Trifluoromethylcopper(I)1

CF3Cu

[77152-08-0]  · CCuF3  · Trifluoromethylcopper(I)  · (MW 132.56)

(trifluoromethylation of aryl, heteroaryl, and allyl halides,2 propargyl tosylates,3 and iodonucleosides4)

Physical Data: obtained only in solution; stabilized by HMPA.20

Preparative Methods: by reaction of copper metal and trifluoromethyl halides, or difluorocarbene precursors for in situ reactions; or preformed by metathesis of trifluoromethyl organometallic reagents, with subsequent reaction with electrophiles (see below).

Handling, Storage, and Precautions: sensitive to air and moisture; undergoes chain-extension reactions to form pentafluorocopper in the absence of electrophiles; several precursors of trifluoromethylcopper are toxic; HMPA is carcinogenic. Use in a fume hood.

General Considerations.

Trifluoromethylcopper was initially prepared by Kobayashi and co-workers by the reaction of Trifluoroiodomethane and Copper metal in the presence of aryl, allyl, or heteroaryl iodides.2 Since these initial studies, many reports of the preparation and reaction of trifluoromethylcopper have appeared.1a,b Trifluoromethyl-substituted nucleosides have been obtained by reaction of iodonucleosides with CF3Cu (eq 1).4

Trifluoromethyl-substituted allenes have been prepared from primary, secondary, or tertiary propargyl tosylates (eq 2).3 Reaction of CF3Cu with 5-iodo-1,3-dioxin-4-ones provides the corresponding trifluoromethyl derivatives which serve as precursors for a-CF3-b-keto esters (eq 3).5 Trifluoromethylation reactions are generally carried out using aryl iodides as the substrate. Aryl bromides or chlorides often result in lower yields and lead to the production of larger amounts of perfluoroethyl byproducts.6 Improved yields of trifluoromethylated aromatics from aryl chlorides have been realized for ortho-substituted substrates, and by adding charcoal to the reaction mixture.7

Methods for the preparation of the reagent can be grouped into two general categories: in situ generation from CF3X and copper metal, by decomposition of metal trifluoroacetates in the presence of Copper(I) Iodide, or from a variety of difluorocarbene precursors in the presence of a fluoride source; and preformation by metathesis reactions. In situ generation is readily accomplished with CF3I; however, the iodide is expensive and the reaction must be carried out at high temperatures in an autoclave.2 CF3Br may also be used, but the yields of trifluoromethylated products are generally not as high as those obtained in reactions using the iodide precursor.8 CF3I/Cu in situ generation and reaction of CuCF3 is best accomplished in pyridine or HMPA. Trifluoromethanesulfonyl Chloride and copper metal also provide in situ generation of CF3Cu for reaction with aryl iodides.9 Generation of CF3Cu from decomposition of metal trifluoroacetates in the presence of copper iodide and an aryl iodide provides the aryl trifluoromethyl derivative in good yield.10 Sodium trifluoroacetate/copper iodide reactions may be effectively carried out in NMP, HMPA, or DMF. The presence of other functional groups such as nitro, chloro, and methoxy on the aryl iodide do not interfere with the reaction (eqs 4 and 5); however, free hydroxy (phenol) or aryl amino groups are not tolerated.11

The reaction appears to be a nucleophilic aromatic substitution reaction, as evidenced by the positive ρ value obtained from a Hammett plot of para-substituted iodobenzene derivatives.11 CF3Cu may also be generated by the reaction of N-nitrosotrifluoromethane sulfonamide (TNS-TF) and copper metal.12 A drawback to this approach is the formation of CF3NO as well as the instability of TNS-TF. Trifluoromethyltriethylsilane has also been employed as a precursor for in situ generation of CF3Cu.13 Aryl and vinyl iodides, as well as allyl and benzyl bromides, undergo trifluoromethylation when admixed with Et3SiCF3/CuI (eq 6). No trifluoromethylation is observed in reactions of Et3SiCF3 without the addition of copper iodide.

Possibly the most common method for the generation of CF3Cu involves in situ formation from difluorocarbene precursors. The reagent may be directly prepared by the reaction of CF2Br2 with zinc, cadmium,14 or copper1a metal in DMF (Scheme 1).

