Fluorobenzene alkylation

Fluorobenzene is readily alkylated with alkenes in the presence of protic acids, however, the isomenc purity of the product is poor, and polysubstitution can result Thus, propene and sulfuric acid alkylate fluorobenzene at 20 C to yield a 45 55 ortho/para ratio of the inonoalkyl product m addition to di- and triiso propylfluorobenzene [i5] The reaction of benzene and trifluoropropene at 25 °C in HF-BF3 gives a mixture of mono-, bis-, and tns(3,3,3-trifluoropropyl)ben zene [72, 75] (equation 12)... 

Vinyl Inflates permit alkylation with vinyl cations [24, 25] Fluorobenzene reacts with 2 methyl 1-phenyl 1 propenyl triflate to form a diaryl alkene [24J (equation 17)... 

The initial series of major tranquilizers consists of alkylated derivatives of 4-aryl-4-hydroxypiperidines. Construction of this ring system is accomplished by a set of rather unusual reactions. Condensation of methylstyrenes with formaldehyde and ammonium chloride afford the corresponding hexahydro-1,3-oxazines (119). Heating these oxazines in the presence of acid leads to rearrangement with loss of water to the tetrahydropyridines. Scheme 1 shows a possible reaction pathway for these transformations. Addition of hydrogen bromide affords the expected 4-bromo compound (121). This last is easily displaced by water to lead to the desired alcohol (122) The side chain (123) is obtained by Friedel-Crafts acylation of p-fluorobenzene with 4-chloro-butyryl chloride. Alkylation of the appropriate arylpiperidinol with 123 affords the desired butyrophenone derivative. Thus,... 

The alkylation of halogen-substituted benzenes such as fluorobenzene and dichlorobenzenes with other (dichloroalkyl)silanes in the presence of aluminum chloride catalyst afforded isomeric mixtures of the corresponding (dihalogen-substituted phenyl)alkylsilanes in moderate yields (Eq. (13)). These results are summarized in Table Xll. 

Bismuth tra-tri lluoromcthancsulfonate, Bi(OTf)3, and BiCh were found to be effective catalysts for the Friedel-Crafts acylation of both activated and deactivated benzene derivatives such as fluorobenzene.19 Ga(III) triflate is also effective for Friedel-Crafts alkylation and acylation in alcohols and can tolerate water.20 This catalyst is water-stable... 

Alkylation of diphenylpiperidinols with bis(p-fluorophenyl)butyl side chains has also led to antipsychotic compounds. For example, reductive cycliza-tion of the acylation product (91) from fluorobenzene... 

Recently, Behiman and coworkers discussed the mechanism of the Elbs oxidation reaction and explained why the para product predominates over the ortho product in this oxidation. According to the authors, semiempirical calculations show that the intermediate formed by the reaction between peroxydisulfate anion and the phenolate ion is the species resulting from reaction of the tautomeric carbanion of the latter rather than by the one resulting from the attack by the oxyanion. This is confirmed by the synthesis of the latter intermediate by the reaction between Caro s acid dianion and some nitro-substituted fluorobenzenes. An example of oxidative functionalization of an aromatic compound is the conversion of alkylated aromatic compound 17 to benzyl alcohols 20. The initial step in the mechanism of this reaction is the formation of a radical cation 18, which subsequently undergoes deprotonation. The fate of the resulting benzylic radical 19 depends on the conditions and additives. In aqueous solution, for example, further oxidation and trapping of the cationic intermediate by water lead to the formation of the benzyl alcohols 20 (equation 13) . ... 

A/-[ F]Fluoropyridinium tiiflate reacts with alkyl- and arylmagnesium salts (Grignard reagents) as well as enolates (Scheme 23) to yield the corresponding radiofluorinated products, often in high radiochemical yields. Examples are the syntheses of [ F]fluorobenzene (62%), 1-p F]fluorohexane (78%), diethyl 2-p F]fluoro-2-phenylmalonate (58%) and ethyl 3-amino-2-p F]fluoropropionate (23%) [83]. 

