Trifluoromethylation DOI: 10.1002/anie.201107414 Ortho-Trifluoromethylation of Functionalized Aromatic Triazenes** Andreas Hafner and Stefan Bräse* Fluorine containing organic agents play a crucial role in the search for new active pharmaceutical and agrochemical compounds. Owing to their fluorine moieties, these com- pounds have unique chemical and physical properties. For example, they can increase the metabolic stability or the lipophilicity, which can enhance the biological activity of a drug. [1] For these reasons, the CF 3 group is an essential moiety of numerous commercially available aromatic and non-aromatic biological active agents. Therefore, the research on new synthetic routes for introducing this group to aromatic systems is an important field of modern organic chemistry. Over the last years, numerous synthetic examples for the direct trifluoromethylation of aromatic compounds were developed. Most of these routes are based on aromatic halides (mainly iodides), which are converted into the corresponding trifluoromethylated compound using a transi- tion metal (Cu or Pd) and (trifluoromethyl)trimethylsilane (“Ruppert–Prakash reagent”). [2,3] The substitution of aro- matic boronic acids is also known. [4] In contrast to these routes, the direct trifluoromethylation by C ÀH substitution has hardly been investigated. To date, this kind of reaction succeeds only with electrophilic CF 3 reagents [5] or on a few heteroaromatic compounds. [6] Recently, independently of our work, Sanford et al. reported a new trifluoromethylation reaction by C À H substitution. However, the synthetic application is limited, because an excess of the required aromatic compound is needed and only a low regioselectivity is achieved. [7] For years, our group has been working on triazenes [8] and their application in solid-phase synthesis, as well as the investigation of new efficient cleavage reactions of tria- zenes. [9] Starting from commercially available aromatic ani- line derivatives, a variety of functionalized aromatic triazenes are accessible by a simple one-step procedure. [9] Note that the toxicity of triazenes can be significantly reduced by using diisopropyl-substituted triazenes. [10] During our investigation for a new cleavage method for triazenes in the presence of Ag 2 CO 3 , KF, and TMS-CF 3 we did not obtain the desired product but the ortho-trifluoromethy- lated triazene 2a in 31 % yield. This reaction probably occurred via in situ generated AgCF 3 . [11] By optimizing the reaction conditions we were able to increase the yield to up to 64%. In this case, a second substitution was observed which led to the di-ortho-substituted triazene 3a in 32 % yield (Scheme 1). In addition to our preferred solvent perfluorohexane, the reaction could be also performed in acetonitrile, but gave lower yields (48 %, 60 8C, 16 h). Furthermore, when higher temperatures (100 8C) were applied in acetonitrile, byprod- ucts were obtained, through the formation of difluorocarbene. This result indicates the in situ generation of AgCF 3 . Changing the solvent to dichloroethane, which was used by the Sanford group, resulted in a conversion of 1a into 2a in only 20% yield. To investigate the scope of the reaction, we synthesized further aromatic triazenes and trifluoromethy- lated these compounds under analogous conditions (Scheme 2). When para-substituted triazenes were used, we always obtained a very high ortho selectivity. In all cases only small amounts (< 4%) of meta substituted byproduct were detected by GC-MS analysis. In the case of mono-ortho-substituted triazenes, the ortho trifluoromethylated triazenes 2f , 2g, and 2h were obtained as Scheme 1. Trifluoromethylation of triazenes 1a. Reaction conditions: 1a (0.40 mmol), TMS-CF 3 (0.80 mmol), AgF (1.60 mmol), C 6 F 14 (1 mL), 100 8C, 4 h. [*] Dipl.-Chem. A. Hafner, Prof. Dr. S. Bräse Institute of Organic Chemistry, KIT-Campus South Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany) E-mail: braese@kit.edu [**] We thank the Landesgraduiertenfçrderung Baden-Württemberg for financial support. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201107414. A ngewandte Chemi e 3713 Angew. Chem. Int. Ed. 2012, 51, 3713 –3715  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim