Togni reagents

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The success story of Togni reagents

The family of cyclic hypervalent iodine-CF3 reagents, also known as Togni reagents, has been first synthesized in the group of Prof. Dr. Antonio Togni at ETH Zurich.

The concept of hypervalent iodine-perfluoroalkyl reagents was at that time nothing new. First examples of non-cyclic perfluoroalkyl-aryliodonium salts were known already in the 70´s and 80´s, pioneered by Yagupolskii[1] and Umemoto[2]. The FIS and FITS reagents were synthesized by oxidizing a perfluoroiodoalkane with in-situ generated peroxotrifluoroacetic acid, forming a perfluoroalkyliodine bis-trifluoroacetate. This reactive intermediate then reacts in the presence of Lewis or Bronsted acid with large excess of arene, typically benzene, giving the target perfluoroalkyl aryliodonium salts. Using salt metathesis, other derivatives with slightly modified reactivity and solubility features could be accessed.

Unfortunately, the same approach could not be applied for the synthesis of the desired trifluoromethyl derivative. The authors speculated this was due to the instability of the trifluoromethyl aryl iodonium salt.

In 2006, there were attempts in Togni group to prepare acyclic trifluoromethyl aryliodonium salt by Umpolung of the nucleophilic CF3-synthon – the Ruppert Prakash reagent CF3TMS; however they met with failure.[3]

CF3TMS umpolung non cyclic

The key success idea was to use a stabilizing cyclic iodane framework as well as the mild conditions for the Umpolung of CF3TMS. This approach enabled to synthesize the otherwise elusive hypervalent iodine-CF3 reagents which are nowadays colloquially termed as Acid-CF3-Togni reagent and Alcohol-CF3-Togni reagent. Later, optimization of the Umpolung procedure appeared in the literature; in the case of Acid-CF3 reagent a one-pot procedure was disclosed.[4]

The Togni reagents react with nucleophiles according to the following simplified reaction scheme:

togni-reagents-3

In 2006, these reagents represented rather a final missing part of the mosaic of perfluoroalkyliodonium reagents than a standard tool of fluoroorganic chemistry. However, during just few years, the situation dramatically changed as their general utility was demonstrated by several research groups in a plethora of novel transformations.

togni-reagents-4

Citing the JOC article[4] reveals how the initial beliefs about their reactivity had to be reevaluated in the course of time: “Recently, the substrate scope and general applicability of these reagents has been considerably expanded thanks to significant contributions from several research groups. The original notion that these reagents are primarily suited for trifluoromethylation of soft phosphorus-, sulfur-, and carbon-centered nucleophiles such as phosphines, thiols, α-nitroesters, β-ketoesters,[5] phosphorothioates, and aromatics[6] was soon overcome because even hard O-centered nucleophiles such as alcohols,[7] sulfonic acids,[7] and hydrogen phosphates[8] undergo trifluoromethylation under proper Lewis or Brønsted acid activation. The concept of Lewis acid activation of the CF3 reagents analogously demonstrated its utility in the trifluoromethylation of nitrogen nucleophiles, such as in Ritter-type functionalizations of nitriles[9] and trifluoromethylations of trimethylsilylated azoles.[10] Transition metal-promoted transformations have provided a facile entry into selective trifluoromethylation of aromatic cores,[6c, 11] allylic trifluoromethylation of alkenes,[12] trifluoromethylation of terminal alkynes[13] and allylsilanes,[14] oxidative functionalization of alkenes,[15] and trifluoromethylation of vinyltrifluoroborates.[16] Substrates bearing enolizable carbon centers were shown to be good candidates for the stereoselective introduction of the CF3 moiety, including α-trifluoromethylation of aldehydes cooperatively using Lewis acid activation and organocatalysis[17] or enantioselective trifluoromethylation of cyclic β-keto esters in the presence of chiral Cu complexes.[18] Finally, chiral enolates featuring the acyloxazolidinone motif were trifluoromethylated in a diastereoselective fashion.[19]

Togni type reagents with other fluoroalkyl groups

In 2008, Hu et al disclosed another hypervalent iodine-fluoroalkyl reagent containing (phenylsulfonyl)difluoromethyl moiety. The compound was accessed using the same Umpolung concept developed previously for the CF3-analogues. This reagent was used primarily for metal-free (phenylsulfonyl)difluoromethylation of thiols.[20]

togni-reagents-5

Later, it was shown that in the presence of copper catalyst, unsaturated carboxylic acids undergo tandem decarboxylation/phenylsulfonyldifluoromethylation, giving products of vinylic[21] or allylic[22] fluoroalkylation, depending on the double bond regiochemistry.

togni-reagents-6

Higher perfluoroethyl analogue of Acid-CF3-Togni reagent was synthesized by Studer et al who demonstrated its similar reactivity in tandem radical perfluoroethylation/aminoxylation of alkenes[23].

togni-reagents-7

The above mentioned examples give at least a quick overview of the large potential of these hypervalent iodine-fluoroalkyl reagents. Due to their simplicity of use, good reactivity and relatively favourable storage characteristics, they experienced a gradual increase in popularity. Nowadays, they find extensive use in design of new molecules in life and material sciences. In the view of the rapid expansion of their scope in the last years, it is reasonable to expect that further useful transformations will be discovered and new, more complex reagents will be synthesized. To get a further insight into the chemistry of hypervalent iodine-CF3 reagents, we recommend the latest review by Charpentier, Früh and Togni.

