Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Gary A. Molander

Abstract

The routine application of Csp3-hybridized nucleophiles in cross-coupling has been an

ongoing pursuit in the agrochemical, pharmaceutical, and materials science industries for over 40

years. Unfortunately, despite numerous attempts to circumvent the problems associated with alkyl

nucleophiles, application of these reagents in transition metal-catalyzed C-C bond-forming

reactions has remained largely restricted. In recent years, many chemists have noted the lack of

reliable, turnkey reactions that exist for the installation of Csp3-hybridized centers - reactions that

would be useful for delivering molecules with enhanced three-dimensional topology and altered

chemical properties. As such, a general method for alkyl nucleophile activation in cross-coupling

would offer access to a host of compounds inaccessible by other means.

From a mechanistic standpoint, the continued failure of alkylmetallics is inherent to the high energy

intermediates associated with a traditional transmetalation. To overcome this problem, we

have pioneered an alternate, single-electron pathway involving 1) initial oxidation of an

alkylmetallic reagent, 2) oxidative alkyl radical capture at a metal center, and 3) subsequent

reduction of the metal center to return its initial oxidation state. This series of steps constitutes a

formal transmetalation that avoids the energy-demanding steps that plague a traditional anionic

approach. Under this enabling paradigm, a host of alkyl precursors (alkyl-trifluoroborates and -

silicates) have been generally used in cross-coupling for the first time.

In summary, the synergistic use of an Ir photoredox catalyst and a Ni cross-coupling catalyst

to mediate the cross-coupling of (hetero)aryl bromides with diverse alkyl radical precursors will be

discussed. Methods for coupling various trifluoroborate classes (α-alkoxy, α-trifluoromethyl,

secondary and tertiary alkyl) will be covered, focusing on their complementarity to traditional

protocols. Finally, a discussion of novel silicate radical precursors and their advantages in a single-electron

transmetalation regime will be included.

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