Mountain Scholar :: Browsing by Author "McNally, Andrew, advisor"

Browsing by Author "McNally, Andrew, advisor"

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Open Access
Expanding the medicinal chemistry toolbox: development of new pyridine and piperidine functionalization strategies
(Colorado State University. Libraries, 2022) Greenwood, Jacob W., author; McNally, Andrew, advisor; Bandar, Jeffrey, committee member; Sambur, Justin, committee member; Chatterjee, Delphi, committee member
Nitrogen-containing heterocycles, such as pyridine, are ubiquitous in pharmaceuticals, agrochemicals, ligands, and materials. Therefore, robust methods for their direct functionalization are highly desired. Chapter one focuses on the importance of pyridine-containing molecules, the reactivity of pyridine, and challenges associated with functionalization of such compounds. In chapter two, a method for bipyridine synthesis is discussed that uses pyridylphosphonium salts as radical precursors. Other radical precursors failed to provide the desired products, highlighting the unique reactivity imparted by the phosphonium group. In chapter three, pyridylphosphonium salts are explored as alternatives to cyanopyridines in photoredox-catalyzed radical coupling reactions. This work expands the scope of the reaction manifold to complex pyridine substrates where installation of the cyano group can be challenging. Chapter four introduces the value of piperidines and challenges associated with their synthesis. A strategy is described to address these limitations using isolable, cyclic iminium salts as a general platform to elaborate the piperidine scaffold with several medicinally relevant functional groups. An alternative piperidine synthesis is presented in chapter five, where the mild transformation of a range of pyridines into pyridinium salts is achieved, followed by mild hydrogenation to the desired piperidine products. This method operates under mild conditions and can tolerate substitution at the 2-position of the pyridine substrate. As a result, a large amount of pyridine starting materials can now be engaged to form piperidines that are challenging to make with other technologies.
Open Access
Functionalization of pyridines and other azines via phosphorus ligand-coupling reactions
(Colorado State University. Libraries, 2019) Hilton, Michael C., author; McNally, Andrew, advisor; Reynolds, Melissa, committee member; Crans, Debbie, committee member; Montgomery, Tai, committee member
Nitrogen heterocycles are ubiquitous in pharmaceutical compounds with pyridine being one of the most frequently occurring examples. The discovery and development of new drugs rely heavily on our ability to modify these commonly occurring structures. The functionalization of pyridine has a long history but despite this, there remain some deficiencies in this area of synthesis. Reactions which expand upon the known methodologies are of tremendous value to medicinal chemists who frequently work with pyridines and similar azines. Chapter one will cover the relevance of pyridines in pharmaceuticals and will explain how structural features contribute to their presence in drugs. Conventional and newer methods to functionalize pyridine are also addressed. Chapter two will describe the work of the McNally lab in the development of heterocyclic phosphonium salts as reagents to selectively functionalize pyridines. An application of these salts is as precursors to form C−O bonds from alkoxide nucleophiles. Chapter three presents the development of a strategy to construct bis-heterobiaryls using phosphorus ligand-coupling. This method offers an alternative to the widely used metal-catalyzed approaches which often struggle in the synthesis of bis-heterobiaryls. Lastly, chapter four will expand upon this work showing a new approach to prepare bis-heterobiaryls using heteroaryl halides. This route enables easy access to 2,2'-bipyridines which are difficult to synthesize using conventional methods.
Open Access
New methods to access functionalized N-heterocycles
(Colorado State University. Libraries, 2021) Patel, Chirag, author; McNally, Andrew, advisor; Bandar, Jeffrey, committee member; Reynolds, Melissa, committee member; Kipper, Matthew, committee member
N-heterocycles are ubiquitous in pharmaceuticals and agrochemicals. Their prevalence is due to the unique properties they can impart to a molecule. Due to their ubiquity, it is vital that synthetic chemists be able to modify the structure of these valuable scaffolds. Despite a great deal of literature on the functionalization of these important motifs, challenges toward the functionalization of N-heterocycles remain. Chapter 1 will highlight the importance of azaarenes in pharmaceuticals and explain the properties that make these structures so prevalent in drugs. Classical and modern methods to functionalize pyridines and diazines will also be discussed. Chapter 2 will describe the development of the phosphonium salt chemistry in the McNally lab and the use of these reactive intermediates to aminate pyridines and diazines via the Staudinger reaction. Chapter 3 will introduce the concept of phosphorus ligand-coupling and briefly describe its previous application toward the synthesis of bis-heterobiaryls. This chapter will also cover the importance of fluoroalkyl groups in both the pharmaceutical and agrochemical industries. Current methods to fluoroalkylate azaarenes will be discussed, and the development of a novel fluoroalkylation strategy via a phosphorus ligand-coupling reaction will be explained. Finally, chapter 4 covers ongoing research into the synthesis of N-alkyl/aryl pyridiniums and their hydrogenation to N-substituted piperidines. The importance of N-substituted piperidines and the limitations to their synthesis are described.
Open Access
New strategies to synthesize complex pyridines and tetrahydropyridines using main group chemistry
(Colorado State University. Libraries, 2021) Fricke, Patrick J., author; McNally, Andrew, advisor; Crans, Debbie, committee member; Chen, Eugene, committee member; Kipper, Matthew, committee member
Pyridine and piperidine are important molecular scaffolds in small molecule drug development in medicinal chemistry research. Because of their importance, methods to synthesize complex pyridines and piperidines are highly desirable. Chapter one discusses the importance of these scaffolds in the pharmaceutical industry along with the history of pyridine and piperidine synthesis and the challenges that still remain. Chapter two discusses the switching strategies for selective installation of phosphonium salts on polyazines. The methods include an acylation, base-mediate, phosphine mediate, and order-of-reagent addition strategies. Additionally, we demonstrate how these methods can be applied to medicinal chemistry research during structure-activity relationship studies by derivatizing the phosphonium salts. Chapter three presents a new strategy for selective pyridine alkylation at the 4-position of the pyridine ring. Using a triazine chloride activating group allows for 4-selective phosphonium ylide formation inside the pyridine ring. A Wittig olefination-rearomatization sequence with an aldehyde then furnishes the alkylated pyridine. This method offers an alternative strategy to conventionally used metal-catalyzed cross coupling and Minisci-type reactions. Chapter four describes a stepwise reduction method for the synthesis of dihydropyridine and tetrahydropyridine. Using N-Tf activation allows for a selective hydride reduction to the dihydropyridine, which can subsequently undergo hydrogenation to the tetrahydropyridine.
Open Access
Phosphorus ligand-coupling reactions for the functionalization of pyridine and other azines
(Colorado State University. Libraries, 2021) Nottingham, Kyle G., author; McNally, Andrew, advisor; Paton, Robert, committee member; Henry, Chuck, committee member; Cohen, Robert, committee member
Pyridines and related azines are ubiquitous in pharmaceuticals, agrochemicals, and materials. The discovery and development of new purpose-built molecules is contingent on our ability to modify these motifs. Described herein are the development of methods that selectively functionalize pyridine and diazine scaffolds through phosphorus ligand-coupling. Novel phosphine reagents were designed and leveraged to construct C–C, C–O, and C–N bonds on azines from their C–H precursors. Chapter one introduces the history of phosphorus ligand-coupling and defines the reactivity explored throughout this thesis. Both seminal and contemporary examples of phosphorus ligand-coupling reactions are also discussed to provide context for this work. Chapter two focuses on a method to incorporate fluoroalkyl groups onto azines and pharmaceuticals using phosphorus ligand-coupling. This method offers a complementary alternative to widely used radical addition approaches which often produce regiomeric product mixtures on azines. Chapter three presents the investigation of a phosphorus-mediated alkenylation reaction on pyridines and quinolines. Examination of the reaction of pyridylphosphines with alkyne acceptors uncovered divergent reaction pathways from alkenylphosphonium salts. Mechanistic studies provide an explanation for the origin of selectivity obtained in these reactions. Lastly, chapter four expands upon one of these reaction pathways and describes the development of a method for the direct conversion of pyridines into pyridones and aminopyridines.
