Togni-CF2CF2X reagents

In 2015, joint cooperation between the groups of Prof. Dr. A. Togni (ETH Zurich) and Dr. P. Beier (IOCB AS CR) resulted in a publication[1] and patenting of a new family of substituted hypervalent iodine-CF2CF2X reagents which represent an extension of the existing cyclic hypervalent iodine-CF3 reagents (the so-called Togni reagents).
These reagents were prepared by the Umpolung of the corresponding fluoroalkyl silanes with the appropriate fluoroiodanes.

umpolung general CF2CF2

Using this strategy, extended Alcohol-type and Acid-type-CF2CF2X reagents could be accessed in moderate to good yields.

portfolio hypervalent iodine cf2cf2 reagents

General characteristics

From the synthetic point of view, these hypervalent iodine-CF2CF2X reagents have in many respects very similar behaviour to their established CF3-counterparts.

The thermal stability, solubility and behaviour towards Brønsted acids is different for Alcohol-CF2CF2X vs Acid-CF2CF2X reagents and resembles that of the CF3-analogues.

While the Alcohol-CF2CF2X reagents generally show good solubility in most popular organic solvents (THF, DCM, MeCN, EtOAc), the Acid-CF2CF2X reagents show a much higher degree of crystallinity and exhibit lower solubilities, particularly when the X substituent represent azoles (most notably benzimidazole).

When it comes to thermal stability, the general rule of thumb says that the Alcohol-CF2CF2X reagents decompose on longer standing at room temperature (days). Therefore we highly recommend to store the reagents at temperatures below 0 °C, preferably at -20 °C. Our present experience shows that when properly stored, the reagents shelf life at -20 °C should be at least 2 years.

The Acid-CF2CF2X reagents are characterized by their higher thermal stability, some highly crystalline derivatives showed good stability over prolonged storage at rt (weeks), but nevertheless, we recommend storing them in a freezer.

The Alcohol-CF2CF2X reagents behave as mild bases (pKa(water) in the range 4-6) and can be protonated with strong acids (HOTf, HNTf2, HCl, CF3COOH) while the Acid-CF2CF2X reagents are far less basic and quickly decompose in acidic environment.

Fluoroalkylation of hydroxylamines

N,N-disubstituted hydroxylamines are O-fluoroalkylated with Alcohol-CF2CF2X reagents without any activators/catalysts.

fluoroalkylation of hydroxylamineN-acyl-N-aryl-O-CF3 hydroxylamines, prepared by trifluoromethylation with Acid-CF3 Togni-reagent, were shown to undergo thermal rearrangement to rare o-trifluoromethoxylated aniline derivatives[2].

trifluoromethoxylation of arenes by rearr

We believe that a similar transformation could be feasible with the CF2CF2X derivatives.

Fluoroalkylation of thiols

The hypervalent iodine-fluoroalkyl reagents show a highly pronounced reactivity towards thiols. With sufficiently soluble thiols, the reaction is usually finished within 1 h at -78 °C and tolerates many functional groups (amino, hydroxyl). The fluoroalkylation of thiols is a radical reaction and free radical scavengers or electron rich olefins can capture the fluoroalkyl radical and inhibit the standard course of the reaction.

fluoroalkylation of thiols

The extreme fast rate of thiol tagging, irreversibility, intrinsically high chemoselectivity and high stability of the S-fluoroalkyl bonds make it an ideal candidate for bioconjugation. For more info, go to chapter bioconjugation.

Fluoroalkylation of aromatic substrates

With proper Lewis-acid activation (CH3ReO3, CuII salts), the hypervalent iodine-CF2CF2X reagents can introduce the CF2CF2X functionality to electron rich aromatic nuclei. 3-substituted indole derivatives proved to be good substrates for fluroalkylation in 2-position.

fluoroalkylation aromatics

 

Enolate fluoroalkylation

Sufficiently nucleophilic enolates or their surrogates give C-fluoroalkylated products on treatment with CF2CF2X reagents, in some cases, all-carbon stereocentres can be formed. Such examples include β-ketoesters, Evans acyloxazolidinones, silyl ketene imines and siloxy enamides.fluoroalkylation of enolates

Construction of fused heterocycles with internal CF2CF2 units

Recently, Charpentier et al. [3]disclosed an elegant approach how to construct tetrafluorinated di- and tetrahydro(benz)imidazopyridines. Treatment of alkenes or alkynes with the azole Acid-CF2CF2X reagents in the presence of catalytic amounts of copper(II) acetate resulted in formation of hitherto unknown fused fluorinated heterocycles. The authors demonstrated that the process is radical in nature.

Charpentier CF2CF2 cyclisation

These novel fluorinated heterocycles with an attractive tetrafluoroethylene unit can find use in design of new drug and pesticide candidates. The polar hydrofobicity imparted by the CF2CF2 grouping can have similar effects as described by DiMagno et al. [4] in his work on heavily fluorinated sugars.

To see the portfolio of the reagents, click here.

Conclusion

The hypervalent  iodine-CF2CF2X can be viewed as „eXtended Togni reagents“. Their unique reactivity resembling that of original Togni-CF3 reagents and the relatively high number of synthetically accessible CF2CF2X motifs enable medicinal chemistry researchers to access a significantly broader chemical space of fluorinated molecules.

References:

  1. V. Matoušek, J. Václavík, P. Hájek, J. Charpentier, Z. E. Blastik, E. Pietrasiak, A. Budinská, A. Togni, P. Beier, Chemistry – A European Journal 2016, 22, 417-424.
  2. K. N. Hojczyk, P. Feng, C. Zhan, M.-Y. Ngai, Angew. Chem. Int. Ed. 2014, 53, 14559-14563.
  3.  J. Charpentier, N. Früh, S. Foser, A. Togni, Org. Lett. 2016, 18, 756-759.
  4. J. C. Biffinger, H. W. Kim, S. G. DiMagno, ChemBioChem 2004, 5, 622-627.

 

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