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Trifluoromethyl Thianthrenium Salt: Synthesis and Applications of a New Trifluoromethylating Agent


Jia,  Hao
Research Department Ritter, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Jia, H. (2022). Trifluoromethyl Thianthrenium Salt: Synthesis and Applications of a New Trifluoromethylating Agent. PhD Thesis, Rheinisch-Westfälische Technische Hochschule, Aachen.

Cite as: https://hdl.handle.net/21.11116/0000-000D-3C6B-9
Trifluoromethylating reagents have boosted academic and industrial research’s interest for trifluoromethylation reactions. Nowadays, trifluoromethylating reagents can be classified according to their nucleophilic, electrophilic, and radical characteristics. The first boom in trifluoromethylation came after the advent of the following reagents appeared: CF3H, trifluorohalomethane, TMS-CF3, phenyltrifluoromethylsulphone, and metal trifluoromethanesulfinates (such as Langlois reagent). The generation in situ of CF3 radicals or CF3 anions induced by the aforementioned reagents greatly expands the field of trifluoromethylation. However, the need for tolerance to different functional groups and compatibility of reductive conditions stimulated further research on novel electrophilic trifluoromethylating reagents. Over the years, chemists reported many types of chalcogen and hypervalent iodine containing electrophilic trifluoromethylating agents. (Trifluoromethyl)dibenzothiophenium salts (Umemoto reagent) and hypervalent iodine-CF3 (Togni reagents) are among the most famous.
Based on the continued interest in the thianthrenium framework, we designed trifluoromethyl thianthrenium salt (TT-CF3+) as a novel trifluoromethylating reagent. Simple mixing of thianthrene with triflic anhydride in DCM under ambient conditions yields trifluoromethyl thianthrenium triflate (TT-CF3+OTf). The reaction does not require an inert atmosphere, can be scaled up, and the product can be purified by washing with ether to deliver an easy to handle, free-flowing off-white powder that can be stored under ambient conditions in light-proof condition without significant decomposition for at least a year. In addition to the ease of synthesis, which is the first advantage of this reagent, TT-CF3+ salts also possess unique reactivity. The S-CF3 bond homolytic energy of TT-CF3+ salt is significantly lower than that of Umemoto reagent I and Togni reagent I/II. For the CF3 radical reactivity, TT-CF3+ salt could generate CF3 radical and thianthrene radical cation under LED irradiation, whereas Umemoto reagent and Togni reagent I/II often require activators. In addition, TT-CF3+ salt is the only reported trifluoromethylating reagent that possesses all three reactivities: electrophilic, nucleophilic, and CF3 radical. Six transformations such as radical trifluoromethylation of heterocycles, electrophilic trifluoromethylation of carbonyl groups under umpolung conditions, and nucleophilic trifluoromethylation of 1,3-dicarbonyl compounds under basic conditions serve as examples of the broad reactivity of TT-CF3+.
To further verify the uniqueness of the fact that TT-CF3+ releases CF3 radicals and thianthrene radical cation under violet irradiation, acrylate was introduced into this system. CF3 radical and the persistent thianthrenium radical cation can carry out conjugated addition with acrylate to produce an α-thianthrenium carbonyl species, as the equivalent of an α-carbonyl carbocation. The subsequent process differs from the conventional Giese reaction, the stability of the persistent radical cation of thianthrene, and the excellent leaving group ability of thianthrenium that allows its displacement even with weak nucleophiles (e.g. acetonitrile) to form amino acid analogues. Addition of hydroxide, methoxide, and even fluoride can afford α-heteroatom substituted α-phenylpropanoates.