Open Access
Regioselective functionalization of pyridines and other azines
(Colorado State University. Libraries, 2021) Boyle, Benjamin T., author; McNally, Andrew, advisor; Chen, Eugene, committee member; Ackerson, Chris, committee member; Montgomery, Tai, committee member
Pyridines and diazines serve as cores in pharmaceuticals and are common motifs in organomaterials and ligands. Selective functionalization of these motifs is of importance for discovery and optimization of new bioactive molecules. Pyridine functionalization is of interest for synthetic chemists, and despite modern advances in derivatization challenges and limitations remain. Chapter one focuses on the impact of pyridines and diazines in the pharmaceutical industry. Classical and modern methods for C-H functionalization are discussed. Chapter two describes work on phosphorus ligand-coupling for bisazine synthesis using a three-stage protocol. This method provides an alternative to traditional metal-catalysis for bisazine synthesis and can be applied to drug-like fragments. This work is expanded on in chapter three by using a tandem SNAr-ligand-coupling strategy for bisazine synthesis, in particular 2,2'-bipyridines. Chapter four describes a facile SNAr reaction by phosphines on iodopyridines. A bis-salt N-phopsphonium pyridinium is the key intermediate and provides a broad scope of reactivity. Chapter five shifts towards functionalization of the 3-position of pyridine through a Zincke-type intermediate. By exploiting a ring-opening-functionlization-rearomatization strategy a selective halogenation of pyridines was achieved. The Zincke imine intermediate is also viable for other functionalizations and provides products directly from the C-H bond on the initial pyridine.
Open Access
Ring-conversion and functionalization of nitrogen-containing heterocycles
(Colorado State University. Libraries, 2024) Josephitis, Celena M., author; McNally, Andrew, advisor; Bandar, Jeff, committee member; Chung, Jean, committee member; Reisfeld, Bradley, committee member
Pyridines and related azines are ubiquitous in pharmaceuticals and agrochemicals development. Chemist rely on the development of new synthetic methods to modify these heterocycles. Described herein are the development of methods to functionalize azines and convert pyridines and diazines into new heterocycles. Novel hydrogenation and molecular editing strategies were designed and leveraged to accomplish this goal. Chapter one introduces the importance of pyridines and related heterocycles in pharmaceuticals as well as methods to access and functionalize these molecules. Both classical and contemporary methods for functionalization and hydrogenation of pyridines are discussed to provide context for this work. Chapter two describes a novel method to selectively reduce pyridines to dihydropyridines, tetrahydropyridines, and piperidines. This method offers a complementary alternative to current hydrogenation or reduction methods, in which the degree of saturation cannot be controlled, and applies to complex azine starting materials. Chapter three explains the importance of structure-activity relationship (SAR) studies and its implications on the drug-discovery process. It also describes classical and contemporary strategies that apply to SAR diversification including de novo heterocycle synthesis and molecular editing strategies. Finally, chapter four presents a novel method for SAR diversification of pyrimidine containing molecules using a deconstruction/reconstruction approach.
Open Access
Selective functionalization of azines via phosphonium salts
(Colorado State University. Libraries, 2020) Koniarczyk, J. Luke, author; McNally, Andrew, advisor; Chen, Eugene, committee member; Barisas, George, committee member; Chatterjee, Delphi, committee member
Pyridines and diazines are ubiquitous in pharmaceuticals, agrochemicals, and materials. Therefore, methods to functionalize these structural motifs are increasingly valuable. We have shown that phosphonium salts can be formed on a range of azines, including complex biologicallyactive compounds. Additionally, these azinyl phosphonium salts serve as a general functional handle to facilitate a variety of bond formations. Chapter 2 focuses on a method to incorporate deuterium and tritium atoms onto azines and pharmaceuticals using azinyl phosphonium salts. Deuteration is commonly used as a means to deter unwanted oxidative metabolism on drugs, and tritium is installed as a radiolabel for metabolic studies in the pharmaceutical industry. The protocol of the reaction is simple, and it functions on a wide range of building blocks and complex molecules. Additionally, the tritiation protocol was effectively applied on a selection of drug molecules through a collaborative effort with Merck. In chapter 3, a pyridine-pyridine coupling reaction is discussed using azinyl phosphonium salts as radical precursors. The reaction functions through a radical-radical coupling mechanism using B2pin2 and 4-cyanopyridine as an electron-transfer reagent for reduction of the phosphonium salt. Azinyl phosphonium salts were found to be the only radical precursor amenable to the reaction, and the process functions as an alternative to the Minisci reaction to form bipyridine products.