The mechanism involves generation of difluorocarbene via radical anion formation with subsequent reaction of CF2: and DMF. The fluoride produced then combines with CF2: to generate CF3-, which reacts with the in situ formed copper halide to provide CF3Cu. Without in situ trapping by an electrophile, CF3Cu will undergo rapid chain extension to C2F5Cu. The chain extension reaction can be suppressed by adding excess fluoride anion to the reaction mixture; however, this procedure frequently results in decreased yields of the desired trifluoromethylated product. Fluorosulfonyldifluoromethyl iodide undergoes a single electron transfer (SET) process with copper metal to ultimately provide CF3Cu via a difluorocarbene intermediate.15 Methyl fluorosulfonyldifluoroacetate also provides CF3Cu upon reaction with CuI by means of a difluorocarbene intermediate;16 the reaction involves initial loss of methyl iodide followed by fragmentation of the copper salt to CO2, SO2, CuI, difluorocarbene, and fluoride. An advantage of this method is that no perfluoroethyl byproducts are observed in reactions with aryl iodides. A similar process from a less expensive source of difluorocarbene, methyl chlorodifluoroacetate, requires excess Potassium Fluoride for the generation of CF3- anion.17 Generation of CF3Cu by the latter method also eliminates the need to prepare FO2SCF2COF, the precursor for both fluorosulfonyl intermediates, from tetrafluoroethylene and sulfur trioxide.

Metathesis reactions of trifluoromethyl organometallic compounds to CF3Cu provide a means to pregenerate the reagent and allow for trifluoromethylation at much lower temperatures than the methods discussed above. The use of preformed CF3Cu, rather than in situ methods, has also allowed for the multiple trifluoromethylation of thermally unstable polyiodoheteroaryl species (eq 7).1a

Trifluoromethylmercury, -zinc, and -cadmium species can all undergo metathesis to CF3Cu. Trifluoromethylmercury has not been generally employed, presumably due to potential toxicity problems.18 Metathesis of trifluoromethylzinc is prohibitively slow and therefore not synthetically useful; however, metathesis of trifluoromethylcadmium with CuBr in DMF at -50 °C allows for clean formation of the copper reagent.19 Warming the mixture leads to the formation of two additional trifluoromethylcopper species, observed by 19F NMR, with the gradual loss of CF3Cu. Storage at rt produces C2F5Cu, with complete consumption of the CF3Cu after 11 h. The conversion of CF3 to C2F5Cu can be accelerated by heating the mixture to 70 °C. The CF3Cu reagent may be stabilized by adding HMPA, allowing trifluoromethylation reactions to be carried out in good yield at elevated temperatures.


1. (a) Burton, D. J.; Yang, Z.-Y. T 1992, 48, 189. (b) McClinton, M. A.; McClinton, D. A. T 1992, 48, 6555. (c) Lipshutz, B. H.; Sengupta, S. OR 1992, 41, 135.
2. (a) Kobayashi, Y.; Kumadaki, I. TL 1969, 4095. (b) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I. TL 1979, 4071.
3. Burton, D. J.; Hartgraves, G. A.; Hsu, J. TL 1990, 31, 3699.
4. Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano, M.; Kumadaki, I. JCS(P1) 1980, 2755.
5. Iwaoka, T.; Sato, M.; Kaneko, C. CC 1991, 1241.
6. (a) Kobayashi, Y.; Kumadaki, I. JCS(P1) 1980, 661. (b) Kobayashi, Y.; Kumadaki, I.; Sato, S.; Hara, N.; Chikami, E. CPB 1970, 18, 2334.
7. Clark, J. H.; McClinton, M. A.; Jones, C. W.; Landon, P.; Bishop, D.; Blade, R. J. TL 1989, 30, 2133.
8. Paratian, J. M.; Sibille, S.; Perichon, J. CC 1992, 53.
9. Heaton, C. A.; Powell, R. L. JFC 1989, 45, 86.
10. (a) Knunyants, I. L.; Komissarov, Y. F.; Dyatkin, B. L.; Lantseva, L. P. IZV 1973. 943. (b) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. CL 1981, 1719. (c) Suzuki, H.; Yoshida, Y.; Osuka, A. CL 1982, 135.
11. Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker, D. G. JCS(P1) 1988, 921.
12. Umemoto, T.; Ando, A. BCJ 1986, 59, 447.
13. Urata, H.; Fuchikami, T. TL 1991, 32, 91.
14. Burton, D. J.; Wiemers, D. M. JACS 1985, 107, 5014.
15. Chen, Q.-Y.; Wu, S.-W. JCS(P1) 1989, 2385.
16. Chen, Q.-Y.; Wu, S.-W. CC 1989, 705.
17. MacNeil, Jr, J. G.; Burton, D. J. JFC 1991, 55, 225.
18. Kondratenko, N. V.; Vechirko, E. P.; Yagupolskii, L. M. S 1980, 932.
19. Wiemers, D. M.; Burton, D. J. JACS 1986, 108, 832.
20. Dictionary of Organometallic Compounds: Third Supplement; Macintyre, J. E., Ed.; Chapman and Hall: New York, 1987; p 75.

Russell J. Linderman

North Carolina State University, Raleigh, NC, USA



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