Fluorodesulfuration

Recently [251], the preparation of [3- F]trifluoropropylamine was achieved in three steps from iV-phthalimido-3-aminopropane dithioate by oxidative- F-fluorodesulfurization, then hydrazinolysis of the resulting iV-phthalimido-[i8F]trifluoropropylamine with an overall chemical yield of 40% and within 60 min from [ F]HF (Scheme 64). This new labelled precursor was used to synthesize the marker of hypoxia [ F] -EF-3. 

Trifluoromethyl hypofluorite reacts with various sulfides in trichlorofluoromethane at — 78 C forming difluoro- 624 and tctrafluorosulfancs 7,25 while fluorodesulfuration is observed in the reaction of amino acids, e.g. formation of 8.26 In a similar manner, trivalent phosphorus compounds react with trifluoromethyl hypofluorite to give difluoro-substituted derivatives 9.27... 

Fuchigami and his coworkers also found that imidazolium ionic liquid and dichloromethane show similar solvent effects on anodic fluorodesulfurization. As shown in Table 8.2, anodic fluorodesulfurization of 3-phenylthiophthalide (4) takes place exclusively in [EMIM][OTf] and CH2CI2 to afford 5, while a-fluorination... 

Very recently it has been shown that anodically fluorinated product selectivity is greatly affected by fluoride ionic liquids, as shown in Scheme 8.14 [27]. The electrolysis of a phenylthioglycoside derivative 7 in Et3N 4HE provides fluorodesulfurization product 8 exclusively, while that in Et3N 3HE affords a-fluorinated product 9... 

Oxidative Fluorodesulfurization of Aryl Sulfides General Procedure ... 

Unsaturated Trifluoromethyl Compounds by Oxidative Fluorodesulfurization of Unsaturated... 

Oxidative fluorodesulfurization can also be achieved by the action of nitrosonium tetrafluo-roborate, as oxidant, and hydrogen fluoridc/pyridine, as a source of fluoride ions, on aryl sulfides.249 The starting compounds are easily prepared from ketones or aldehydes and ben-zenethio) using boron trifluoride monohydrate as catalyst, and subsequent reduction with triethylsilane.249 250... 

Hypervalent iodine compounds, such as l-(difluoroiodo)-4-methylbcnzcnc or l-(difluoroiodo)-4-methoxybenzene, can serve as oxidant and simultaneously as the source of fluoride ions. They are used for fluorodesulfurization reactions under mild conditions.229 230 The reagents arc crystalline and soluble in organic solvents. 

A very generally applicable method for converting a variety of different functional groups into their partially or fully fluorinated analogs is the oxidative fluorodesulfuration of thiocarbonyl compounds, dithiolanes, dithianes, and dithianylium salts. 

The sulfur species is thus activated by S-halogenation into a nucleofugic leaving group, which is substituted by fluoride. The fluorodesulfuration of thiocarbonyl compounds is supposed to follow a similar principal pathway. 

Scheme 2.68 Proposed mechanism of oxidative fluorodesulfuration of dithiolanes [142] (X stands for electrophilic bromine Br+ , iodine 1+ , or the nitrosyl cation, NO+).

From the viewpoint of atom economy [155], dithiolane or dithiane fluorodesulfuration chemistry suffers from a drawback - as a result of oxidation of the sulfur-ous protecting (and activating) group a relatively large part (by molecular mass) of the starting material is lost and cannot be recovered or recycled. 

Many varieties of fluorodesulfuration of protected (or activated) carbonyl compounds are known. Some contain an intermediate reductive step, leading to a wiorto-fluoromethylene instead of a gem-difluoromethylene group [146]. 

Scheme 2.69 Examples of the versatility of the different varieties of fluorodesulfuration reactions [145, 154, 155, 157].

In carbohydrate chemistry fluorodesulfuration has become a convenient tool for switching between different, orthogonal modes of glycosidic activation [158] (Scheme 2.70). 

Scheme 2.70 Syntheses of glycosyl fluorides from thioglycosides by oxidative fluorodesulfuration [145, 152].

Since the late 1990s, fluorodesulfuration has gained importance as a valuable synthetic tool, especially for preparation of liquid crystals [161, 162], The methodology enables convenient access to aliphatic trifluoromethyl ethers and, more recently, to c(,a-difluoroalkyl [147a] and perfluoroalkyl ethers also [163] (Scheme 2.72). 

Scheme 2.72 Synthesis of liquid c stals by oxidative fluorodesulfuration of xanthogenates (aboi e) [162], and by the oxidative alkoxydifluorodesulfuration of dithianylium salts (beloiv) [163].

Mechanistically the only difference from the chemistry depicted in Scheme 2.68 is the formation of a dithioorthoester as the central sulfur-containing intermediate if this is generated from strongly electron-deficient perfluoroalkyl dithianylium salts (Scheme 2.73) it can be isolated at room temperature. For alkyl or aryl dithia-nylium salts with less fluorination the dithioorthoester is a labile intermediate which is only stable at low temperatures (up to ca. —50 °C). This intermediate is subsequently fluorodesulfurated to yield the corresponding a,a-difluoroether. 

Scheme 2.73 Synthesis of ,c -difluoroether-linked liquid crystals by oxidative alkoxydi-fluorodesulfuration of dithianylium salts. The intermediate dithioorthoester is only stable at temperatures below ca — 50 C [147a].

Dithianylium salts in combination with oxidative fluorodesulfuration chemistry are also useful reagents for synthesis of gem-difluoromethylene analogs of carboxylic acid derivatives other than esters. If the fluorodesulfuration is conducted in the presence of other O- or M-nucleophiles the corresponding a.a-difluoroalkyl compounds are obtained in reasonable to good yields (Scheme 2.74). 

O Hagan and coworkers recently found that fluorodesulfuration is not only a versatile tool for the synthetic organic chemist but also - in a non-oxidative variant - so far the only known pathway in nature for enzymatic incorporation of inorganic fluoride ions into secondary metabolites [166] (Scheme 2.75). As the key step of this enzymatic reaction sequence a trialkylsulfonium ion (SAM) reacts with inorganic fluoride in a nucleophilic replacement with methionine as the leaving group. 

Scheme 2.74 Fluorodesulfuration of dithianylium salts in the presence of different O- and N-nucleophiles enables convenient access to a variety of rz/z-difluoroalkylated products (R = n-CjHz or n-CsH,) [147b].

Scheme 2.75 Biological fluorodesulfuration and subsequent enzymatic conversions (SAM = S-adenosyl methionine, 5 -FDA = 5 -fluorodesoxyadenosine,...

Perfluoroalkoxy groups and, especially, the trifluoromethoxy group, are commonly used as structural elements in pharmaceuticals (Section 4.5) and organic materials (Section 4.4). Aromatic and aliphatic perfluoroalkoxy groups are conveniently accessible via fluorodesulfuration chemistry (see also Section 2.1.5.4). Nevertheless, the technically important trifluoromethoxy arenes, in particular, are produced on a larger scale by a different method, based on chlorine-fluorine exchange with hydrofluoric acid [17] (Scheme 2.172). 

Generation of a Trifluoromethoxy Croup by Oxidative Fluorodesulfuration of a Xanthogenate... 

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