Chemistry and Chemical Biology ETDs

Publication Date

Summer 7-10-2018

Abstract

This thesis is divided into two parts. The first part focuses on the Cu-catalyzed cross-coupling of organoaluminum reagents with organohalides. One of the most powerful tools for the construction of C-C bonds is cross-coupling. But, this reaction is predominantly catalyzed by Pd, a rare and expensive transition metal, which inevitably makes the process unsustainable in the long-term. Furthermore, Pd-catalyzed cross-coupling also shows low tolerance for alkyl and heteroaryl substrates because of β-hydride elimination and catalyst deactivation, respectively. Although these issues remain largely solved by using sterically hindered and electron-rich ligands, however making these types of ligands is synthetically challenging and often involves multi-step processes. As such, the use of these ligands in large scale productions is also cost-prohibitive. In order to alleviate these problems, we have developed the cross-coupling reaction with Cu, an earth-abundant and inexpensive transition metal. Regarding this, we have been able to discover the Cu-catalyzed coupling of alkyl-, aryl- and alkynylaluminum reagents with organohalides. This Cu-catalyzed cross-coupling does not suffer from β-hydride elimination and no rearrangement is seen when secondary alkylaluminum reagents are used. It also shows tolerance with heteroaromatic substrates. Unexpectedly, no ligand is needed when heteroaryl halides are used for cross-coupling. We have also conducted mechanistic studies through radical clock experiments, competition experiments and kinetic studies, and proposed a catalytic cycle for the Cu-catalyzed coupling of organoaluminum reagents with aryl halides. These mechanistic studies designate that the reaction proceeds through an oxidative addition-reductive elimination pathway.

The second part of this thesis is about the development of Ni-catalyzed regioselective dicarbofunctionalization of olefins in styrene derivatives by intercepting Heck C(sp3)-NiX intermediates with arylzinc reagents. This method utilizes a readily removable imine as a coordinating group that plays a dual role of intercepting oxidative addition species derived from aryl halides and triflates to promote Heck carbometallation, and stabilizing the Heck C(sp3)-NiX intermediates as transient metallacycles to suppress β-hydride elimination and facilitate transmetalation/reductive elimination steps. This approach affords diversely-substituted 1,1,2-triarylethyl products that occur as structural motifs in various natural products and bioactive molecules like cassigarol B, 4-[1-(p-hydroxyphenyl)-2-phenylethyl]phenoxyacetic acid, etc.

Language

English

Keywords

Cross-coupling, Dicarbofunctionalization

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Prof. Ramesh Giri

Second Committee Member

Prof. Richard Kemp

Third Committee Member

Prof. Wei Wang

Fourth Committee Member

Prof. Jeffrey J. Rack

Fifth Committee Member

Dr. Timothy J. Boyle

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