Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations

This short review highlights the copper-mediated fluoroalkylation using perfluoroalkylated carboxylic acid derivatives. Carbon–carbon bond cleavage of perfluoroalkylated carboxylic acid derivatives takes place in fluoroalkylation reactions at high temperature (150–200 °C) or under basic conditions to generate fluoroalkyl anion sources for the formation of fluoroalkylcopper species. The fluoroalkylation reactions, which proceed through decarboxylation or tetrahedral intermediates, are useful protocols for the synthesis of fluoroalkylated aromatics.


Introduction
Organofluorine compounds attract attention because of their applicability in various fields, such as medicine, agrochemical and material science. It has been widely reported that nearly 15% of pharmaceuticals and 20% of agrochemicals on the market contain fluorine atoms, including several of the top drugs. Of particular interest are compounds containing the structural motif of a (trifluoromethyl)aryl group (Ar-CF 3 ) [1][2][3][4][5][6][7]. The characteristic size, strong electron-withdrawing ability, and the high lipophilicity of the trifluoromethyl group are key properties of biologically active CF 3 -containing molecules [8]. Perfluoroalkylcopper compounds (C n F 2n+1 Cu), which are soft and relatively stable perfluoroalkyl organometallic reagents (C n F 2n+1 M) with high reactivity, act as prominent cross-coupling participants in aromatic perfluoroalkylation reactions . In order to prepare C n F 2n+1 Cu species, several representative protocols have been reported. Among these protocols, each method has individual merit. Particularly, Ruppert-Prakash reagents (C n F 2n+1 SiR 3 ) have been used as the source of perfluoroalkyl Scheme 2: Decarboxylative pentafluoroethylation and its application.
anions (C n F 2n+1 − ) for the generation of C n F 2n+1 Cu. However, perfluoroalkylsilane sources are costly for large-scale operation.

Review
Decarboxylation of perfluoroalkylacetates A pentafluoroethyl group (C 2 F 5 ) was fixed at the arene with sodium pentafluoropropionate [35] (Scheme 2). The reaction mechanism is similar to that of the trifluromethylation using CF 3 CO 2 Na [33,34]. Upon heating, the mixture of CF 3 CO 2 Na and CuI in NMP, 3-chloroiodobenzene underwent crosscoupling to provide the pentafluoroethylated compound in 80% yield. The pentafluoroethylated aromatic product was applied to the synthesis of 2,2-difluorostyrenes through Mg(0)-promoted defluorinative silylation followed by fluorine- From a mechanistic aspect, Vicic and co-workers explored the direct generation of CF 3 Cu from CF 3 CO 2 Cu. The use of (N-heterocyclic carbene)copper-trifluoroacetates prepared from trifluoroacetic acid (TFA) was investigated in the decarboxylative trifluoromethylation of aryl halides [37] (Scheme 4). Not only iodobenzene but also 4-bromotoluene was trifluoromethylated by the [(NHC)Cu(TFA)] complex.
The perfluoroalkylation reactions mentioned above require a stoichiometric amount of copper reagent, whereas it was found that the addition of silver salts is effective for the copper-mediated trifluoromethylation of aryl iodides [38] (Scheme 5). The amount of copper used in the reaction was reduced to 30 or 40 mol % by adding a small amount of Ag 2 O. As a related decarboxylative transformation, silver-mediated aromatic tri- fluoromethylation was recently developed. Zhang et al. reported the direct aryl C-H trifluoromethylation in which TFA works as a trifluoromethylation reagent [39] (Scheme 6). In this reaction, TFA releases a CF 3 radical via decarboxylation, which reacts with the arenes to yield trifluoromethyl-substituted products. This report suggests that TFA can act as a trifluoromethyl source in the reaction with inactivated aromatic compounds, while the control of regioselectivity is difficult. Trifluoromethylation with difluorocarbene and fluoride ions The reaction system with ClCF 2 CO 2 Me/KF/CuI also generates CF 3 Cu in situ [40,41] (Scheme 7). The demethylation of ClCF 2 CO 2 Me proceeds by iodide, followed by decarboxylation of the resulting chlorodifluoroacetate to provide difluorocarbene (:CF 2 ), trapped by fluoride to give the CF 3 − species. This reacts with CuI leading to CF 3 Cu.

