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Browsing by Author "Bandar, Jeffrey, advisor"

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    Advancing the utility of organic superbases in synthetic methodology
    (Colorado State University. Libraries, 2023) Sujansky, Stephen J., author; Bandar, Jeffrey, advisor; Miyake, Garret, committee member; Sambur, Justin, committee member; Cohen, Robert, committee member
    Deprotonation is one of the most fundamental and important modes of molecular activation, making Brønsted bases a critical part of a synthetic chemist's toolbox. An exceptional class of Brønsted bases are organic superbases, which are finding increased use in modern synthetic methods due to their unique properties. This thesis describes the use of these unique properties to advance the synthetic utility of superbases in two ways; 1) improving superbase- catalyzed alkene hydrofunctionalization reactions; and 2) developing air-stable and convenient organic superbase prereagents. Chapter One describes organic superbases in detail to provide background and context for Chapters Two and Three. Within Chapter One, various classes of superbases are presented, as well as their unique properties, syntheses, and example applications. Finally, the limitations and challenges associated with the use of superbases are discussed. Chapter Two describes the Bandar Group's superbase-catalyzed alkene hydrofunctionalization methodology. Within this chapter mechanistic studies as well as computational modeling, done as part of a collaboration with the Paton Group, are presented. These mechanistic studies provided insight into the factors controlling the reaction equilibrium. This insight was then used to logically address the limitations associated with the original conditions reported by the Bandar Group in 2018. The results of this work help to improve reaction efficiency and to expanded substrate scope. This understanding also led to the development of a catalytic anti-Markovnikov aryl alkene hydration method that allows convenient access to β-aryl alcohols. Chapter Three describes the development of air-stable organic superbase precatalysts and prereagents. Superbase salts that decarboxylate were developed as a first strategy method to generate the neutral superbase in solution. This initial salt system then led to the discovery of stable superbase carboxylate salts that react with and open epoxide additives in situ to neutralize the superbase conjugate acid. This ring strain release strategy is shown to be effective at promoting a range of reactions including Michael-type addition, ester amidation, deoxyfluorination, SNAr and Pd-catalyzed cross coupling reactions. These superbase precatalysts and prereagents provide a means to access the unique properties of organic superbases from air-stable and easy-to-handle salts. Overall, Chapters Two and Three represent significant progress in advancing the utility of organic superbases in synthetic methodology. My work in Chapter Two, along with the Bandar's and Paton Group's efforts, meaningfully expanded the scope and usefulness of superbase- catalyzed alcohol addition reactions. Our new mechanistic understanding proved to be fundamental to a range of addition reactions and pushed the boundary of possible nucleophilic addition reactions. My efforts in Chapter Three, along with Garrett's significant contributions, have made organic superbase much more convenient to use, synthesize and store. This greater convenience and potentially lower cost can be expected to improve access to superbase chemistry and serve as the foundation for future discoveries. Additionally, the ability to control the concentration of superbase in solution will have many benefits in expanding substrate scopes and modulating reaction profiles where a strong base is required but is also detrimental to the overall process.
