarized miscellaneous contributions I have made to the basic science of 1,2-azaborines. This dissertation includes previously published and unpublished co-authored material. / 10000-01-01

Die Arbeit befasst sich mit zwei Themengebieten, wobei im ersten Teil der Fokus auf der postsynthetischen Funktionalisierung von 1,2-Azaborininen liegt. Im zweiten Teil wird die Reaktivität von Pyridin gegenüber cAACMe (1-(2,6-Diisopropylphenyl)-3,3,5,5-tetramethylpyrrolidin-2-yliden) in Anwesenheit borhaltiger Lewis-Säuren behandelt. Im ersten Abschnitt wurde die Bibliothek an borheterocyclisch-substituierten 1,2-Azaborininen erweitert und es wurde gezeigt, dass 1,2-Azaborinine in Kombination mit reaktiven, reduzierbaren borhaltigen Substituenten für den Aufbau neuartiger BNB-Heterocyclen geeignet sind. Hierbei wurde eine C–H Aktivierung des am Azaborinin C4-gebundenen Phenylrests beobachtet, die sowohl spontan durch Addition an die 2,5-Position des Borols, als auch reduktiv unter Ausbildung eines Borats hervorgerufen wurde. Eine analoge Aktivierung wurde anschließend erfolgreich selektiv durch Reduktion eines Halogenboryl-substituierten 1,2-Azaborinins realisiert. Lediglich bei einem entsprechenden Diboraanthracenderivat konnte anstatt einer C–H-Aktivierung eine reversible, Diboraanthracen-zentrierte Ein- und Zweielektronenreduktion beobachtet werden. Im weiteren Verlauf wurden Ferrocenylboryl-substituierte 1,2-Azaborinine dargestellt und diese auf ihre Reaktivität untersucht. Hierbei zeigte sich bei Reaktionen gegenüber Pyridin erneut die Neigung zu einer C–H-Aktivierung in ortho-Position des C4-gebundenen Phenylrests am Azaborinincyclus. Außerdem reagieren diese Verbindung unter thermischer Belastung in einer Protodeborylierungsreaktion zu BN-dotierten Borafluorenen und freiem Ferrocen. Darüber hinaus wurde ausgehend von dem literaturbekannten B-Mesityl-N-Trimethylsilyl-1,2-Azaborinin selektiv das 1H-1,2-Azaborinin durch Abspaltung der Silylgruppe und daraus die entsprechenden Alkalimetallsalze dargestellt. Diese wurden für eine Reaktivitätsstudie gegenüber einer Vielzahl an Elementhalogeniden genutzt. So wurden zunächst Boryl-substituierte 1,2-Azaborinine dargestellt, welche anschließend mit verschiedenen Reagenzien zu BN-Borafluorenen umgesetzt wurden. Die Reaktivität N-metallierter 1,2-Azaborinine gegenüber Dimethylsulfid-stabilisiertem Bortrichlorid dagegen führte zur direkten Darstellung von BNBNB-dotieren polyaromatischen Verbindungen. Als alternative Syntheseroute wurde ausgehend von 1-Mesityl-2,3,4,5-tetraphenylborol das N-Trimethylstannyl-1,2-Azaborinin dargestellt, welches ebenfalls zur Synthese von Boryl-substituierten 1,2-Azaborininen genutzt wurde, allerdings in geringeren Ausbeuten. Um tiefere Einblicke in die unterschiedlichen elektronischen und sterischen Eigenschaften des B-Mesityl-1,2-azaborinins im Vergleich zu B-Phenyl-1,2-Azaborinin zu erhalten, wurde zudem deren Reaktivität gegenüber den schweren Homologen der Gruppe 13, Aluminium und Gallium, und im weiteren Verlauf auch gegenüber Elementhalogeniden der Gruppe 14 und 15 untersucht. Hierbei zeigten sich deutliche Unterschiede und es wurden neben typischen Salzeliminierungsreaktionen auch Austauschreaktionen wie im Fall von GaCl3 mit dem Kaliumkation, welches ein Gallat-Salz liefert, beobachtet. Bei der Reaktivität gegenüber (deuteriertem) Dichlormethan wurde eine Ringerweiterungsreaktion zu einem siebengliedrigen BN-substituierten Makrocyclus beobachtet, welche über ein in situ gebildetes Carben von statten geht. Zudem wurden Pnictogen-substituierte 1,2-Azaborinine dargestellt und gezeigt, dass mit Hilfe der Lewis-Base Pyridin das endocyclische Boratom durch Quarternisierung adressiert und die Aromatizität aufgelöst werden kann. Zuletzt wurde durch die Umsetzung mit Münzmetallkomplexen die Analogie zu m Terphenylkomplexen