Photoredox Generated Radicals In Csp2-Csp3 Bond Construction

The routine application of Csp3-hybridized nucleophiles in cross-coupling has been an\nongoing pursuit in the agrochemical, pharmaceutical, and materials science industries for over 40\nyears. Unfortunately, despite numerous attempts to circumvent the problems associated with alkyl\nnucleophiles, application of these reagents in transition metal-catalyzed C-C bond-forming\nreactions has remained largely restricted. In recent years, many chemists have noted the lack of\nreliable, turnkey reactions that exist for the installation of Csp3-hybridized centers - reactions that\nwould be useful for delivering molecules with enhanced three-dimensional topology and altered\nchemical properties. As such, a general method for alkyl nucleophile activation in cross-coupling\nwould offer access to a host of compounds inaccessible by other means.\nFrom a mechanistic standpoint, the continued failure of alkylmetallics is inherent to the high energy\nintermediates associated with a traditional transmetalation. To overcome this problem, we\nhave pioneered an alternate, single-electron pathway involving 1) initial oxidation of an\nalkylmetallic reagent, 2) oxidative alkyl radical capture at a metal center, and 3) subsequent\nreduction of the metal center to return its initial oxidation state. This series of steps constitutes a\nformal transmetalation that avoids the energy-demanding steps that plague a traditional anionic\napproach. Under this enabling paradigm, a host of alkyl precursors (alkyl-trifluoroborates and -\nsilicates) have been generally used in cross-coupling for the first time.\nIn summary, the synergistic use of an Ir photoredox catalyst and a Ni cross-coupling catalyst\nto mediate the cross-coupling of (hetero)aryl bromides with diverse alkyl radical precursors will be\ndiscussed. Methods for coupling various trifluoroborate classes (α-alkoxy, α-trifluoromethyl,\nsecondary and tertiary alkyl) will be covered, focusing on their complementarity to traditional\nprotocols. Finally, a discussion of novel silicate radical precursors and their advantages in a single-electron\ntransmetalation regime will be included.