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    New base-catalyzed processes enable new approaches to C–H functionalization reactions
    (Colorado State University. Libraries, 2022) Puleo, Thomas R., author; Bandar, Jeffrey, advisor; McNally, Andy, committee member; Zadrozny, Joseph, committee member; Chatterjee, Delphi, committee member
    Brønsted bases are ubiquitous, inexpensive, and widely available reagents used in synthetic chemistry due to their well-studied and predictable activation mode. This thesis details the discovery and incorporation of new Brønsted base-catalyzed processes into fundamental proton transfer equilibria to enable new approaches to C–H functionalization reactions. The direct functionalization of C–H bonds represents a streamlined and attractive approach to access valuable synthetic targets, and this utility will be highlighted throughout the discussion of each method.Chapter one describes the discovery and development of a base-catalyzed α-selective styrene deuteration reaction. The mechanistic studies that led to the conceptualization and optimization of this reaction will be highlighted. α-Deuterated styrenes are compounds frequently utilized in the mechanistic studies of alkene functionalization reactions and this work represents the first method to achieve α-selective hydrogen isotope exchange on styrene derivatives. Chapter two provides an overview of existing approaches to catalytic aryl halide isomerization reactions. A particular focus on base-catalyzed aryl halide isomerization reactions will be provided, as these reports serve as the mechanistic foundation for the reactions developed throughout the remainder of the thesis. Chapter three describes our discovery and application of a general approach to base-catalyzed aryl halide isomerization. Aryl halides are valuable compounds in synthetic chemistry, and this new catalytic isomerization process unlocks a new mode of reactivity for these compounds. The scope of this process is demonstrated on several simple aryl bromides and iodides. The second part of this chapter will highlight an application of this process to enable the 4-selective nucleophilic substitution of 3-bromopyridines. Chapter four describes our approach to achieve nucleophilic C–H etherification of electron-deficient N-heteroarenes via a base-catalyzed halogen transfer mechanism. 2-Halogenated thiophenes efficiently transfer halogens to N-heteroaryl anions to generate N-heteroaryl halide intermediates that undergo nucleophilic aromatic substitution with alkoxide nucleophiles. Additionally, C–H etherification can be sequenced with a cascade base-promoted elimination to enable N-heteroarene C–H hydroxylation. The scope of process is highly general, and regioselective C–H etherification and hydroxylation is demonstrated on thiazoles, oxazoles, imidazoles, pyridines, pyrimidines, pyridazines, and polyazines. Chapter five briefly highlights two new C–H functionalization reactions currently being developed that are enabled by base-catalyzed halogen transfer. First, use of this approach to enable the C–H hydroxylation of benzenes will be described. Second, the monoselective and site-selective benzylic C–H etherification of toluenes and polyalkyl benzenes will be detailed. In the final part of the chapter, I will summarize my contributions and discuss the future outlooks on this chemistry.
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    Reductive coupling reactions of organosilanes for the monoselective C–F functionalization of trifluoromethylarenes
    (Colorado State University. Libraries, 2022) Wright, Shawn E., author; Bandar, Jeffrey, advisor; Paton, Robert, committee member; Borch, Thomas, committee member; Herrera-Alonso, Margarita, committee member
    The mono-selective defluorofunctionalization of trifluoromethylarenes is an emerging strategy to access ⍺,⍺-difluorobenzylic derivatives, which are difficult to access in a divergent manner. Fluorine incorporation is a common strategy employed during the optimization of potential pharmaceuticals in the drug discovery process. Much effort has been spent over the past few decades in developing fluorination methodologies, and the result has been tremendous growth in aryl and alkyl fluorination and trifluoromethylation reactions. On the other hand, methods to install other fluoroalkyl motifs are less developed. Due to the abundant availability of trifluoromethylarenes, mono-selective defluorofunctionalization reactions would be an ideal route to access ⍺,⍺-difluorobenzylic derivatives, which are becoming increasing examined in drug discovery settings. Chapter one will provide the necessary background to understand the context of the work described throughout the following chapters. First, there will be an overview of the importance of fluorine for the development of pharmaceutical compounds. Then there will be a brief summary of the different strategies that have been developed to achieve the trifluoromethylation of arenes as well as the common routes to access ⍺,⍺-difluorobenzylic compounds. Finally, a thorough discussion of the challenges and reported solutions to achieve mono-selective defluorofunctionalization of trifluoromethylarenes will be provided. Chapter two will describe the initial discovery, development, and mechanistic investigation of the defluoroallylation reaction reported by the Bandar group. This discovery led to the identification of a new strategy to achieve reductive coupling through the use of Lewis base activated organosilanes, which provides the basis for the reactions discovered and developed in chapters three and four. Chapter three will describe the discovery, development, and mechanistic investigation of a reductive coupling reaction of trifluoromethylarenes with formamides. This reaction generates a silylated hemiaminal product which is a valuable synthetic intermediate to access a broad scope of ⍺,⍺-difluorobenzylic derivatives. Mechanistic investigations support the generation of a ⍺,⍺-difluorobenzylsilane intermediate in the reaction. Isolated of the ⍺,⍺-difluorobenzylsilane and subsequent derivatizations further broaden the scope of transformations accessible via this reductive coupling process. Chapter four will describe the discovery and preliminary development of the mono-selective hydrodefluorination of trifluoromethylarenes using hydrosilanes activated by a Lewis basic catalyst. Two different catalytic systems are demonstrated that operate via different mechanisms, which provides access to different reaction scopes. A short discussion on the future work of this project will also be provided, where a junior graduate student is developing conditions to enable the mono-selective hydrodefluorination of electron-neutral trifluoromethylarenes.