Synthesis of perfluoroalkylcopper from perfluoroalkyl ketones or esters
Langlois et al. reported that trifluoromethylation with methyl trifluoroacetate was successfully carried out in DMF or sulfolane at 180 °C [43] (Scheme 9). Methyl trifluoroacetate, which is more readily available than methyl chlorodifluoroacetate, acts as a trifluoromethylating agent. In this synthesis, the methyl trifluoroacetate/CsF/CuI system would form the tetrahedral intermediates to generate CF 3 Cu species in situ.
Mikami and co-workers accomplished the synthesis of CF 3 Cu at room temperature with perfluoroalkyl ketone derivatives and appropriate nucleophiles. It is indicated that the CF 3 Cu reagent is directly formed from tetrahedral intermediate A [44] (Scheme 10). The CF 3 Cu reagent was applied to aromatic trifluoromethylation with aryl iodides, which have electron-withdrawing or electron-donating functional groups, in good to high yields (Scheme 11).
The preparation of the C 2 F 5 Cu reagent was investigated as well [45]. Pentafluoropropionate was reacted with CuCl salt in the presence of KOt-Bu to afford C 2 F 5 Cu. A variety of aryl bro-

Copper-catalyzed group transfer from fluoral derivatives
Catalytic systems in organic synthesis are desirable from an environmentally benign point of view. With regard to aromatic trifluoromethylation, the effort is devoted to reduce the copper reagents employed in the reactions. Copper-catalyzed aromatic trifluoromethylation with CF 3 SiMe 3 was developed using phen as a ligand [50]. On the other hand, Billard and Langlois et al. described silylated hemiaminals of fluoral (trifluoroacetaldehyde) that act as a nucleophilic trifluoromethyl source for electrophiles such as aldehydes and ketones [51,52] (Scheme 14).
The substrate scope of the catalytic trifluoromethylation is shown in Scheme 16. Nitro, cyano, and ester groups in iodoarenes were tolerable under the reaction conditions of copper-catalyzed nucleophilic trifluoromethylation. Electronrich iodoarenes underwent the nucleophilic trifluoromethylation to afford the corresponding trifluoromethylated benzenes. Furthermore, the trifluoromethyl group was introduced into naphthalenes and thiophene with hemiaminal 1.
A catalytic amount of copper was enough to complete the reactions. In the synthesis of trifluoromethylarenes (Ar-CF 3 ), the cross-coupling proceeded via the pathway shown in Scheme 17 [53]. First, the fluoride-ion-induced reaction of hemiaminal 1 with CuI-diamine complex 2 gave copper alkoxide 3. Then the trifluoromethyl group in 3 migrates to generate the trifluoromethylcopper(I) complex 5 with the elimination of N-formylmorpholine (4) [54]. Finally, Ar-CF 3 is formed by the coupling of CF 3 Cu complex 5 with Ar-I, and CuI-diamine complex 2 is regenerated.

Conclusion
Fluorine has greatly contributed to the advancement of human life and the global demand for organofluorine compounds will continue to increase. Therefore, the introduction of fluorinecontaining functional groups into organic molecules is recognized as a general strategy for the design of drugs and functional materials. In fact, the research activity on selective fluorination and trifluoromethylation has reached a mature state.
The progress in fluoroalkylation of organic compounds could be accelerated by the use of fluoroalkylating reagents, which are inexpensive and easy to handle. Perfluoroalkyl carboxylic acid derivatives, such as perfluoroalkyl acetates, trifluoroacetic acid, chlorodifluoroacetates, trifluoromethyl ketones and hemiami-Scheme 17: Plausible mechanism of Cu-catalyzed aromatic trifluoromethylation [53].
nals of trifluoroacetaldehyde, are attractive perfluoroalkyl anion sources for aromatic perfluoroalkylation reactions. The generation of perfluoroalkylcopper from perfluoroalkyl carboxylic acid derivatives via carbon-carbon bond cleavage demands a high reaction temperature or basic conditions. Nevertheless, the simplicity of the operation and the reliability of higher yields would help the synthesis of fluorinated compounds in various fields.