Open Access
Selective functionalization of pyridines and diazines via nucleophilic addition to heterocyclic phosphonium salts
(Colorado State University. Libraries, 2018) Anderson, Ryan Gerald, author; McNally, Andrew, advisor; Paton, Robert S., committee member; Chatterjee, Delphi, committee member
Nitrogen heterocycles, specifically pyridines and pyrimidines, are common motifs found in pharmaceuticals, agrochemicals and materials. Site-selective functionalization of these azines are highly sought after for medicinal chemistry purposes. It has previously been found in our lab that heterocyclic phosphonium salts can potentially serve as a useful functional handle to selectively functionalize these valuable scaffolds. This work describes the utility of heterocyclic phosphonium salts as electrophiles to selectively form C-O, C-S, C-N and C-Se bonds in a diverse range of pyridines and diazines. First, the addition of thiolate nucleophiles to heterocyclic phosphonium salts to selectively form heteroaryl thioethers is described. This coupling reaction proceeds through deprotonation of the alkyl thiol followed by addition of the heterocyclic phosphonium salt under mild conditions. The reaction scope was tested for a variety of alkyl thiol nucleophiles as well as different pyridine phosphonium salts. The extent of the method's utility was demonstrated through late-stage functionalization of some complex pharmaceuticals. Additionally, initial results on the reactivity of sulfinate nucleophiles with heterocyclic phosphonium salts is communicated. Second, aromatic heteronucleophiles were explored for reactivity with heterocyclic phosphonium salts. Aromatic heteronucleophiles can be classified as either exocyclic or endocyclic. Exocyclic aromatic heteronucleophiles, such as phenols, thiophenols and anilines, were able to be selectively coupled to azines and pharmaceuticals. Endocyclic aromatic heteronucleophiles, such as pyrroles, pyrazoles and imidazoles, also proved to be compatible. All these nucleophiles were able to be coupled to complex drug-like fragments as well as other bioactive molecules via the phosphonium ion. The method also enabled a convergent coupling reaction between two elaborate coupling partners to form a novel tyrosine kinase inhibitor that would be difficult to access using conventional methods.
Open Access
Selective halogenation of pyridines and diazines via unconventional intermediates
(Colorado State University. Libraries, 2022) Levy, Jeffrey N., author; McNally, Andrew, advisor; Bandar, Jeffrey, committee member; Neilson, Jamie, committee member; Hansen, Jeffrey, committee member
Pyridines and diazines are prevalent in pharmaceuticals, agrochemicals, ligands, and other organic materials, and it's vital that synthetic chemists can selectively functionalize these heterocycles. We have shown that heterocyclic phosphonium salts and Zincke imine intermediates can be used to regioselectively functionalize pyridine rings. This dissertation describes the development of these strategies with an emphasis on new approaches to selectively halogenate pyridines, which we view as a long-standing challenge in organic chemistry. Chapter One introduces the importance of pyridines and diazines, as well as established methods and limitations in halogenating these azines. Chapter Two provides an overview of the synthesis and reactivity of heterocyclic phosphonium salts, and then describes a new strategy to access 4-halogenated pyridines via these reagents. Chapter Three examines further developments of heterocyclic phosphonium salts, including as how they can be used to selectively add amines and fluoroalkyl substituents to pyridines. Chapter Four provides an overview of pyridine ring-opening reactions and then shows how this approach can be applied to selectively halogenate the 3-position of pyridines. Chapter Five describes how modifications to the ring-opening strategy can be used to change halogenation site-selectivity. This chapter also shows that the ring-opened intermediates can be used to form isotopically labeled pyridines and aniline derivatives.
Open Access
Site-selective functionalization of azines and polyazines via heterocyclic phosphonium salts
(Colorado State University. Libraries, 2020) Dolewski, Ryan D., author; McNally, Andrew, advisor; Paton, Robert, committee member; Henry, Chuck, committee member; Kanatous, Shane, committee member
Pyridine and diazines are frequently found in FDA approved drugs, biologically active compounds, agrochemicals, and materials. Given the importance of these structural motifs, direct methods that selectively functionalize pyridine and diazine scaffolds have been developed. These methods and their associated challenges are discussed in chapter one. In chapter two, a strategy to directly and selectively functionalize pyridines and diazines via heterocyclic phosphonium salts is presented. The process is broadly applicable for pyridines and diazines and the late-stage functionalization of pharmaceuticals. Four reaction manifolds are amenable to transforming heterocyclic phosphonium salts into valuable derivatives. In chapter three, inherent factors that control site-selectivity in polyazine systems are described along with mechanistically driven approaches for site-selective switching, where the phosphonium ion can be predictably installed at other positions in a polyazine system. The fourth chapter focuses on a new strategy to selectively alkylate pyridines via a traceless dearomatized phosphonium salt intermediate. Preliminary studies show this protocol is amenable to building-block pyridines, drug-like fragments and pharmaceuticals. A late-stage methylation strategy is also presented.
