Aryl amination is an essential transformation for medicinal, process, and materials chemistry. In addition to classic Buchwald–Hartwig amination conditions, blue-light-driven metallaphotoredox ...catalysis has emerged as a valuable tool for C–N cross-coupling. However, blue light suffers from low penetration through reaction media, limiting its scalability for industrial purposes. In addition, blue light enhances unwanted side-product formation in metallaphotoredox catalysis, namely hydrodehalogenation. Low-energy light, such as deep red (DR) or near-infrared (NIR), offers a solution to this problem as it can provide enhanced penetration through reaction media as compared to higher-energy wavelengths. Herein, we show that low-energy light can also enhance the desired reactivity in metallaphotoredox catalysis by suppressing unwanted hydrodehalogenation. We hypothesize that the reduced side product is formed by direct photolysis of the aryl–nickel bond by the high-energy light, leading to the generation of aryl radicals. Using deep-red or near-infrared light and an osmium photocatalyst, we demonstrate an enhanced scope of (hetero)aryl bromides and amine-based nucleophiles with minimal formation of hydrodehalogenation byproducts.
State-of-the-art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high-energy light (λ < 500 nm) for substrate ...or photocatalyst sensitization can lead to background activation of photoactive small-molecule probes and reduce its efficacy in complex biological environments. Here we describe the development of targeted aryl azide activation via deep red-light (λ = 660 nm) photoredox catalysis and its use in photocatalysed proximity labelling. We demonstrate that aryl azides are converted to triplet nitrenes via a redox-centric mechanism and show that its spatially localized formation requires both red light and a photocatalyst-targeting modality. This technology was applied in different colon cancer cell systems for targeted protein environment labelling of epithelial cell adhesion molecule (EpCAM). We identified a small subset of proteins with previously known and unknown association to EpCAM, including CDH3, a clinically relevant protein that shares high tumour-selective expression with EpCAM.
Aromatic rings are important molecular components of many pharmaceuticals, agrochemicals, organic materials and natural products, and the development of selective arene functionalization ...transformations has been broadly applied in basic and translational research. Photoredox catalysis is an invaluable synthetic tool for the activation of organic molecules via single electron redox pathways. This synthetic strategy enables the construction of carbon-carbon and carbon-heteroatom bonds with orthogonal reactivity to classical two-electron pathways. An introduction to both topics is provided in the first two chapters.The Nicewicz lab has recently developed a variety of transformations that proceed by reactive cation radical species. These systems rely on the ability of an acridinium photoredox catalyst to promote single electron oxidation of a target organic substrate by photoinduced electron transfer. Noting the importance of aromatic molecules, we sought to develop photoredox-catalyzed chemo- and site- selective arene functionalizations that proceed through arene radical cations. As a result, two general reaction methodologies emerged from our investigations into the reactivity of arene radical cations: selective aromatic carbon-hydrogen (C–H) bond and carbon-oxygen (C–O) bond functionalizations.These photoredox-catalyzed aryl C–H amination and C–H (radio)fluorination reactions feature the use of a nitroxyl radical co-catalyst and oxygen to achieve a net oxidative transformation, which furnishes aryl amines and radiolabeled fluoroarenes with high site- selectivity. A diverse range of arenes were compatible with both transformations and the application of 18F-labeled aromatics to positron emission tomography (PET) imaging was demonstrated. These two projects are covered in Chapters 3 and 5.Photoredox-catalyzed aryl C–O functionalizations occur by a complementary strategy to nucleophilic aromatic substitution (SNAr). The generation of arene radical cations enables an inversion of traditional SNAr selectivities such that electron-rich aromatics are selectively functionalized at an electron-donating C–O bond-containing substituent. This reaction mode enables the synthesis of aryl amines, fluoroarenes, and 18Ffluoroarenes. Additionally, we demonstrate that this reactivity pattern is dependent on the presence of a terminal oxidant, wherein its exclusion promotes selective C–O substitution over C–H functionalization. These two projects are covered in Chapters 4 and 6.
