Semester

Summer

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Brain Popp

Committee Member

Gregory Dudley

Committee Member

Carsten Milsmann

Committee Member

Margaret Hilton

Committee Member

Benoit Dreisschaert

Abstract

Organoboron compounds are some of the most synthetically versatile compounds in organic chemistry due to the many valuable transformations of the C-B bond. This synthetic versatility combined with the pharmacophoric nature of carboxylic acids has led to an increased interest in the one-pot difunctionalization of vinyl arenes using CO2 and pinacol boranes. Recently, much progress has been made to improve the scope and versatility of boracarboxylation reactions to now include electron-deficient and α-methyl substituted vinyl arenes. However, the potential transformations of boracarboxylated products have remained unexplored. Here, methodologies to transform the β-aryl alkylboronic ester into new C-C, C-N, and C-X bonds will be described.

Medically relevant 2,3-diarylpropionic acids can now be accessed via a two-step protocol consisting of boracarboxylation of a vinyl arene followed by a palladium(0)-catalyzed Suzuki cross-coupling. This methodology provides access to both the α- and β-regioisomers independently whereas traditional strategies to access these compounds afford only one regioisomer, and in most cases, a mixture of regioisomers. Interesting biaryl and heterocyclic products can be accessed and to demonstrate the synthetic utility of this protocol, a glucagon receptor antagonist was synthesized in 4 less steps than the previously reported method while maintaining similar yields.

The transformative capability of boracarboxylated products is further demonstrated through a base- and external oxidant-free copper(II)-catalyzed amination to generate β2-amino acid derivatives. While the β-carboxylic acid was intolerable to the conditions, protection via esterification or amidation allowed for successful amination of the alkylboronic ester to occur. Amination of two bora-NSAIDs, bora-ibuprofen and bora-naproxen, was successful and a number of cyclic and acyclic amines are suitable for the transformation. Preliminary mechanistic work suggests that this amination does not proceed through a free-radical intermediate but rather a two-electron pathway.

Finally, a novel halogenation of boracarboxylated products is achieved to generate the corresponding β-aryl alkyl halides. This methodology is performed in a base, metal, and additive free manner that utilizes cheap and readily available sources of electrophilic halide. Both bromination and iodination are demonstrated and can be achieved on a variety of electron-rich and electron-poor boracarboxylated products and can subsequently undergo amination to provide an alternative route to β2-amino acid derivatives. Mechanistic experiments suggest that the β-carboxylic acid is required to achieve the activation of the C-B bond. Radical trapping experiments also indicate that this transformation may occur through the formation of an alkyl radical although this is unlikely.

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