zunächst nasschemisch durch die Synthese der dimeren BN-substituierten Kupfer- und Silberkomplexe demonstriert und anschließend mit quantenchemischen Berechnungen bestätigt. Außerdem wurden die Phosphan-stabilisierten 14 Valenzelektronenkomplexe sowohl ausgehend von den Dimeren als auch ausgehend von N-metallierten 1,2-Azaborininen dargestellt. Im zweiten Teil wurde die Reaktivität von Pyridin gegenüber cAACMe untersucht. In Anwesenheit verschiedener borhaltiger Lewis-Säuren wurde eine C–H-Aktivierung in para-Position des Pyridins mit cAACMe beobachtet, welche ohne Zusatz des Borans nicht auftritt. Dieses Reaktionsverhalten wurde durch Umsetzung verschieden substituierter Pyridin-Arylboran-Addukte mit cAACMe untersucht und bestätigt. Dies führte im weiteren Verlauf der Forschung zur Untersuchung von borhaltigen Lewis-Säuren als Katalysatoren dieser C–H-Aktivierung, wodurch schlussendlich das Lewis-Säure-freie und in para-Position des Pyridins cAACMe-aktivierte Produkt (py-cAACMe) isoliert wurde. Zuletzt wurden auch H-Borane in die Untersuchungen mit einbezogen, wobei neben dem Pyridin-stabilisierten Stammboran (py∙BH3), das Durylboran (py∙DurBH2) und Didurylboran (py∙Dur2BH) untersucht wurden. Deren Reaktivität gegenüber cAACMe stellte sich aufgrund der Neigung zur Hydridmigration als sehr komplex und weitreichend heraus. Aufgrund der nicht vorhandenen sterischen Abschirmung geht py∙BH3 zunächst ein Pyridin-C‒H-Aktivierung ein, wird anschließend jedoch nicht katalytisch aktiv, sondern reagiert weiter zu dem zweifach cAACMe-stabilisierten Boran und freiem py-cAACMe. Aufgrund dessen ist ein Überschuss cAACMe bei der Reaktion notwendig. Die Reaktion von py∙DurBH2 zeigt dagegen einen deutlich komplexeren Reaktionsverlauf. Zunächst wurde hierbei auch die Aktivierung in para-Position des Pyridins beobachtet, jedoch wird im weiteren Verlauf über eine postulierte Zwischenstufe entweder mit der Hilfe von cAACMe molekularer Wasserstoff abgespalten und eine chinoide Verbindung gebildet, oder es wird ein dreifach cAACMe-aktiviertes Aminoboran dargestellt. Außerdem wurde das sterisch anspruchsvollere 2,6-Lutidin-stabilisierte Durylboran (lut∙DurBH2) hergestellt, um dieses mit den zuvor beobachtete Reaktionsmustern zu vergleichen. Allerdings zeigte sich hier lediglich ein Lewis-Basen-Austausch zu dem cAACMe-stabilisierten Durylboran, welches ebenfalls ausgehend von dem Lewis-Basen-freien Boran synthetisiert werden konnte. Bei dem sterisch anspruchsvollsten py∙Dur2BH findet in Benzol ebenfalls ein Lewis-Basen-Austausch mit cAACMe statt, allerdings folgt diesem eine 1,2-Hydridmigration auf das Carbenkohlenstoffatom des cAACMe. Dieses Produkt kann auch durch Umsetzung des Lewis-Basen freien Borans mit cAACMe erhalten werden. / This work addresses two topics, the first part focusing on the postsynthetic functionalization of 1,2-azaborinines, the second part dealing with the reactivity of pyridine towards cAACMe (1-(2,6-diisopropylphenyl)-3,3,5,5- tetramethylpyrrolidin-2-ylidene) in the presence of boron-based Lewis acids. In the first section, the library of boron-containing heterocycle-substituted 1,2-azaborinines was expanded. It was shown that 1,2-azaborinines with reactive, reducible boron-containing substituents are suitable for the construction of novel BNB-heterocycles (Scheme 1). In most cases, ortho-C–H-activation of the C4-phenyl residue was observed, both spontaneously by addition to the 2,5-position of a borolyl substituent (Scheme 1 A), as well as reductively under formation of a borate (Scheme 1 B). An analogous activation was realized selectively by reduction of a haloboryl-substituted azaborinine (Scheme 1 C). With a related diboraanthracene derivative, reversible, diboraanthracene-centered one- and two-electron reduction was observed instead of C–H-activation (Scheme 1 D). ...

