orthocat · ortho-Disubstituted Arenes as Orthogonal Organophotocatalysts for Reduction and Cross-Coupling Reactions

Organocatalytic analogues of transition metal catalysts can future-proof organic synthesis against the depletion of metals, improve the sustainability of chemical production, circumvent catalyst deactivation by Lewis-basic motifs, and avoid toxic metal impurities in drugs. Organocatalytic strategies for the reduction of unactivated C=C bonds and the C–C cross-coupling of unactivated halides, which are among the most common transformations in medicinal chemistry, remain difficult to develop with broad scope as oxidative substrate activation requires highly reactive species. Photocatalysis is a potential solution since it can selectively activate even unreactive motifs under mild conditions. Yet, the generated open-shell species are often difficult to control without a metal co-catalyst. EDA complexes, which have emerged as a photocatalyst-free means for light-mediated reactions, in principle, enable selective transformations without a metal co-catalyst by proximity-control within contact ion pairs. In practice, however, such reactions often depend on a fragmentation step that generates free radicals, which are subject to the same limitations as those generated by classical photocatalysis. Project ORTHOCAT aims to achieve selective organophotocatalytic C=C bond reduction and C–C cross-coupling reactions via rearrangement reactions of contact ion pairs derived from EDA complexes with ortho-disubstituted arenes. The key design principle is the bond polarization upon single electron transfer, which enables a nucleophilic substitution step that mimics migratory insertion or reductive elimination steps of transition metal mediated reactions. The successful development of this proposal will establish an orthogonal catalysis strategy, address the pervasive and vexing deactivation of Lewis-acidic metal catalysts in medicinal chemistry, and enable new transformations to sought-after motifs.