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Engaging α‑Fluorocarboxylic Acids Directly in Decarboxylative C–C Bond Formation

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journal contribution
posted on 26.03.2020, 11:42 by Hongyu Wang, Chen-Fei Liu, Zhihui Song, Mingbin Yuan, Yee Ann Ho, Osvaldo Gutierrez, Ming Joo Koh
Fluorine-containing organic molecules, particularly those that bear (sp3)­C–F bonds, are rapidly gaining prominence in modern chemical synthesis. Although extensive studies have been devoted to the preparation of secondary and tertiary fluorides, crucial shortcomings remain: for example, lengthy substrate synthesis, contrived installation of difficult-to-remove directing/activating units, excessive waste generation and/or limited functional group compatibility. Here, we show that readily accessible α-monofluoro carboxylic acids, which are conventionally difficult substrates for cross-coupling, undergo direct decarboxylative cross-coupling with sp2- and sp3-hybridized organohalides to afford a wide assortment of fluorinated products. Reactions are typically promoted by a combination of 1 mol % of an Ir-based photocatalyst and 2–15 mol % of a bipyridine–Ni complex, delivering products in up to 86% yield under blue LED light irradiation. Concise synthesis of key therapeutic candidates underscores utility, complementarity, and distinct advantages compared with existing methods. DFT calculations are used to rationalize the distinct reactivity of α-fluoro carboxylic acid substrates (vs nonfluorinated parent acids) under decarboxylation conditions.