Thesis advisor: Shih-Yuan Liu / Described herein are four projects focused on the elaboration of aromatic 1,2-azaborine core structures through late-stage functionalization strategies. In the first chapter, the gram scale, protecting group-free synthesis of the direct BN isostere of benzene is developed. This protocol is used to produce large quantities of pure 1,2-azaborine suitable for use in fundamental investigations. Second, the first general solution for the functionalization of the C4, C5, and C6 ring positions of 1,2-azaborines is described, featuring iridium catalyzed C-H borylation as the key strategy. Azaborine boronates produced via this method are successfully elaborated through cross coupling and oxidation to access azaborines that serve as N,N-ligands for electrophilic boron sources. The third project is an extension of the borylation/cross coupling project, and introduces the first polymer consisting of repeating azaborine units that displays highly efficient extension of conjugation along the azaborine chain. Finally, a copper catalyzed radical process is developed that enables removal of azaborine boron protecting groups during synthetic routes to simple azaborine targets of high interest. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Shih-Yuan Liu / Described herein are three projects that derive from in-depth studies of the distinct electronic structure of monocyclic 1,2-dihydro-1,2-azaborine (heretofore referred to as simply 1,2-azaborine). In the first chapter, the first comprehensive review of the late-stage functionalization methods available for 1,2-azaborines as well as their bicyclic and polycyclic (BN-PAH) counterparts is presented. In the second chapter, the development of a general method for both C4 and C5 functionalization based on the building block approach is described. The distinct electronic structure of 1,2-azaborine enables the chemical separation and further functionalization of C4 and C5 borylated isomers. In the second part, the C4, C5, and C6 isomers of BN-styrene analogues were prepared using the newly developed azaborine building blocks. The corresponding polymers were synthesized and extensively characterized in order to compare the effects of the BN-bond positioning relative to the polymer chain. In the fourth and final chapter, 1,2-azaborine-containing phosphine ligands featuring a P-B bond are synthesized. A comparative electronic structure analysis is performed between the BN-phosphine ligands and their direct all-carbon counterparts. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Homogenous Au(I)-catalysis has become a valuable synthetic tool to activate a host of unsaturated carbon functional groups towards nucleophilic addition. Over the course of the past two decades, many have embarked on new journeys within this field. Notably, the advancements in this field hinge on the development of new ligand systems that impart novel reactivity at the metal. Our group has focused on this area, as we have successfully demonstrated the utility of 1,2,3-triazoles as ligands for gold and a host of other transition metals and Lewis acids. With respect to gold catalysis, these ligands enhance the stability of the metal center, thus inhibiting typical reductive decomposition pathways that have plagued this field. The enhanced stability comes with a price though as higher temperatures can be required. We’ve addressed this challenge by discovering an interesting synergy between triazole-gold and Lewis acids, allowing us to overcome the lower reactivity of these catalysts. During my time as a graduate student, I have focused heavily on enlisting these catalytic systems for new reaction discovery. In my first experimental chapter, I was able to develop an interesting reaction cascade in which triazole-gold and secondary amine catalysts were used. I started with a well-known gold-catalyzed Claisen rearrangement of propargyl vinyl ether, yielding functionalized allenes. The identical oxidation state between these allenes and synthetically appealing dienals was an impetus to develop a new isomerization strategy. After screening various conditions, I was able to successfully execute this design. Most of the work I have been involved in over the past two years has surrounded a gold-catalyzed hydroboration to yield interesting hetercocycles containing a N-B bond. The N-B bond offers some unique properties as it is isoelectronic to a C-C double bond. Despite the simplicity in this design, it would become apparent early on in this research that mitigating the reducing strength of the starting materials was absolutely critical. Starting materials that were too strongly reducing led to rapid catalyst decomposition. Through thorough reaction screening, we have been able to identify a catalytic system that performs extremely well in this context. Ultimately, our goal in this work is to access 1,2-azaborines, which are isosteres of benzene. This compound exhibits aromaticity, as determined through structural and quantitative analyses by several groups. However, subtle differences in properties between the azaborine and benzene, such as its polarity, have intrigued many researchers across various disciplines. Moreover, the ubiquity of its carbonaceous parent in biological systems has prompted many to pursue new synthetic routes to access 1,2-azaborines.

