Date of Award
Doctor of Philosophy (PhD)
Gary A. Molander
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.
Primer, David Neal, "Photoredox Generated Radicals In Csp2-Csp3 Bond Construction" (2017). Publicly Accessible Penn Dissertations. 2537.