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    The development of new synthetic methods and techniques using strong Brønsted bases
    (Colorado State University. Libraries, 2024) Hoteling, Garrett A., author; Bandar, Jeffrey, advisor; Miyake, Garret, committee member; Menoni, Carmen, committee member; Peebles, Christie, committee member
    Brønsted bases are indispensable tools in synthetic chemistry and, as such, deprotonation serves as a ubiquitous mode of molecular activation. By pushing the boundaries of what is possible within the acid-base reaction paradigm, unique synthetic methods and techniques can be developed. The work described in this thesis focuses on gaining a fundamental understanding of strong-base chemistry in efforts towards the development of new base-promoted synthetic methods. Herein, Brønsted bases have been investigated in two ways; 1) the design and application of benchtop-stable precatalyst salts for valuable organic superbases; and 2) the implementation of base-promoted halogen-transfer to develop benzylic oxidative coupling reactions with alkyl (hetero)arenes. This dissertation consists of five chapters. Chapters One and Three provide background and motivation for the work disclosed in this dissertation. Chapters Two, Four and Five represent project areas I have developed with Chapter Two adapted from published work and Chapters Four and Five as drafts of unpublished work. Below is a list of the chapters including a summary of the content for each. Chapter One describes the importance of organic superbases and their relevance to the synthetic community and the Bandar Group as a whole. Presented here will be the various classes of superbases and their unique properties that distinguish them from other classes of bases. Additionally, applications and known limitations to use of these bases will be discussed here. Chapter Two describes work along with Dr. Stephen J. Sujansky on the development of benchtop-stable organic superbase salts and the method for their facile in situ activation. Here, air-sensitive organic superbases form salts when mixed with carboxylic acids that are indefinitely stable on the benchtop. When combined with an epoxide additive, the carboxylate will react to open the epoxide and generate an alkoxide that can neutralize the superbase conjugate acid. This strategy is effective at promoting catalytic Michael-type additions and polymerizations as well as stoichiometric substitution and Pd-catalyzed cross-coupling reactions. This strain-release mechanism not only provides an accessible precatalyst for air-sensitive superbases but provides a new opportunity for controlling base concentration in situ. Chapter Two describes the development of the Bandar Group’s base-promoted halogen transfer research program. The history and importance of this mechanistic platform will be discussed as well as previous reports in the area by our group. In this chapter, the mechanism of base-promoted halogen-transfer is described, which enables the exchange of weakly acidic C–H bonds for C–X bonds that can be subsequently substituted with a pronucleophile in situ. This section will also provide the necessary background and motivation for Chapters Four and Five. Chapter Four describes the development of a new method for the synthesis of benzylic amines from alkyl (hetero)arenes. The development, optimization, and scope investigation of this reaction are described herein. The results of this work represent the first general approach for benzylic C–H amination, functioning on a broad scope of alkyl (hetero)arenes and amine coupling partners. Chapter Five describes the use of base-promoted halogen-transfer to enable alkyl (hetero)arene desaturation. With ethyl- and longer alkyl-substituted arenes, after benzylic halogenation, elimination takes place in the presence of excess base, a process that is competitive iv with the substitution protocol described in Chapter Two. Here, this reactivity has been exploited to develop a general desaturation technique for alkyl (hetero)arenes. Under desaturation conditions, an amine pronucleophile can be added, at which point β-addition followed by subsequent desaturation affords the β -aryl enamine, which is a diversifiable functional handle. This chapter describes the development of desaturation, cascade enamine formation, and the modification of enamine products.