MIRA: C(sp3)-H Heteroatom Incorporation Using Photoexcited Nitroarenes - Project Summary Heteroatom units, such as C(sp3)–OH and C(sp3)–NH2, are prevalent motifs in many pharmaceutically relevant drugs and natural products. Methods to incorporate these important functional groups at the expense of C–H bonds rely on the use of non-commercial heteroatom transfer agents, precious transition metals, and/or costly engineered enzymes. Also, these methods often require harsh exogenous oxidants to promote the C–heteroatom bonding event, which greatly limits substrate scope. In this proposal, we highlight the employment of economical nitroarenes as versatile reagents that can serve as the C(sp3)–H bond activator and the oxygen atom source for the C–H hydroxylation of aliphatic systems under benign visible-light irradiation. Notably, the heteroatom transfer event occurs anaerobically, thereby allowing for significant expansion of substrate scope compared to previous state-of-the-art methods. Asymmetric C–H hydroxylation protocols can be achieved with the use of recyclable photoexcited nitroarene atropisomers, leading to a sustainable approach for the late-stage installation of chiral alcohol groups. The development of a universal platform for C–H heteroatom incorporation of aliphatic systems can be engendered under this reaction paradigm via a formal polar crossover event and coupling with nucleophiles. The merger of chiral H-bond donor catalysts or chiral phosphoric acid catalysts to this approach can enable a general platform for asymmetric heteroatom incorporation directly from C–H bonds without the need for a leaving group, which is an underdeveloped area in synthesis. For C–N bond formation, chemoselective transfer of the nitrogen atom from the nitroarene moiety to aliphatic systems can be achieved under photoirradiation empowering facile formation of imines directly from methylene units. In-situ hydrogenation of the formed imine products generates amines formally from C–H bonds; thus, resulting in a C–H amination event from the multi-fold reactivity of photoexcited nitroarenes. The synthetic utility of the proposed protocols illustrates that late-stage C–H heteroatom incorporation events promoted by photoexcited nitroarenes can provide a cost-effective means for the synthesis of complex molecular scaffolds. Overall, novel C–H heteroatom events can be achieved in a mild, general, and sustainable manner by exploiting the multifunctional role of photoinduced nitroarenes. It is anticipated that photoexcited nitroarenes will serve as useful tools for the anaerobic heteroatom incorporation of organic molecules.
