I. Reaction mining—a next-generation platform for reaction discovery II. Rapid, anhydrous, homogenous Suzuki-Miyaura cross-coupling of aryl and alkylboronates

Bock, Matthew Joseph

Permalink

https://hdl.handle.net/2142/132759 Copy

Description

Title

I. Reaction mining—a next-generation platform for reaction discovery II. Rapid, anhydrous, homogenous Suzuki-Miyaura cross-coupling of aryl and alkylboronates

Author(s)

Bock, Matthew Joseph

Issue Date

2025-11-17

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

• Denmark, Scott E
• Sarlah, David

Doctoral Committee Chair(s)

• Denmark, Scott E
• Sarlah, David

Committee Member(s)

• Chan, Jefferson
• Mirica, Liviu

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• High-Throughput Experimentation
• Reaction Discovery
• Cross-Coupling
• Miyaura Borylation
• Suzuki-Miyaura
• Transmetalation

Abstract

Herein, this work informs two distinct areas of research and development on: (1) a reaction discovery platform enabled by the merger of high-throughput experimentation (HTE) and data science, and (2) preparative methods for aryl-aryl and B-alkyl Suzuki-Miyaura cross-coupling of boronic esters and boronates. Chapter 1 describes previous efforts by Sarlah and Shved to accelerate the reaction discovery process with the combination of data science, HTE, and artificial isotope distributions. A workflow was subsequently designed with this strategy and showcased with a multimetallic catalyst screen, resulting in the discovery of a few new reactions. Chapter 2 provides an overview of the Suzuki-Miyaura reaction, with a focus on studies pertaining to its mechanism and its B-alkyl variant. This section includes a description of the pioneering reports by Denmark, where a tremendous rate enhancement was observed for the anhydrous Suzuki-Miyaura cross-coupling of neopentyldiol arylboronic esters with a soluble base, potassium trimethylsilanolate (TMSOK). However, the commercial availability of these organoboron species is poor, rendering the method inaccessible for most practitioners. To address this limitation, in Chapter 3, a rapid one-pot Miyaura borylation/Suzuki-Miyaura cross-coupling of aryl halides that leverages commercially available bis(neopentylglycolato)diboron is described. The TMSOK-promoted cross-coupling conditions reported by Denmark were found to be also applicable to alkylboronic esters, facilitating the discovery of a rapid B-alkyl Suzuki-Miyaura cross-coupling of primary alkylboronic esters, However, the extension of this method to secondary alkylboronic esters resulted in failure, owing to significant protodehalogenation. Mechanistic studies aimed at identifying the origin of this unproductive side reaction revealed that the boronic ester itself was surprisingly the predominant hydride source. After a survey of boronic esters, in collaboration with the Burke lab, tetramethyl N-methyliminodiacetic boronates (BTIDA) were identified as a precursor to a highly reactive boronate species, mitigating protodehalogenation while affording rapid cross-coupling. Compared to previous methods, this advance demonstrates unparalleled generality for both aryl halide and organoboron reaction partners. To highlight this feature, the development of an HTE-informed substrate scope is shown. Moreover, the reaction is highly stereospecific, proceeding with either retention or inversion of configuration depending on the choice of ligand and substrate. Lastly, the identity of the unknown boronate has been determined through structural studies, suggesting RB(OTMS)3 as a likely candidate.

Graduation Semester

2025-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/132759

Copyright and License Information

Copyright 2025 Matthew Bock

Owning Collections