The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides

By E. Cho, T. Senecal, T. Kinzel, Yong Zhang, D. Watson, S. Buchwald. Science, 2010

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Three Fluorines at Once The trifluoromethyl (CF3) group is playing an increasingly important role in the design of pharmaceutical and agrochemical compounds. CF3 is a powerful attractor of electron density within a given molecular framework, and recently fluorine-hydrocarbon interactions have emerged as a distinct complement to the more traditional hydrophilic/hydrophobic interplay that governs docking between small molecules and proteins. Cho et al. (p. 1679) now present an efficient method for appending CF3 groups to a broad range of aryl substrates. A carefully optimized palladium catalyst was able to speed up a critical elimination step that has plagued previous efforts to realize a general solution to this synthetic challenge. Careful catalyst tuning enables addition of trifluoromethyl groups to many intermediates in pharmaceutical and agrochemical synthesis. The trifluoromethyl group can dramatically influence the properties of organic molecules, thereby increasing their applicability as pharmaceuticals, agrochemicals, or building blocks for organic materials. Despite the importance of this substituent, no general method exists for its installment onto functionalized aromatic substrates. Current methods either require the use of harsh reaction conditions or suffer from a limited substrate scope. Here we report the palladium-catalyzed trifluoromethylation of aryl chlorides under mild conditions, allowing the transformation of a wide range of substrates, including heterocycles, in excellent yields. The process tolerates functional groups such as esters, amides, ethers, acetals, nitriles, and tertiary amines and, therefore, should be applicable to late-stage modifications of advanced intermediates. We have also prepared all the putative intermediates in the catalytic cycle and demonstrated their viability in the process.

Subfields: Inorganic Chemistry, Pharmaceutical Science

View Paper: https://www.semanticscholar.org/paper/d04a6e7aac500c27c727342d73e7ce7e8aef1fd9

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