The Art of Adding an Atom of Fluorine

July 2012

Replace a hydrogen atom in a molecule with a fluorine and there can be a dramatic boost to its biological effects. Witness, for example, the healing power of fluorinated drugs and the efficacy of today’s organofluoro pesticides. An upsurge of interest in fluorination in the past decade has seen new reagents to replace the older ones like HF/SbF5, SF4, and even F2 itself, which were not only difficult to control and focus but hazardous. A useful summary of fluorinating agents can be accessed at www.alfa.com/en/docs/FluorinatingAgents.pdf [1.4 MB].

As a result of research in the past decade, there are now fluorinating agents capable of putting a fluorine atom in an organic molecule in a targeted manner, as hundreds of paper attest. In many of these reagents the active center is either a fluorine atom attached to a nitrogen atom, or to a sulfur.

Selected, Recent Reports on Fluorination

Rank Paper Citations
1 S.H. Kang, D.Y. Kim, “Catalytic enantioselective fluorination of α-chloro-β-keto esters in the presence of chiral nickel complexes,” Adv. Synthesis & Catalysis, 325(16): 2783-6, 2 November 2010 16
2 J.H. Lee, D.Y. Kim, “Organocatalytic highly enantioselective Mannich-type reactions of fluoromalonate with N-Boc-aldimines,”  Synthesis, 11: 1860-4, June 2010. 15
3 M. Kawatsura, et al., “Iron- or cobalt-catalyzed Nazarov cyclization: Asymmetric reaction  and tandem cyclization-fluorination reaction,” Synlett, 8: 1243-6, May 2010. 15
4 A. L’Heureux, et al., “Aminodifluorosulfinium salts: selective fluorination reagents with enhanced thermal stability and ease of handling,” J. Organic Chem., 75(10): 3401-11, 21 May 2010. 13
5 T. de Haro, C. Nevado, “Gold catalyzed synthesis of α-fluoro acetals and α-fluoro ketones from alkynes,” Adv. Synthesis & Catalysis, 352(16): 2767-72, 2010 12
6 S.J. Yoon, et al., “Organocatalytic enantioselective Mannich-type reactions of fluorinated keto esters with N-Boc-aldimines,” Synlett, 3: 420-4. February 2011. 9
7 B.J. Wang, et al., “Improved arene fluorination methodology for I(III) salts,” Organic Lett., 12(15): 3352-5, 6 August 2010. 8
8 R. Surmont, et al., “Synthesis of 4-substituted 3,3-difluoropiperidines,” J. Org. Chem., 75(3): 929-32, 2010. 7
9 J. Erb, et al., “Combining asymmetric catalysis with natural product functionalization through enantioselective α-fluorination,” J. Org. Chem., 75(3): 969-71, 5 February 2010. 7
10 G. Stavber, S. Stavber, “Towards greener fluorine organic chemistry: Direct electrophilic fluorination of carbonyl compounds in water and under solvent-free reaction conditions,” Adv. Synthesis & Catalysis, 352(16): 2838-46, 2 November 2010. 6

SOURCE: Thomson Reuters Web of Knowledge

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For a flavor of recent research on fluorination, the adjoining table provides a selection of 10 papers published during the last two years.

A NEW AGENT

The door to this area was opened by Antonio Togni and Lukas Hintermann in 2000 when they announced the first catalytic, enantioselective fluorination of β-ketoesters. Their paper (Angew. Chemie Int. Ed., 39[23]: 4359, 2000) has since been cited around 220 times. It introduced the fluorinating agent N-fluorotriethylenediammonium BF4–, aka Selectfluor.

Interest in fluorination even justified a 2010 issue of Advanced Synthesis & Catalysis dedicated to the subject (352[16], 2 November 2010). This contained four review articles, concerning four kinds of fluorination: (1) using BrF3 (written by Schlomo Rozen, p. 2691); (2) catalytic enantioselective fluorination (Sylvain Lectard, et al., p. 2708); (3) stereoselective synthesis using ethyl bromodifluoroacetate and ethyl dibromofluoroacetate (Atsushi Tarui, et al., p. 2733 ); and (4) on the related subject of  trifluormethylation (Yan Zheng and Jun-An Ma, p. 2745).

As a result of research in the past decade, there are now fluorinating agents capable of putting a fluorine atom in an organic molecule in a targeted manner, as hundreds of paper attest.

