Selective Direct Fluorination

Two approaches to the synthesis of molecules which contain either one or two fluorine atoms or a trifluoromethyl group are the reaction of fluorine with a precursor which then gives the required molecule directly, and the introduction of fluorine into small molecules which are subsequently used as building blocks in the synthesis of more complex products [2,4, 5, 8,117-120]. Direct reaction between a substrate, or a simple derivative of a substrate, and elemental fluorine has a role to play in both of these approaches. Preparation of fluorina-ting agents by the reaction of fluorine with various molecules will be discussed but further chemistry of the derived reagents themselves will not be described. 

Most successful selective fluorination reactions are carried out under conditions which limit any free radical processes and encourage nucleophilic attack on fluorine either by a one- or two-electron transfer process (see Sect. 3.1.1.3). 

Fluorine is a highly reactive and toxic gas and should be handled only under a well-ventilated hood, with protective goggles and gloves. Even low concentrations can be detected by its characteristic smell. Exposure to fluorine, even at low concentrations, carries a significant health risk. Even after apparently minor body contact with fluorine gas competent medical help should be sought immediately. 

Copyright 2004 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-30691-9 

3 Synthesis of Bis(4-nitrophenyl)tetrafluorosulfurane (4) (Isomer Mixture 15% trans/iS % cis) 

After crystallization for 18 h at — 20 °C the crude product was isolated by filtration. 

A second recrystallization from acetonitrile yielded 20 g (80 %) of yellow crystals, consisting of a mixture of 15 % trans-4 [3] and 85 % cis-4 m. p. 180 °C, dec. correct elemental analysis. 

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R. C. H., Sandeord, G., Elemental fluorine Part 13. Gas-liquid thin film reactors for selective direct fluorination. 

Chambers RD, Fox MA, Sandford G (2005) Elemental fluorine - Part 18. Selective Direct Fluorination of 1,3-Ketoesters and 1,3-Diketones using Gas/ Liquid Microreactor Technology. Lab Chip 5 1132-1139 Cheng RP, Gellman SH, DeGrado WF (2001) Beta-Peptides From Structure to Function. Chem Rev 101 3219-3232... 

De Mas N, Gunther A, Schmidt MA, Jensen KF (2003) Microfabricated Multiphase Reactors for the Selective Direct Fluorination of Aromatics. Ind Eng Chem Res 42 698-710... 

R.D. Chambers, C.J. Skinner, J. Flutchinson, J. Thomson, Elemental fluorine.1. Synthesis of fluoroaromatic compounds, J. Chem. Soc. Perkin Trans. 1 (1996) 605-609. J.S. Moilliet, The use of elemental fluorine for selective direct fluorinations, J. Fluor. Chem. 109 (2001) 13-17. 

An important special case of selective direct fluorination is the reaction of elemental fluorine with uracil to produce 5-fluorouracil in 55—80% yield, which was first reported by Schuman, Tarrant et al. (94) and also studied by Hesse et al. (95). 

The fluorination of 12, easily prepared from the corresponding triketo steroid, with an equimolar amount of 1 (Scheme 2) shows the remarkable ability of 1 to distinguish di-substituted from tri-substituted enol silyl ethers. The 9a-fluoro steroid 13 is produced in 51% yield (78% based on recovered triketo steroid) and the combined yield of the other fluorinated products is only 4.6%.17 it thus is apparent that 1 reacts almost exclusively with the trisubstituted enol ether moiety. The new, selective direct fluorination at the 9a-position holds considerable promise as a means to prepare biologically important 9a-fiuoro steroids.18... 

One of the first examples of industrial application of selective direct fluorination was the synthesis of the cytostatic 5 -fluorouracil. In the most commonly used process the precursor uracil is treated with nitrogen-diluted fluorine in hot water and the intermediate fluorohydrin is subsequently dehydrated either by heating the aqueous solution to 100 °C or with sulfuric acid [18] (Scheme 2.6.). 

During the last few years, especially, there have been great advances in the selective direct fluorination of even sensitive organic substrates. Some of the methods introduced by R. D. Chambers and coworkers are even fulfilling the requirements of robust and reproducible industrial processes, and the resulting products have... 

Scheme 2.5 Selective direct fluorination of double bonds in complex organic compounds [17].

Chambers, R.D., et al., Gas-hqnid thin film microreactors for selective direct fluorination. Lab on a Chip, 2001, 1 132-137. 

R.D. Chambers, M.A. Fox, G. Sandford, Elemental fluorine — Part 18. Selective direct fluorination of 1,3-ketoesters and 1,3-diketones using gas/liquid microreactor technology. Lab on a Chip, 2005, 5, 1132-1139. 

N. de Mas, et al., Microfabricated multiphase reactors for the selective direct fluorination of aromatics, Industrial and Engineering Chemistry Research, 2003, 42, 698-710. 

Elemental fluorine. Part 18. Selective direct fluorination of 1,3-ketoesters and... 

R.D. Chambers, D. Holling, G. Sandford, H. Puschmarm, J.A.K Howard, Selective direct fluorination of quinoline derivatives,/. Fluorine Chem. 2002, 117, 99-101. 

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