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A Ritter-type Reaction: Direct Electrophilic Trifluoromethylation At Nitrogen Atoms Using Hypervalent Iodine Reagents.

Katrin Niedermann, N. Frueh, E. Vinogradova, Matthias S. Wiehn, A. Moreno, A. Togni
Published 2011 · Chemistry, Medicine

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The unique features the trifluoromethyl group imparts to pharmaceuticals, crop-protection agents, and functional materials emphasize the necessity to design and develop new reagents and methods for the direct trifluoromethylation of a wide range of organic substrates. Electrophilic trifluoromethylation, that is, the reaction of a suitable reagent capable of formally transferring an intact CF3 + unit, has been shown to be one of these methods. However, despite the availability of several such effective reagents, the electrophilic trifluoromethylation of hard nucleophiles, for example, oxygenor nitrogen-centered ones, remains challenging. In particular, the formation of a N CF3 bond by such a reaction is still extremely rare. In fact, the NCF3 unit is usually constructed by the interconversion of suitable functional groups. Thus, fluorination of N-formylamines, thiuram sulfides, isocyanates, and trichloromethylamines, the reaction of secondary amines with CBr2F2 and tetrakis(dimethylamino)ethylene, and the electrochemical fluorination of alkylamines constitute the still relatively modest set of methods. Of these, the most frequently used approach is the oxidative desulfurization–fluorination of dithiocarbamates first described for the generation of NCF3 groups by Hiyama and Kuroboshi. [8] The single, still very recent report of a direct trifluoromethylation at nitrogen is due to Umemoto and co-workers. They describe the direct N-trifluoromethylation of amines, anilines, and pyridines under very mild conditions achieved with in situ generated and thermally unstable O-(trifluoromethyl)dibenzofuranium salts (corresponding reactions of alcohols and phenols are also known). However, this type of reagent suffers from several shortcomings. The active CF3 source is obtained by photochemical decomposition of diazonium salts at very low temperature, and the synthesis requires several steps including the construction of a CF3O–aryl moiety. It is therefore likely that this methodology will not replace the corresponding functional-group interconversions in the near future. We have shown that a new generation of readily accessible trifluoromethylation reagents based on hypervalent iodine, such as compounds 1 and 2 (Scheme 1), display the desired
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