Hydrazones, fluorination

Substituted aryl hydrazones can be converted to geminal difluondes in satis factory yields by molecular fluorine [H4, iodine fluoride [ 5], and N bromo-suc-cinimide-pyridinium polyhydrogen fluoride or A -bromosuccinimide-polyvi-nylpyridinium polyhvdrogen fluoride [5(5] (equation 21) (Table 6)... 

Iodine fluoride is a more versatile reagent than molecular fluorine in geminal fluorination of other hydrazones and related compounds under milder reaction conditions [55] Substrates fluorinated include hydrazones of simple cyclic or steroidal ketones (e g, 4 tert butylcyclohexanone, 70%, 3 cholestanone, 70%), W methyl and A/N dimethylhydrazones [R2C=NNH(CH3) 70%, R2C=NNC(CH3)2, 50%], semicarbazones (R2C=NNHCONH2, 25-50%), and 2,4-dinitrophenylhy-drazones [R2C==NNH-C6H3-2,4(N02)2, 25-50%]... 

The fluorination of enolates of ketone, amide, or hydrazone bearing a chiral auxiliary (SAMP, Evans oxazolidine) with nonchiral fluorination reagent (A-fluoro sulfonimides, A-fluoropyridine) occurs with excellent diastereoselectivities. ... 

Arylcinnolin-4-amines 246 could be obtained from o-trifluoromethylphenyl hydrazones 245 via treatment with NaHMDS in THF at —78°C (Equation 60). The mechanism consists of quinine methide formation followed by electrocyclization and elimination of HF yielding 3-aryl-4-fluorocinnolines. Nucleophilic aromatic substitution of the fluorine atom with NaFlMDS gave, after basic hydrolysis, 3-arylcinnolin-4-amines 246 <1999TL5111>. 

Although the last method gives satisfactory results, it requires a large excess of iodine monofluoride which has to be prepared from iodine and fluorine just prior to use. Furthermore, most of the unsubstituted hydrazones are rather unstable and undergo transformation into azines which are unrcactive towards iodine monofluoride. O-Methyloximes are also inactive with respect to iodine monofluoride. The procedure with bromine trifluoride is free of such limitations. 

Hydrolytic replacement of a fluorine attached to a C = C bond by a hydroxy group leads to the hydroxy compound or its tautomeric carbonyl compound. For example, 2,3,3,4,4,4-hexa-fluoro-l-(phenyldiazenyl)but-l-ene (7) is hydrolyzed in acidic media to give the phenyl-hydrazone in a mixture with its tautomer.13... 

Aryl ketone hydrazones are oxidized and fluorinated by fluorine to give a mixture of mono and difluoro hydrocarbons [74 (equation 10)... 

Very dilute fluorine was reacted with aromatic hydrazones to produce a benzylic CF2 moiety (equation 174)294. Aromatic fluorination with elemental fluorine had also been attempted. Purrington and Woodard found that ortho fluorination usually took place with systems carrying either electron-donating or electron-withdrawing substituent, although neither the yields nor the conversions were very high. They studied the influence of strong... 

The anion formed on nucleophilic attack of the hydrazine stabilizes by fluoride and subsequent HF elimination to give an o ,/3-unsaturated hydrazone, which undergoes an electrocyclic ring closure with HF elimination to yield 5-fluoro-4-trifluoromethylpyrazoles. The single fluorine bonded to C(5) can be exchanged by a wide variety of nucleophiles (88S194 90BAU2338). 

Functional groups containing the C = N bond, such as hydrazones, oximes and diazo compounds, can also be used in the synthesis of fluorinated derivatives and these reactions are the subject of this section. The reaction products in these procedures are usually the corresponding g cw-difluoromethylene compounds. Since oximes and hydrazones arc obtained from aldehydes and ketones, these reactions can be considered as an alternative to the direct transformation of a carbonyl group into the difluoromethylene group. As indicated in Section... 

Other reagents, such as bromine monofluoride, generated in situ from A -bromosuccinimide and pyridinium poly(hydrogen fluoride) [NBS, (HF) /pyridine] or poly(4-vinylpyridinium) poly(hydrogen fluoride) [NBS, (HF) /PVP], and elemental fluorine, as well as electrochemical methods, have been described for the transformation of hydrazones into. gem-difluoro compounds. 

In the reaction of hydrazones with bromine monofluoride (Table 3), the best yields of fluorinated compounds are obtained with bromine monofluoride generated from NBS, (HF) / pyridine (entries 1-3). No satisfactory results were obtained with A-iodosuccinimide. 

The reaction of hydrazones with elemental fluorine can also be used for the synthesis of gem-in ally difiuorinated compounds (Table 4). The procedure, however, can have severe limitations it is only applicable to aryl ketone hydrazones (no reaction is observed with the hydrazones of benzaldehyde, cyclohexanone, or cyclopentanone), and mixtures ofdi- and monolluorinated compounds are obtained. In some cases, monofiuorinated derivatives are the only reaction products (entries 4 and 5). 

Mono- and Difluorinated Compounds by the Reaction of Hydrazones with Elemental Fluorine General Procedure "... 

In contrast to the chemical oxidation of hydrazones with iodine monofluoridc. bromine tri-fluoride, bromine monofluoride, or elemental fluorine, which provides the corresponding gem-inally difluorinated compounds (vide supra), monofluorination of diaryl ketone hydrazones can be achieved by anodic oxidation in the presence of fluoride ions (Table 5). In this case geni-... 

The best results in the fluorination of benzophenone hydrazone (95%) are obtained at a low current density (1.3 mA cm in triethylamine trishydrofluoride/dichloromethane (entry 3), but these results could not be extended to other diaryl ketone hydrazones (entries 7-12). 

Monolluorinated Compounds by Electrolytic Fluorination of Hydrazones Typical Procedure ... 

For experimental procedures for fluorinations with iodine monofluoridc and bromine trifluoride, sec the reactions of hydrazones (Section 1.1.9.1.). 

In addition, diazo compounds can be prepared from hydrazones upon reaction with various oxidizing reagents. Despite the satisfactory results obtained using this procedure, fluorination of hydrazones or oximes is actually a more efficient method as these derivatives are easier to handle than diazo compounds. 

Hydrazones can be converted into gc/n-difluorides upon reaction with either fluorine [245], bromine monofluoride (generated in situ) [246] or iodine monofluoride [247], and the reaction of diazoketones with fluorine results in similar transformations [248] (Figure 3.50). 

Oxidation of fluorinated hydrazones with lead tetra-acetate forms a useful method for the synthesis of bis(perfluoroalkyl)diazomethanes [318] (Figure 8.121). 

The hydrazone (100-500 mg) was dissolved in anhyd MeOH (50mL). Dilute F2 gas (1 -5% in N2) was bubbled through the stirred, icc-cold solution until TLC showed that nearly all of the hydrazone had been consumed. The overall reaction time was 3-7 mill. The mixture developed an orange-red color which dissipated on further fluorination. After concentration of the mixture with a rotary evaporator, the flu-orinated components were analyzed by l0F NMR speciroscopy, followed by separation by HPLC or column chromatography. 

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