Laurie Smith

Copper-Mediated Fluorination of Aryl Iodides

Blog Post created by Laurie Smith on Oct 8, 2012

Patrick S. Fier and John F. Hartwig

University of California

Journal of the American Chemical Society, 2012, 134, 10795-10798.

Highlight by: Jiang Wang, Shanghai Institute of Materia Medica

 

This report describes an operationally simple and high-yielding route to synthesize fluorine-substituted aromatic rings, providing access to molecules that could impact agrochemistry, medicinal chemistry, and other fields. Starting with iodine-substituted aryl rings, the researchers apply a combination of the copper complex ((tBuCN)2CuOTf) and AgF for the synthesize aryl fluoride. Sensitive functional groups, including esters, amides, aldehydes, ketones, and indole heterocycles are stable under the reaction conditions. The researchers also proposed the mechanism of this reaction, as the authors pointed out, “We propose that this reaction occurs by oxidative addition to form a Cu(III) intermediate and C−F reductive elimination from an arylcopper(III) fluoride.

 

Modern fluorine-organic chemistry has dramatically widened the synthetic repertoire for the specific introduction of fluorine into organic molecules. This work improved the method for last-stage aromatic fluorination, so it is very important for diversification in agrochemistry, medicinal chemistry, and other fields. Fluorinated compounds comprise a substantial proportion in the agrochemicals and therapeutic drugs. It is an important strategy to introduce fluorine and fluorinated substitutes in the small molecule for structure-based medicinal chemistry. Fluorine can modulate the physicochemical and pharmacokinetic properties to improve bioavailability, alter the conformation of a molecule to enhance the selectivities and binding affinity to target proteins, and block metabolically labile sites to increase the metabolic stability of drugs. Hartwig and Fier’s new method to a wide range of aryl fluorides may provide a straightforward way of synthesizing new molecules containing fluorine. The wider range of accessible fluorinated compounds will, in turn, allow for further applications in agrochemistry and medicinal chemistry will emerge.

 

Recommended reading:

- C-F Bond Formation in organic synthesis:  (a) “Palladium-catalyzed allylic fluorination.” Hollingworth, C.; Hazari, A.; Hopkinson, M. N.; Tredwell, M.; Benedetto, E.; Huiban, M.; Gee, A. D.; Brown, J. M.; Gouverneur, V., Angew. Chem., Int. Ed. Engl. 2011, 50, 2613-2617. (b) “Silver-catalyzed late-stage fluorination.” Tang, P.; Furuya, T.; Ritter, T., J. Am. Chem. Soc. 2010, 132, 12150-12154.

- Fluorine in medicinal chemistry: (a) “Fluorine in pharmaceuticals: Looking beyond intuition” Müller, K.; Faeh, C.; Diederich, F., Science 2007, 317, 1881-1886. (b) “Fluorine in medicinal chemistry”  Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V., Chem. Soc. Rev. 2008, 37, 320-330. (c) “Fluorine in Medicinal Chemistry” Böhm, H.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, Martin. Chem. Bio. Chem. 2004, 5, 637-643.

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