University of Illinois Urbana-Champaign

I. Anhydrous Suzuki-Miyaura cross-coupling of boronic esters enabled by potassium trimethylsilanolate II. investigations into the atropselective n-arylation of benzimidazoles utilizing the Chan-Evans-Lam coupling

Kassel, Vincent Michael

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https://hdl.handle.net/2142/121226

Description

Title
I. Anhydrous Suzuki-Miyaura cross-coupling of boronic esters enabled by potassium trimethylsilanolate II. investigations into the atropselective n-arylation of benzimidazoles utilizing the Chan-Evans-Lam coupling
Author(s)
Kassel, Vincent Michael
Issue Date
2023-07-12
Director of Research (if dissertation) or Advisor (if thesis)
Denmark, Scott E
Doctoral Committee Chair(s)
Denmark, Scott E
Committee Member(s)
  • Sarlah, David
  • Mehta, Angad P
  • Miricia, Liviu M
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
  • Cross-Coupling
  • Suzuki-Miyaura
  • Chan-Evans-Lam
  • Palladium
  • Transmetalation
Abstract
The body of work described herein outlines preparative advances in Suzuki-Miyaura cross-coupling inspired by earlier mechanistic findings from this laboratory. Mechanistic work by the prior authors successfully characterized pre-transmetalation intermediates in the Suzuki-Miyaura cross-coupling reaction for both boronic acid and boronic ester coupling partners. Two salient observations from these prior results that are relevant to the findings shown here are: (1) boronic esters were shown unambiguously to undergo transmetalation without prior hydrolysis, and (2) some boronic esters were identified to transmetalate significantly faster than their parent boronic acids. The former point is significant for having established a proof-of-concept for the work in this thesis. The latter is significant for providing the impetus to explore the work described herein, as the prospect of leveraging rate enhancements for a turnover-limiting step was exciting. Chapter 1 provides an historical perspective of the Suzuki-Miyaura cross-coupling reaction, as well as modern developments. A discussion of the prior mechanistic work from this laboratory is also included. Chapter 2 outlines the development of a preparative method leveraging the previous mechanistic findings from this laboratory, wherein potassium trimethylsilanolate (TMSOK) was identified as an active soluble base in the Suzuki-Miyaura cross-coupling of boronic esters. The base allows for anhydrous reaction conditions which preclude boronic ester hydrolysis and lead to preparative rate enhancements, as evidenced by the rapid rate of coupling. The overall findings establish boronic ester identity as a novel parameter for Suzuki-Miyaura reaction optimization. Chapter 3 details further advances in the TMSOK-promoted reaction to accommodate refractory heteroaryl-heteroaryl coupling partners. A limitation of the first-generation coupling was the inability to cross-couple many types of heteroaryl nucleophiles and electrophiles. The identification of trimethyl borate as a beneficial reaction additive to overcome this limitation is described. Chapter 4 discusses the investigation of an atropselective Chan-Evans-Lam (CEL) coupling. This project was initiated to explore whether the transmetalation rate enhancements leveraged with palladium could be translated to copper. A novel method for hindered benzimidazole N-arylation is described, with 4-dimethylaminopyridine (DMAP) as an additive being required for high product conversion.
Graduation Semester
2023-08
Type of Resource
Thesis
Copyright and License Information
Copyright 2023 Vincent Kassel

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