Difluorine production

The heterocyclic system bimane produces a difluorinated product on fluonnation with acetyl hypofluorite [34] (equation 11)... 

GL4] [R 5] [P 5] A yield of 62% was achieved at 90% conversion [15], The amount and nature of difluorinated products was also specified in [16], Besides this performance in single micro-channels, conversion and yield for a fhree-micro-chan-nel reactor given [16],... 

The thallium trinitrate-mediated ring contraction of frani-decal-2-ones has opened up a new route to the hydrindane system, and fluorinative ring contraction of cyclic alkenes to afford difluorocycloalkanes has been induced by iodotoluene difluoride and EtsN-HF. A possible mechanism is shown in Scheme 78. The double bond of the cyclohexene ring is attacked by iodotoluene difluoride activated by HF from the axial direction, followed by the addition of a fluoride ion from the trans direction. Reductive elimination of iodotoluene from the resulting adduct, ring contraction and the addition of the fluoride ion to the carbocation stabilized by fluorine then take place to give the ring-contracted difluorinated product. 

Substrates Difluorinated products Yield (%) Selectivity (di mono)... 

Bis(perfluoroalkyl) selenides quantitatively react with chlorine monofluoride at — 78 C to give difluorinated products. 

The preparation of fluorinated pyridine derivatives continues to be of considerable importance due to the effect that the fluorine atom can have on the physical, chemical, and biological properties of the heterocycle. Despite this, there are few reports on the direct electrophilic fluorination of pyridines. The treatment of various quinoline derivatives with elemental fluorine in acidic reaction media afforded mono- and difluorinated products where the halogenation occurred on the benzene ring of the heterocycles <2004JFC661>. 

In the reaction of a-(trihalomcthyl)sulfanyl ketones with hydrogen fluoride,, -difluoroalkyl fluoridothiocarhonates 14 are obtained instead of the expected trifluoromethyl sulfides.The reaction is thought to proceed via an initial chlorine-fluorine exchange reaction followed by rearrangement into the /i-difluorinated product. 

The reaction of a-fluoro-/f-hydroxy-a-phenylsulfanyl esters 4, which can be readily synthesized from aldehydes and ethyl bromofluoroacetate, with diethylaminosulfur triduoride leads to the formation of a,o -difluoro-/I-phenylsulfanyl esters Instead of the expected substitution of the j8-hydroxy group by fluorine, a rearrangement via an episulfonium ion and addition of a fluoride ion % to the ester function gives the a,a-difluorinated product 5. The reaction proceeds under mild conditions with moderate to good yields. In the case of ethyl 2-fluoro-3-hydroxy-3-phenyl-2-(phcnylsulfanyl)propanoate only the nonrearranged product ethyl 2.3-di-fluoro-3-phenyl-2-(phenylsulfanyr)propanoate was isolated. 

The fluorination of adamantane and its derivatives can also be achieved with oxygen difluoride in the presence of sodium hydrogen carbonate as a hydrogen fluoride trap however, this reaction is complicated by competing oxidation.22 When the fluorination of adamantane is performed with cesium fluoroxysulfate, a mixture of monofluorinated products 4 and 5 arising from fluorination at tertiary and secondary sites, respectively, and difluorinated product 6 is obtained.23 The thermally initiated fluorination of adamantane using xenon difluoride gives a similar mixture but includes a small amount of trifluoride 7.24 25... 

Anodic oxidation of olefins in the presence of fluoride ions provides mono- and/or difluorinated products [Eqs (2) and (7)] [10,33,34]. Butadiene gives a 1 2 mixture of 1,2-and 1,4-adducts [35]. Anodic fluorination of vinyl sulfides such as 2-(phenylthio)styrene provides vicinal difluorides [36]. 

In contrast, anodic oxidation of hydrazones in the presence of fluoride ions provides mainly monofluorinated products, and gem-difluorinated products are formed in low yields [90]. 

Scheme 2.7 Selective direct a-fluorination of carbonyl compounds. Copper salt catalysis supposedly acts via formation of the copper enolate complex [19, 20], The formation of the corresponding copper complex of monofluoromalonate, the precursor of difluorinated products, is energetically disfavored.

The so far most advanced protocol employs a catalyst based on nickel instead of palladium, and the BlNAP-complex 5 of nickel dichloride was identified as a suitable catalyst precursor [36]. The resulting catalysis readily converts ester equivalents into the corresponding monofluorinated derivatives. No difluorinated product is formed and the reaction proceeds with good to very good enantiomeric excesses of up to 88%, with no racemization encountered under the chosen conditions. Importantly, the thiazolidinone group could readily be removed within a two-step procedure as demonstrated for the phenyl-substituted product. Hence, enantiomerically enriched a-fluoro aryl acetates are now available from this protocol. 

However, the current efficiency for this difluorination reaction is extremely low because of competitive oxidation of EtjN-SHF and the starting compound. On the other hand, gm-difluorinated products 64 can be obtained directly from the organic sulfur compounds 41 by using the less oxidizable salt Et4NF4HF as shown in Scheme 50. In these cases, theoretical amounts of electricity must be employed to bring about complete fluorination. 

Hydrazones are known to be alternative precursors to gem-di-fluoromethylene compounds. Oxidative gg/n-difluorination of hydra-zones has been performed with fluorine gas, in situ prepared IF from I2 and Fj, or in situ generated BrF from A -bromosuccininiide/Py(HF) . In contrast, anodic oxidation of hydrazones in the presence of fluoride ions provides monofluorinated products predominantly along with smaller amounts of ge/ra-difluorinated products (Scheme 52). ... 

This reagent has been shown to be a good base for the generation of highly reactive potassium enolates for example, treatment of various ketones and esters bearing a-hydrogens with KN(TMS)2 followed by 2 equiv of N-F-saccharinsultam allowed isolation of the difluorinated product (eq 3). 

TV-fluorobenzenesulfonimlde also reacts with lactone and lactam enolates to afford the corresponding a-fluoro deiivatlve. Glutamates can be monofluoiinated in the 4-posItion by this method. Repeating the reaction sequence affords the corresponding difluorinated product (eq 15). ... 

Electrochemical fluorination of olefins provides mono- and/or difluorinated products. In the cases of a-acetoxystyrene and 1-acetoxy-3,4-dihydronaphthalene, the corresponding a-fluoroketones are formed as shown in Scheme 3 [7],... 

The selectivity of fluorination was strongly influenced by supporting fluoride salts (Scheme 9) [14], Since EtsN-SHF contains the free base EtsN, the difluorinated product, once formed, was dehydrofluorinated to the monofluoro product. 

Similar selectivity issues can be found in triflamide-directed reactions (Scheme 23.48) [153]. Using a modified fluorinating reagent 26, mono- and difluorinated products can be obtained. A more recent development focuses on addressing this selectivity issue with an auxihary-based approach [ 154]. Finally, quinoxaline-based directing groups are also able to promote mono-selective C-H bond fluorinations in combination with N-fluorobenzenesulfonimide as F+ source [151],... 

Excluding pyrimidine derivatives electrophilic fluorination of other diazines was almost not studied. To the best of our knowledge there is no examples of electrophilic fluorination of pyridazines and only 1 paper and 1 patent devoted to fluorination of pyrazines and quinoxaline. Chambers and co-workers described fluorination of quinoxalines 29 in good yields using elemental fluorine-iodine mixtures at room temperature (Scheme 8). Mono- (30) and difluorinated products 31 were formed in different ratio depending on amount of fluorine used in the reaction. It should be noted that pyrazine, pyrimidine and pyridazine were recovered unchanged using similar condition [42]. 

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