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Advancing the utility of organic superbases in synthetic methodology

Abstract

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.

Description

2023 Summer.
Includes bibliographical references.

Rights Access

Embargo expires: 08/28/2025.

Subject

anti-Markovnikov hydroethrification
organic superbase
anti-Markovnikov hydration
superbase precatalyst
controllable superbase generation

Citation

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