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References:

  1. a) L. M. Yagupolskii, I. I. Maletina, N. V. Kondratenko, V. V. Orda, Synthesis 1978, 1978, 835-837;
    b) V. V. Lyalin, V. V. Orda, L. A. Alekseeva, L. M. Yagupolskii, Zh. Org. Khim. 1971, 7; cL. M. Yagupolskii, N. V. Kondratenko, G. N. Timofeeva, J. Org. Chem. USSR (Engl. Transl.) 1984, 20.
  2. a) T. Umemoto, Y. Kuriu, H. Shuyama, O. Miyano, S.-I. Nakayama, J. Fluorine Chem. 1982, 20, 695-698; b) T. Umemoto, Y. Kuriu, H. Shuyama, O. Miyano, S.-I. Nakayama, J. Fluorine Chem. 1986, 31, 37-56.
  3. P. Eisenberger, ETH Zurich, Diss. No. 17371 (Zurich), 2007.
  4. V. Matoušek, E. Pietrasiak, R. Schwenk, A. Togni, J. Org. Chem. 2013, 78, 6763-6768.
  5. I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. Int. Ed. 2007, 46, 754-757.
  6. a) M. S. Wiehn, E. V. Vinogradova, A. Togni, J. Fluorine Chem. 2010, 131, 951-957; b) E. Mejía, A. Togni, ACS Catalysis 2012, 2, 521-527; c) T. Liu, Q. Shen, Org. Lett. 2011, 13, 2342-2345.
  7. R. Koller, K. Stanek, D. Stolz, R. Aardoom, K. Niedermann, A. Togni, Angew. Chem. Int. Ed. 2009, 48, 4332-4336.
  8. N. Santschi, P. Geissbühler, A. Togni, J. Fluorine Chem. 2012, 135, 83-86.
  9. K. Niedermann, N. Früh, E. Vinogradova, M. S. Wiehn, A. Moreno, A. Togni, Angew. Chem. Int. Ed. 2011, 50, 1059-1063.
  10. K. Niedermann, N. Früh, R. Senn, B. Czarniecki, R. Verel, A. Togni, Angew. Chem. Int. Ed. 2012, 51, 6511-6515.
  11. a) Y. Huang, X. Fang, X. Lin, H. Li, W. He, K.-W. Huang, Y. Yuan, Z. Weng, Tetrahedron 2012, 68, 9949-9953; b) T. Liu, X. Shao, Y. Wu, Q. Shen, Angew. Chem. Int. Ed. 2012, 51, 540-543.
  12. a) J. Xu, Y. Fu, D.-F. Luo, Y.-Y. Jiang, B. Xiao, Z.-J. Liu, T.-J. Gong, L. Liu, J. Am. Chem. Soc. 2011, 133, 15300-15303; b) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2011, 133, 16410-16413.
  13. Z. Weng, H. Li, W. He, L.-F. Yao, J. Tan, J. Chen, Y. Yuan, K.-W. Huang, Tetrahedron 2012, 68, 2527-2531.
  14. R. Shimizu, H. Egami, Y. Hamashima, M. Sodeoka, Angew. Chem. Int. Ed. 2012, 51, 4577-4580.
  15. a) P. G. Janson, I. Ghoneim, N. O. Ilchenko, K. J. Szabó, Org. Lett. 2012, 14, 2882-2885; b) R. Zhu, S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 12462-12465; c) H. Egami, R. Shimizu, S. Kawamura, M. Sodeoka, Angew. Chem. Int. Ed. 2013, 52, 4000-4003.
  16. A. T. Parsons, T. D. Senecal, S. L. Buchwald, Angewandte Chemie 2012, 124, 3001-3004.
  17. A. E. Allen, D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132, 4986-4987.
  18. Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012, 134, 10769-10772.
  19. V. Matoušek, A. Togni, V. Bizet, D. Cahard, Org. Lett. 2011, 13, 5762-5765.
  20. W. Zhang, J. Zhu, J. Hu, Tetrahedron Lett. 2008, 49, 5006-5008.
  21. Z. He, T. Luo, M. Hu, Y. Cao, J. Hu, Angew. Chem. Int. Ed. 2012, 51, 3944-3947.
  22. Z. He, M. Hu, T. Luo, L. Li, J. Hu, Angew. Chem. Int. Ed. 2012, 51, 11545-11547.
  23. Y. Li, A. Studer, Angew. Chem. Int. Ed. 2012, 51, 8221-8224.

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