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Synthesis

Cross-Coupling Fluorinations Ramp Up

Chemists devise several new ways to prepare difluoroalkylarenes, which are important in medicinal chemistry

by Stephen K. Ritter
October 13, 2014 | A version of this story appeared in Volume 92, Issue 41

As organic chemists have continued to advance catalytic cross-coupling reactions in recent years, one of the biggest beneficiaries has been fluorinations. Incorporating fluorine into organic compounds has traditionally required hazardous stoichiometric reagents, but the new methods are ushering in gentler approaches. In one example, Xingang Zhang and coworkers of Shanghai Institute of Organic Chemistry have developed nickel- and palladium-catalyzed cross-coupling reactions between functionalized difluoromethylhalides and aryl boronic acids to make aryldifluoromethyl phosphonate, aryldifluoroacetic acid, and aryldifluoromethane derivatives (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201309535 and 10.1002/anie.201405653). In another example, John F. Hartwig and coworkers of the University of California, Berkeley, have reported palladium-catalyzed cross-couplings of difluoroketones with aryl and heteroaryl halides and cross-couplings of trimethylsilylacetamides with aryl and heteroaryl bromides to make difluoromethylarenes and aryldifluoroacetamides (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja501117v and 10.1021/ja508590k). These methods provide additional options for preparing building block molecules containing fluorine atoms at the metabolically labile benzylic position that is important for medicinal chemistry.

Two reaction schemes show additon of fluorinated groups.

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