The journal issue also had an original paper which appears on our fluorination “Hot 10” list at #1, coming from the group of Dae Young Kim of Soonchunhyang University, Asan, South Korea. (Other papers from Kim are at #2 and #6.) Paper #1 reports the use of Selectfluor to fluorinate α-chloro-β-keto esters under mild conditions yielding products which were 99% of one enantiomer. The catalyst for the reaction was a chiral nickel complex. Papers #2and #6 build on this and are about enantioselective Mannich reactions involving fluorinated derivatives.

FLOURISHING FLUORINATION

Selectfluor was also the fluorinating agent chosen by Teresa de Haro and Cristina Nevado—see #5. They used gold as a catalyst and converted alkynes to α-fluoroacetals and α-fluoroketones.  

Thomas Lectka at Johns Hopkins University, Baltimore, Maryland, has developed a method of α-fluorination using N-fluorobenzenesulfonimide (NFS) in conjunction with selected catalysts (JACS, 130; 17250, 2008). He then used it to fluorinate a range of natural products such as taxol, cholesterol, and vitamin D3 with yields up to 98% and 99% selectivity—see paper #9.

Paper #3, by Motoi Kawatsura and Toshiyuki Itoh of Tottori University, Japan, also reports the use of NFS in tandem with an iron-catalysed Nazarov cyclization reaction that forms five-membered rings, and gives yields—up to 90%--of a single stereoisomer.

A particularly interesting fluorinating agent is reported at #4: diethylaminofluorosulfinium tetrafluoroborate, aka XtalFluorE, which has the advantage of being a crystalline material, with a melting point of 83-85 o C, and can be used in ordinary laboratory glassware because it does not generate HF. (A morpholino version is also available as XtalFluorM and this has m.pt. of 129-132 oC..

The key feature of these reagents is the N=SF2 moiety, and it is claimed that they are more stable and easier to handle than those reagents which rely on N-SF3 for their reactivity, such as the commercially available bis(2-methoxyethyl)aminosulfur trifluoride (aka DeoxoFluor) and diethylamino sulfur trifluoride (aka DAST).

XtalFluorE has been developed by a collaboration between four commercial firms: OmegaChem Inc. and Crystallization Engineering Technologies, based in Quebec, Canada; Manchester Organic, at Runcorn, Cheshire, UK; and Pfizer Inc, of Groton, Connecticut. Paper #4 by A. L’Heureux et al. describes the use of XtalFluorE to convert alcohols to alky fluorides and carbonyls to gem-difluroides.

Used under the right conditions, the conventional fluoride, tetramethylammonium fluoride (MTMAF), can be used to fluorinate arenes, and this has recently been demonstrated by Stephen G. DiMagno and colleagues—see #7. Starting with diaryliodonium(III) PF6– compounds, the reactions are carried out in solvents such as benzene, and yields can be as high as 86%.

POSSIBLE BUILDING BLOCKS

Paper #8 is the work of Norbert de Kimpe’s group at Ghent University, Belgium, and reports the preparation of difluoropiperidines by means of ethyl bromodifluoroacetate. The work was done in conjunction with Johnson & Johnson Pharmaceutical Research and offers a route to possible building blocks of future drugs.

Gaj Stavber and Stojan Stavber of the Jožef Stefan Institute at Ljubljana, Solvenia, complete the list at #10. They have shown it is possible to carry out fluorinations with Selectfluor in water as the solvent, and also under solvent-free conditions. The target molecules were 1,3-dicarbonly compounds, and these were converted to 2,2-difluoro- substituted derivatives.

The element fluorine has several unique features: a weak F-to-F bond so it is easily broken, a very strong bond when it attaches itself to other elements, and the highest electronegativity of any element so it greatly influences the polarity of a molecule and thereby its behavior. Given these properties, it is not surprising that chemists have been fascinated by it. Even so, for most synthetic chemists, fluorine was an element to avoid, and if it had to be used then it was best left to those with special equipment.

Nevertheless, there were obvious benefits to be gained by inserting fluorine atoms in a molecule, especially when that molecule was meant to occupy a key site that controlled the behavior of pathogens and pesticides and thereby help to destroy them. The presence of a fluorine atom might well enable the molecule to bond to the site so strongly that it could not be dislodged.

Thanks to the development of new reagents, it has become possible for fluorination to join mainstream synthetic organic chemistry, and there is every indication that its role will increase in the years ahead.


Dr. John Emsley is based at the Department of Chemistry, Cambridge University, U.K.

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