Advances in synthetic methodology: dearomative aminofunctionalization of arenes and high-throughput reaction discovery

Davis, Christopher William

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https://hdl.handle.net/2142/127264 Copy

Description

Title

Advances in synthetic methodology: dearomative aminofunctionalization of arenes and high-throughput reaction discovery

Author(s)

Davis, Christopher William

Issue Date

2024-12-05

Director of Research (if dissertation) or Advisor (if thesis)

Sarlah, David

Doctoral Committee Chair(s)

Sarlah, David

Committee Member(s)

• White, M Christina
• Mirica, Liviu M
• Chan, Jefferson

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• arenes
• dearomatization
• aminofunctionalization
• 1,2-hydroamination
• 1,2-carboamination
• 1,4-hydroamination
• 1,2-diamination
• catalysis
• high-throughput experimentation
• reaction discovery

Abstract

Methodological research and development lies at the heart of synthetic organic chemistry, providing the tools that chemists use to construct organic molecules from pharmaceuticals and agrochemicals to plastics and dyes. Natural product total synthesis, medicinal chemistry, and polymer chemistry each provide an arena in which to test the limits of these tools and reveal potential avenues of progress. Research to discover and develop new modes of chemical reactivity not only advances the field of chemistry but is routinely applied to solve problems in biochemistry and physics. We sought to contribute to this effort first through the development of novel methods for the dearomative functionalization of arenes, and then more broadly through the establishment of a platform for the discovery of chemical reactivity using high-throughput screening. Chapter 1 describes four distinct dearomative functionalization reactions developed using N-methyl-1,2,4-triazoline-3,5-dione (MTAD) as an arenophile, a small molecule which can undergo dearomatizing photochemical [4+2] cycloadditions with a wide range of simple, nonactivated arenes. The resulting cycloadducts can be intercepted using transition-metal catalysis to afford value-added unsaturated products. The novel transformations reported herein are named as formal dearomative aminofunctionalizations since the vestigial arenophile can be cleaved to reveal a primary amine. These reactions include a 1,2-hydroamination, trans-1,2-carboamination, 1,4-hydroamination, and syn-1,2-diamination of abundant aromatic precursors. We uncover and explain unprecedented substrate selectivity through computational studies and showcase the utility of these methods to the broader synthetic community through the rapid synthesis of diversely functionalized and stereochemically rich products. Chapter 2 addresses a more fundamental concern of synthetic methodology—the discovery process itself. By combining modern high-throughput experimentation techniques, automated data processing, and a robust strategy for product identification, we have developed a system for the discovery of novel chemical reactivity. We highlight prior approaches towards this goal, the design and validation of our system, and current discoveries made using the platform. One of the novel reactions observed through these efforts was further developed into a synthetically useful three-component coupling after mechanistic studies identified unproductive reaction pathways. Current limitations and future improvements are discussed as well.

Graduation Semester

2024-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/127264

Copyright and License Information

Copyright 2024 Christopher Davis

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