Alkylation of the basic amino group in (19-6) with butyrophenone (20-1), available from the acylation of fluorobenzene with 4-chlorobutyryl chloride, affords the antipsychotic drug droperidol (20-2) [21]. Alkylation of the fully reduced intermediate (19-7) with a side chain (20-3) yields pimozide (20-4) [22]. 

The decomposition of arenediazonium tetrafluoroborates in the resulting fluoroarene as solvent has also been utilized.179 This method is very fruitful in the synthesis of fluorobenzene (96% yield) or fluorotoluenes (85-88% yield for the three isomers) but fails with substrates such as anisolediazonium tetrafluoroborates which probably arylate the reactive fluoroaromatic solvent. In contrast, perfluorinated tertiary amines (EF-L 174, F-C 40), perfluorinated alkyl tetrahydropyran (EF-L 102), perfluorodecahydronaphthalene (Flutec PP7) or other per-fluorocycloalkanes (Flutec s) are claimed to be the best media for fluorodediazoniation of all types of diazonium tetrafluoroborates.224 These media seem to be more efficient, at least in the synthesis of 1,2-difluorobenzene, than silicone oil which has also been claimed to improve fluorodediazoniation.225... 

The results obtained in the gas-phase isopropylation of various aromatic hydrocarbons with isopropyl chloride over Nafion-H catalyst showed only a relatively small variation of reactivity in going from fluorobenzene to xylenes.235 Therefore, it has been assumed that the reaction rate is controlled by the formation of a reactive electrophilic intermediate (possibly, protonated alkyl halide 61, or some form of incipient alkyl cation) rather than by cr-complex formation between the electrophile and the aromatic nucleus [Eq. (5.89)]. 

Prakash, Olah, and co-workers256 have prepared Mosher s acid analogs by the hydroxyalkylation of substituted benzenes with ethyl trifluoropyruvate [Eq. (5.95)]. Deactivated aromatics (fluorobenzene, chlorobenzene) required the use of excess triflic acid indicative of superelectrophilic activation.3 5 In contrast to these observations, Shudo and co-workers257 reported the formation gem-diphenyl-substituted ketones in the alkylation of benzene with 1,2-dicarbonyl compounds [Eq. (5.96)]. In weak acidic medium (6% trifluoroacetic acid-94% triflic acid), practically no reaction takes place. With increasing acidity the reaction accelerates and complete conversion is achieved in pure triflic acid, indicating the involvement of diprotonated intermediates. 

C o solubility increases in the similar sequence, from iodobenzene to chlorobenzene. The exception is fluorobenzene in which C6o solubility is lower than in iodobenzene. Apparently, in the case of interaction between fluorobenzene and C6o fullerene the factor of high fluorine electronegativity prevails. Moreover, as Table 3 indicates the fluorobenzene nitration gives rise to mainly para-isomer and very little ort/zo-isomers. Consequently, the entire negative charge is localized in the /jara-position in a fluorobenzene molecule. Therefore, as with Cgo solubility in alkyl derivatives of benzene (Table 2), one can anticipate that for the C6o molecule that is an electrophilic reagent, the ortho-position will be the more preferential location for electrophilic attack than the /w/ra-position. 

In 1972, Screttas10 reported that the reductive lithiation of aryl halides (including fluorobenzene) and (to a lesser extent) alkyl halides was successful even at -50 °C when carried out in THF in the presence of a stoichiometric quantity of naphthalene. Carbonation of the products gave carboxylic acids in high yields.11... 

Since these results are based on the data for neat liquids, similar objections may be made as those for the case of alkyl amines. Since the range of the shifts (Table IX) is less than 10 ppm, if we exclude the shift of 2-methoxyaniline, any correlations with either INDO-MO calculated electron densities for isolated molecules (48) or with the 13C and 19F chemical shifts of the corresponding toluenes and fluorobenzenes (68) may be of little significance. 

Benzene can be formylated very easily. Fluorobenzene gives fluorobenzaldehyde with a total selectivity in para isomer. On the contrary chloro and bromobenzene are transformed in poor yield, and chloro and bromo toluenes 17 are obtained next to halobenzaldehydes 16, showing that methyl formate can act as an alkylating agent. 

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