Thesis advisor: Shih-Yuan Liu / Described herein are three research projects that focused on 1) the catalytic activities of Pd/azaborine-derived biary phosphine (Senphos) complexes in 1,3-enyne difunctionalization reactions and 2) the coordination behaviors of these Pd/Senphos complexes. In the first chapter, expansion of the substrate scope and mechanistic studies of the reported Pd/Senphos catalyzed site-, regio- and trans-selective hydroboration of 1,3- enynes are described. In the second chapter, the first intermolecular site-, regio- and transselective chloroboration and cyanoboration of enynes that are enabled by the Pd/Senphos catalytic system are presented. The cyanoboration products, namely vicinal boronsubstituted alkenylnitriles, are demonstrated as versatile synthetic building blocks. In the last chapter, the κ2-P-η2-B,C coordination behavior in a series of 1,2-, 1,3- and 1,4-Senphos ligated Pd(0) or Pd(II) complexes are evaluated based on solid-state structures and variable-temperature NMR measurements. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Shih-Yuan . Liu / Chapter 1. Use of boron as a pharmacophore is as growing but still underdeveloped strategy for expanding chemical space in biomedical research. In addition to more established methods of incorporating boron in drug development, an attractive and emerging method of introducing boron into biologically active compounds is through boron-nitrogen containing heterocycles. In particular, the Liu group has focused on exploring the interactions of monocyclic 1,2-azaborines in biological space. In order to install complicated chemical functionality needed for further studies, methods for late stage functionalization of 1,2-azaborines must be developed. Described herein is a method for functionalizing 1,2-azaborine at the C3- and C5-positions, with bromine and iodine handles, respectively. Chapter 2. Described is the application of the turbo Grignard reaction to 1,2-azaborines bearing a B–Cl bond. The reaction utilizes iPrMgCl·LiCl to form aryl carbon nucleophiles and is tolerant of sensitive functional groups such as nitriles and esters. Development of the reaction obviates the need to use toxic organotin reagents to install aryl groups at the B-position that bear sensitive, electrophilic functionalities. / Thesis (MS) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Shih-Yuan Liu / This dissertation describes the utility of 1,2-azaborine motif as a 4C+1B+1N synthon in organic synthesis, especially for the preparation of densely functionalized cyclobutanes based on the framework of the 1,2-azaborine photoisomerization. The substitution of a CC unit with a BN unit in benzenes significantly modifies the properties of classic benzenoid compounds, leading to new reactivities and functionalities. In this vein, Chapter 1 discloses photoisomerization of 1,2-azaborines to selectively form BN-analogues of the Dewar benzene. Three applications of the Dewar photoisomers are described herein: 1) a rhodium-catalyzed ring-opening reaction to form 1,2-azaborines; 2) furnishing cis aminoborylated cyclobutanes with the boron unit as a further functionalization handle; 3) a stereospecific ring-opening reaction to afford diene which can engage in Diels-Alder reaction. Chapter 2 elaborates on a modular and stereoselective strategy to access a variety of cyclobutane β-amino alcohols. Discussed herein are regioselective functionalizations and di-functionalizations of the 1,2-azaborine core and a tandem photoisomerization-hydrogenation-oxidation protocol to translate the functionalized azaborine core to cyclobutane amino alcohols. Also examined herein are the scope of azaborine photoisomerization and Dewar hydrogenation. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.