Chemistry and Chemical Biology ETDs

Publication Date

Spring 5-12-2018

Abstract

Cross-coupling reactions are exceptionally powerful tools to construct carbon-carbon (C-C) bonds. These reactions are widely used to synthesize natural products, polymers, agrochemical, organic materials and pharmaceutical compounds. However, these reactions are typically catalyzed by Palladium. Although these reactions are widely utilized and well developed, the use of noble metals like Pd raises a question about its long-term sustainability. We believe copper can be one of the best alternatives to palladium as it is more abundant, less expensive and less toxic. In addition, Pd-catalyzed transformations usually suffer from β-hydride elimination to afford undesired olefin and rearranged products, when it comes to the coupling of alkylorganometallic reagents bearing β-hydrogen.

In this respect, we have so far developed Cu-catalyzed cross-couplings of organometallic reagents of B, Si, In, Zr and Zn with alkyl, aryl, and heteroaryl halides. Our results show that copper is less likely to suffer from β-hydride elimination and tolerates heteroaryl halides very effectively. We discovered that CuI-salts with and without ligands are efficient catalysts for the coupling of alkylorganometallic reagents of In and Zn with electron-deficient aryl iodides and heteroaryl halides. Primary alkylorganometallic reagents afford coupled products in good to excellent yields. Reactions of secondary alkylindium and alkylzinc, and tertiary alkylzinc reagents proceeded without complications from β-hydride elimination and afforded products without rearrangement. This property of Cu also enabled us to develop tandem cyclization-coupling of olefin-tethered organozinc reagents that possess β-hydrogens. This reaction enabled us to synthesize complex carbo- and N/O-heterocycles that are found as privileged motifs in a wide variety of pharmaceuticals and natural products. In addition, the unique reactivity of Cu-catalysts allows ‘ligandless’ cross-couplings for aryl-heteroaryl and heteroaryl-heteroaryl bond formation.

We were also able to synthesize and characterize different ligated CuI-complexes and show their reactivity towards aryl iodides. Our investigation also helped to understand the underlying mechanism of CuI-catalyzed coupling reactions, and these studies suggest that the Cu-catalyzed couplings with organosilicon, organoboron, organoindium and organozirconium reagents are less likely to involve any free radicals. In addition, our investigation revealed that the transmetallation with the neutral arylboronate ester was a two-step process that proceeded via the formation of a cation-anion pair complex.

Language

English

Keywords

Copper, Cross-couplings, Tandem-couplings, Organozinc, β-Hydride elimination, Heterocycles

Document Type

Dissertation

Degree Name

Chemistry and Chemical Biology

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Prof. Ramesh Giri

Second Committee Member

Prof. Richard A. Kemp

Third Committee Member

Prof. Yang Qin

Fourth Committee Member

Prof. Plamen Atanassov

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