Thiols fluorination

Displacement of the sulfhydryl group in primary thiols, like L cysteine and 2-diethylaminoethanethiol, requires elemental fluorine, the most active oxidant Elemental sulfur is the major by-product in those reactions [7] (equation 2)... 

Perfluoroalkyl)ethane thiols have been used as precursors to fluorinated surfactants and products for hydro- and oligophobic finishing of substrates such as textiles and leather (1). The synthesis of 2-(perfluoroalkyl)ethane thiol and a byproduct bis-(-2-perfluoroalkylethane)-disulfide (5-10%) has been practiced via the reaction of 2-(perfluoroalkyl)ethane iodide with thiourea to form an isothiuronium salt which is cleaved with alkali or high molecular weight amine as shown in Equation 1 for 2-(perfluorohexyl)ethane iodide (1). 

Ethers and sulfides bearing the CF3CHFCF2- group are readily prepared by addition of the alcohol or thiol to hexafluoropropene. Some data from their fluorine spectra are given in Scheme 6.16, along with proton data. With the CHF carbon being chiral, the CF2 group should appear as an AB quartet. 

As we have seen (pp. 50 et seq.) the reaction between phosphorus oxydichlorofluoride and alcohols, phenols and thiols, affords dialkyl, dicyctoalkyl, diaryl phosphorofluoridates and dialkyl phosphorodithiolates. In a Report1 to the Ministry of Supply on fluorophosphonates a description was given of a new type of nitrogen fluorophosphonate formed by the action of 4 mol. of aniline on 1 mol. of phosphorus oxydichlorofluoride, the fluorine atom being unaffected ... 

Anodic fluorination of thiols was reported [28] providing a route to perfluo-roalkyl derivatives of sulfur hexafluoride though the yields of products are not high. The process, achieved in a system of HF/NaF at a Ni anode with helium bubbling through the solution, leads to different perfluorinated products (Scheme 8). 

Difluorodifluoroaminomethanesulfenyl fluoride, NFgCFgSF, is formed among other products by the fluorination of AgSCN or KSCN 32). Perfluorooctanesulfenyl fluoride, CF3(CF2)7SF, is obtained by electrolytic fluorination of the appropriate thiol 152). 

Yet a further variation of this theme consists in the replacement of the bridging methylene group by sulfur to give a thiadiazepine as the central ring. The starting thiophene ether (26-3) is obtained by the nucleophilic aromatic displacement of fluorine in nitrobenzene (26-1) by the anion from imidazole-2-thiol (26-2). The nitro... 

Sulfur is oxidatively fluorinated up to its highest valence state, six. For instance, alkyl thiols give perfluoroalkyl-sulfurpentafluorides (Fig. 40) [104] and sulfides give perfluorodialkyl-sulfurtetrafluorides (Fig. 41) [105,106]. Similarly, phosphorous is oxidatively fluorinated up to the pentavalent state (Fig. 42) [107]. 

A halogen directly attached to the 1,2,4-triazine ring is very reactive and can be replaced by most other nucleophiles as outlined in Scheme 9. Tlie reactivity toward neutral nucleophiles decreases from the 5-position to the 3- and 6-positions, while that towards anionic nucleophiles decreases from the 5-position to the 6- and 3-positions. Among nucleophiles which displace halogen atoms are water, alcohols, amines, hydrazine, hydroxyl-amine, thiols and hydrogen sulfide. It is also reported that the bromine in 6-bromo-1,2,4-triazine-3,5-dione can be replaced by fluorine (323) or by a cyano group (324). 

In organo-fluorine compounds fluorine atoms can be eliminated by nucleophilic sulfur species to form C —S bonds. In principle, the fluorine to be eliminated can be bonded to aliphatic or araliphatic compounds, as well as to aromatic or heterocyclic compounds however, the replacement proceeds more efficiently the more the fluorine is activated. Therefore, the synthetic usefulness of these reactions is the broadest with fluoroaromatic compounds, including heteroaromatics, with which the reactions often proceed smoothly under mild conditions. The nucleophilic sulfur compound to be reacted is. in most cases, an aliphatic or aromatic thiol or a metal sulfide, but reactions with, for example, thiourea or ammonium thiocyanate have also been described. The sulfur introduced this way can be either oxidized or removed by reduction, opening additional possibilities for modifications of the original fluoro compounds. 

Multiple, but not complete, substitution of fluorine by sulfur nucleophiles proceeds under conditions rather similar to those for single elimination, i.e. generally in diethylene glycol/ pyridine mixture with sodium hydroxide as base, but with an increased molar ratio of the respective thiol, corresponding to the number of fluorines to be eliminated. On reaction in ethylene glycol/ pyridine, rather than in dimethylformamide or, particularly, in hexamethyl-phosphoric triamide, at least two fluorine atoms remain in the molecule, even under drastic... 

In different types of condensed polycyclic systems, mostly nitrogen-containing systems, the elimination of attached fluorine by thiols has proved a valuable synthetic tool for the introduction of sulfur moieties. In 4-(aminosulfonyI)-7-fluoro-2,l,3-benzoxadiazole(l) the reactivity of the fluorine towards sulfur nucleophiles is sufficiently high that it can be used analytically for the detection of thiols14 (c.g., in peptides). The reaction proceeds almost quantitatively. 

Due to the pharmaceutical importance of their reaction products, a number of fluorinated 4-oxo-l,4-dihydroquinoline-3-carboxylic acid derivatives have been treated with various thiols (Table 8). The displacement of fluorine proceeds under moderate conditions regiosclcctively at C-7 or C5 giving 2 or 3, respectively in the ease of the 5,6,7,8-tetrafluoro derivative, fluorine is replaced at C5 in a nonpolar solvent, e.g. toluene, and at C7 in polar solvents, e.g. ethanol.18... 

Substitution of fluorine in oligofluorinated compounds by diamines or amino thiols has been occasionally used for the synthesis of heterocycles, c.g. diazepines,2,33,34 pyrazoles,20,30,35 pyrimidines36 and thiazines,37 sometimes with participation of carbonyl or ester functions in the substrate. 

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