Embargo
Site-selective pyridine functionalization via nucleophilic additions to activated pyridiniums
(Colorado State University. Libraries, 2024) Nguyen, Hillary M. H., author; McNally, Andrew, advisor; Bandar, Jeff, committee member; Chung, Jean, committee member; Shoemaker, Mark, committee member
Pyridines and diazines are important heterocycles commonly found in pharmaceuticals, agrochemicals, ligands, and various other organic molecules. Pyridines existing in these molecules usually have multiple bonds connected to them that contribute to their reactivity and characteristics. Therefore, there are ongoing efforts l to find new methods to functionalize these heterocycles. Our lab has contributed to this field by developing methods to functionalize pyridines directly from the C–H bond through phosphonium salts or Zincke imines. Chapter One gives an overview of the current methods for pyridine functionalization and their limitations. Chapter Two describes the synthesis of N-Tf Zincke imines and their use for regioselective 3-position pyridine functionalization. Bipyridines and pyridine-piperidine coupled products are accessed through this method. Chapter Three discusses using N-Tf Zincke imines to form 15N pyridines and coupled with deuteration forms higher mass isotopologues. Chapter Four describes the formation of N-alkyl pyridinium salts from N-Tf Zincke imines. This chapter focuses on optimizing the ring-opening of 2-ester pyridines and ring-closing them with amino esters to access pipecolic esters for macrocyclization. Chapter Five highlights direct nucleophile additions to the 4-position of N-Tf pyridinium salts for pyridine functionalization. 4-aminated pyridines are formed with both aliphatic amines and anilines from the C–H bond. The regioselectivity of this amination is controlled by the basicity of the reaction. In addition, 4-NH2 pyridines are achieved through this method by adding benzophenone imine, an ammonia surrogate. This reaction extends to adding in heteroatom nucleophiles including alcohols, thioesters, amides, and sulfonamides.
Open Access
Understanding selectivity in organic reactions through density functional theory
(Colorado State University. Libraries, 2024) de Lescure, Louis Raymond Philibert, author; Paton, Robert, advisor; McNally, Andrew, advisor; Bandar, Jeffrey, committee member; Kennan, Alan, committee member; Herrera-Alonso, Margarita, committee member
The success of chemical reactions is often expressed through the lens of selectivity, defined as the preference for a desired reaction pathway over an undesirable one. A profound understanding of the rationale behind the selectivity of chemical reactions is crucial for the progression of synthetic methodologies in organic chemistry. Utilizing quantum chemical approximations, density functional theory (DFT) calculations offer unparalleled insights into the electronic structures and mechanisms of reactions, which can be correlated with observed empirical selectivities. This dissertation demonstrates the significant utility of DFT, in tandem with experimental evidence, in elucidating the intricate mechanisms of reactions. Chapter 1 defines the thematic and methods used throughout this thesis. Chapters 2 and 3 detail collaborative work with the McNally group at Colorado State University. Here, we developed innovative methods for the halogenation of pyridines and advanced modifications of pyrimidine rings utilizing redesigned Zincke chemistry. This chapter focuses on the factors influencing the regioselectivity of halogenation processes and provides mechanistic insights into the formation of crucial intermediates. Chapter 3 outlines a joint project with the Race group at the University of Minnesota, where we explored the homologation of benzylic carbon-bromide bonds. Our investigations centered on the ring-opening of phenonium intermediates, a critical step in determining the success of the reaction. Chapter 4 presents a collaboration with the Aggarwal group at the University of Bristol. This chapter examines the nuanced interplay between kinetic and thermodynamic factors that govern the enantioselectivity of the reaction discussed. This comprehensive study underscores the integration of theoretical and experimental approaches in advancing our understanding of complex chemical reactions.

Browsing by Author "McNally, Andrew, advisor"

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