Fluorodenitration

Fluorodenitration of nitroaromatics represents an exchange duorination technique with commercial potential. For example, y -duoronittoben2ene [402-67-5] from y -dinitroben2ene [99-65-0] and KF in the presence of various promoters can be reali2ed (69—72). This is not feasible under Halex conditions with y -chlotonittoben2ene [121 -73-3]. 

Fluorodenitration of nitroaliphatics has been primarily restricted to polyni tromethanes (Table 9) Side reactions involving potassium nitnte by-product reduce yields of fluoromtromethane The novel use of the adduct of potassium fluoride with hexafluoroacetone in diglyme as a source of fluoride ion for the fluorodenitration of tetranitromethane significantly increases the yield of fluorotn nitromethane [102] (equation 29)... 

Aliphatic fluorodenitration has also been applied to mononitro compounds, specifically to an a-nitroepoxide Thus, l,2-anhydro-3 4 5,6-di-O isopropyli dene-1-C-nitro D mannitol and labeled potassium bifluonde give 2-deoxy-2-fluo-ro-3,4 5,6-di-O-isopropylidene aldehydo D glucose [J03, 104] (equation 30)... 

Aromatic fluorodenitration was first discovered in the reaction of polychloro-nitrobenzenes with potassium fluoride, when 2,3,5,6-tetrachlorofluorobenzene was prepared in 37% yield from 2,3,5,6-tetrachloronitrobenzene 105] The technique has been adapted to prepare aryl fluorides from other activated nitro aromatics for applications in pharmaceutical and polymer chemistry (equation 31) Fluorodenitration also has been applied to prepare radiolabeled ( F) fluo-roaromatics [74, 106]... 

A characteristic feature of aromatic fluorodenitration is modest yield due to side reactions promoted by potassium nitrite and/or its decomposition product, potassium oxide, with the aryl fluoride or starting material... 

Although potassium fluoride is the preferred nucleophile, tetiabutylam-monium fluoride (TBAF) is successfully used for aromatic fluorodenitration o Fluoronitrobenzene can be obtained in quantitative yield from o-dinitrobenzene in tetra hydrofuran at 25 °C after 1 5 h 7]... 

Fluorodenitration with potassium fluoride has been applied to mtropyndines and nitrothiazoles 2 Nitropyridine can be converted to 2 fluoropyridme in 55-60% yield [107] (equation 34)... 

Anhydrous hydrogen fluoride can also effect fluorodenitration of nitrohetero-cyclics such as 3(5) mho 1,2,4 triazoles and 8-nitropurine to give 3(5)-fluoro-1,2,4-triazoles and 8-fluoropurine, respectively [iiS] (equation 35)... 

Moderate yields of the 1- (47%) and 4- (51%) fluoro derivatives of benzo[c]cinnoline were obtained by fluorodenitration of the nitro precursors using tetrabutylammonium fluoride. The 2- and 3-fluoro isomers have been made by Schiemann reactions, though yields were only 25 and 35%, respectively (92SC545). 

In more complex structures, F-fluorodenitration ([ F]nBu4NF or [18F]KF/K222> 150°C, DMSO) are not always successful [142] and a combination of all the electronic effects of the different substituents (alkyl substituents at the meta and para positions of the estrogen systems in the example given in Scheme 22) have to be taken into account. 

Ph4P HF2 378.42 + + fluorodenitration good thermal stability excellent solubility in polar solvents 4... 

Another fluorodenitration technique features 3 mtrophthaloyl chloride in a dual role as both substrate and potassium nitrite trapping agent to give 3-fluoro phthalic anhydride in 82% yield in sulfolane at 130 °C after 1 5 h [116]... 

Aqueous hydrofluoric acid is ineffective in fluorodenitration of activated aromatics, hexamtrobenzene in benzene does not react at 25 °C [779]... 

Aromatic fluorodenitration.s This substitution of nitroarenes by fluorine can be accomplished with anhydrous Bu4NF obtained by evaporation of the commercial trihydrate at 50-60° and <1 mm. for 18-24 hours. However, only activated or sterically hindered nitroarenes undergo this substitution. 

Nevertheless, nucleophilic displacement of an activated aromatic nitro group by fluoride is much more common and constitutes an efficient method of linking fluorine to an aromatic ring. The availability and low cost of nitroaromatics make fluorodenitration an attractive alternative to halogen exchange for the synthesis of selectively fluorinated aromatic compounds via nucleophilic fluorination. Various salts, such as rubidium [ F]fluoride, - tctrabutylam-monium fluoride, or potassium fluoride. can be used as fluoride sources. 

In comparison with conventional nucleophilic displacement of other groups, such as chlorine, bromine and iodine, fluorodenitration is much faster. Therefore, substitution can be carried out under milder reaction conditions. In particular, lower temperatures allow the synthesis of complex, thermolabile derivatives, e.g. [ F]spiroperidol from its inactive nitro analog using rubidium [ F]fluoride. ... 

Rubidium [ F]fiuoride is used as a reagent for the [ F]fluorodenitration of nitroaromatic compounds containing activating groups (e.g., CN, COR, CO2R, OH. OMe, etc.). Rubidium [ F]fluoride gives better yields than other fluoride salts, such as potassium fluoride or cesium fluoride, which are extremely hygroscopic. This method constitutes a very convenient route to [ F]fluorine-labeled aromatics, which are often required in radiopharmaceutical studies. 

F]Fluorodenitration is faster than the isotopic exchange reaction of activated fluorobenzenes with [ F]fluoride and has the advantage of yielding no-carricr-added derivatives. ... 

Batchwise Fluorodenitration Using Anhydrous Tetrabutylammonium Fluoride... 

Anhydrous tetrabutylammonium fluoride (TBAF) has been reported as being a very powerful fluoride source for the preparation of fliioroaromalic derivatives, via fluorodenitration, under mild reaction conditions. In fact, this reagent is not totally anhydrous and water, in less than one molar equivalent, is present together with < 10 mol% of decomposition products that arise during the synthesis of TBAF from commercially available tetrabutylammonium fluoride trihydrate. 

Fluoroaromatic Compounds by Fluorodenitration with Azeotropically Dried Tetramethylammonium Fluoride General Procedure ... 

The TMAF was dried in situ, before adding the substrate, by azeotropically removing the HjO present with benzene or cyclohexane for 2-12 h. Fluorodenitrations were carried out using 1.2-3 molar equivalents of TMAF in DMSO at 60-100 C. 

Fluorodenitration can be realized with the less reactive potassium fluoride when bromo(tetra-phenyl)-4 -phosphanc (Ph PBr) is used as a phase-transfer catalyst. - Bromo(tetraphenyl)-A -phosphane acts by enhancing the nucleophilicity of the fluoride anion in aprotic solvents of medium or high polarity, in which it is very soluble. The catalytic effect of bromo(tetraphenyl)-... 

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