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20.1 Minisci-Type Radical Addition to Hetarenes

DOI: 10.1055/sos-SD-229-00341

DiRocco, D. A.; Schultz, D. M.Science of Synthesis: Photocatalysis in Organic Synthesis, (20181611.

The Minisci reaction, one of the original forms of CH functionalization dating back to the early 1900s, is defined as the addition of alkyl radicals to heteroaromatic systems. However, despite the potential utility of this reaction, its application in the pharmaceutical industry has been hampered by low yields and limited functional group compatibility due to the use of excess oxidant, acid, and elevated reaction temperatures. Through the use of visible-light photocatalysis, the scope and yields of the Minisci reaction have been greatly enhanced. Specifically, visible-light photocatalysis allows the alkyl radicals to be generated in a mild and controlled fashion, greatly improving the overall yields of these transformations and the diversity of radical precursors. As a result, the pharmaceutical industry has begun adapting and developing Minisci-type alkyl radical additions to hetarenes as a tool for late-stage functionalization of complex drug-like molecules to quickly probe biological targets. Moreover, while the first reports of this chemistry utilized iridium-based photocatalysts for radical generation, considerations regarding sustainability and potential cost of scale-up have been addressed through the development of non-precious metal and organic photocatalysts that exhibit similar reactivity profiles.