Fluoroarene

Halogenoly n i of the nitro substituent in fluoroarenes or fluoroalkylarenes provides a route to the corresponding chloro compounds [47, 48 (equations 30 and 31)... 

Milner (1992) recently described a novel and versatile modification of the Balz-Schiemann reaction. The amine is diazotized with solid nitrosonium tetrafluoro-borate in CH2C12 and, without isolation, the diazonium salt is heated and yields the fluoroarene in good yield. The method is also applicable to aniline derivatives bearing carboxy and hydroxy substituents, compounds which give poor yields in the classical procedure. 

A kinetic study of the hydrodefluorination of C F H in the presence of EtjSiH indicated a first-order dependence on both [fluoroarene] and [ruthenium precursor] and a zero-order dependence on the concentration of alkylsilane, implying that the rate-limiting step in the catalytic cycle involves activation of the fluoroarene. The regioselectivity for hydrodefluorination of partially fluorinated substrates such as CgFjH has been accounted for by an initial C-H bond activation as shown in the... 

With consideration of the shortcomings and advantages of the Medicinal Chemistry route discussed above, a retrosynthesis of 1 was designed to incorporate the convergent coupling of hydroxypyridine 9 and fluoroarene 11 as the key step (Scheme 8.2). Enantioselective preparation of the a-arylpyrrolidine 12 was identified as the key challenge. 

There are only a few examples of displacement of a fluorine atom in a cross-coupling reaction. With tricarbonylchromium complexes of fluoroarenes as substrates, cross-coupling with both boronic acids and vinylstannanes has been realized. Interestingly, only PMe3 is effective as ligand in this reaction (89).2" See Section 9.6.3.4.10 for an example of the involvement of unactivated fluoroarenes in cross-coupling reactions. 

A comparison of the yields of para-substituted [18F]fluoroarenes indicate that (i) acetyl hypofluorite is an inferior fluorination agent for the fluorodegermylation reaction and (ii) the aromatic substituents have considerable influence over the reactivity of the fluorination. A decrease in the fluorodegermylation yield was observed with electron-withdrawing aromatic substituents. The electrophilic aromatic degermylation reaction is thought to proceed via a cr-complex intermediate (Scheme 3). It has been hypothesized that the yield of aryl fluoride is influenced to some extent by the aromatic substituents ability to stabilize the cr-complex intermediate. 

Fluoroarene formation from arylamines. Also known as the Balz-Schiemann reaction. 

Due to its strong activating effect in nucleophilic aromatic substitutions and to the possibility of its removal by decarbonylation, the aldehyde function has been used for the preparation of [ F]fluoroarenes not bearing electron-withdrawing substituents. Decarbonylations, possible in the presence of Pd/C [ 161 ], are more efficient in terms of time (15 min vs 1 h) and yields (80%) when using Wilkin-... 

Suzuki and co-workers achieve aromatic substitution of fluoroarenes with a variety of aldehydes in good yields [91, 92], Imidazolilydene carbene formed from 143 catalyzes the reaction between 4-methoxybenzaldehyde 22a and 4-fluoroni-trobezene 141 to provide ketone 142 in 77% yield (Scheme 20). Replacement of the nitro group with cyano or benzoyl results in low yields of the corresponding ketones. The authors propose formation of the acyl anion equivalent and subsequent addition to the aromatic ring by a Stetter-like process forming XXVIII, followed by loss of fluoride anion to form XXIX. 

The trilluoromethyl group behaves in a similar way , but it is now clear that deprotonation of sites ortho to such acidifying but non-coordinating and non-electrophilic substituents is best carried out with BuLi-KOBu-t superbases (see Section VI). A combination of BuLi metallation and superbase metallation of fluoroarenes has been used in the synthesis of components 163 and 164 for fluorinated liquid crystals (Scheme 82). ... 

V.W. Pike, F. Aigbirhio, Reactions of cyclotron-produced [ F]fluoride with diarylio-donium salts—a novel single-step route to no-carrier-added f F]fluoroarenes,... 

A. Shah, V.W. Pike, D.A. Widdowson, The synthesis of [F-18]fluoroarenes from the reaction of cyclotron-produced [F-18]fluoride ion with diaryliodonium salts, J. Chem. Soc. Perkin Trans. I Organic and Bio-Organic Chemistry 13 (1998) 2043-2046. 

ArNHj remains (as it is a weak base), but the concentration is low enough to prevent as yet undiazotised amine undergoing a coupling reaction with the first formed ArNj (c/. p. 147). Aromatic diazonium chlorides, sulphates, nitrates, etc., are reasonably stable in aqueous solution at room temperature or below, but cannot readily be isolated without decomposition. Fluoroborates, ArN2 BF4 , are more stable cf. stabilising effect of BF on other ion pairs, p. 136) and can be isolated in the dry solid state thermolysis of the dry solid is an important preparative method for fluoroarenes ... 

This reaction is easily controlled, uses an inexpensive reagent, and gives benign products that are easily disposable. The method also shows promise as a means of converting inert saturated fluorocarbons into more reactive fiuoroalkenes or fluoroarenes for use in syntheses. 

The first example of exchange of a nuclear chlorine for fluorine was reported in 1936,28 2,4-dinitrofluorobenzene (a compound made first by Holleman) being formed by reaction of the chloro analog with potassium fluoride. Thus, three of the main routes to fluoroarenes originated in this period. 

The development of fluoroarene chemistry up to the 1960s is described in contemporary books and review articles.9,24 26,29 31... 

The diazotization stage plays the most important part in yielding fluoroarenes effectively. It is greatly influenced by the composition of the hydrogen fluoride solution and is enhanced by employing appropriate amounts of base such as pyridine under carefully controlled conditions. The fluorodediazoniation stage was effectively accelerated photochemically to afford fluoroarenes with polar substituents (hydroxy, nitro, etc.).329... 

Aryltrimethylsilanes underwent fluorodesilylation upon the action of two equivalents of xenon difluoride in dichloromethane, chloroform, trichlorofluoromethanc or hexafluoroben-zene at room temperature to form the corresponding fluoroarenes in preparative yields 65-80%.73 No reaction was observed in acetonitrile solutions. 

Table 3 shows that the fluoroarene yield increases with the irradiation power and is dependent again on the hydrogen fluoride/pyridine ratio (cf. 2-methoxy-4-nitroaniline). An optimum ratio must, most probably, be determined for each substrate. It should also be noted that photochemical fluorodediazoniation does not occur in pure hydrogen fluoride. This observation probably implies that not only light is involved in the weakening of the C-N bond. On the other hand, benzene is formed together with fluorobenzene when pyridine is replaced by 2,4,6-trimethylpyridine such a phenomenon is consistent with the occurrence of aryl radicals."... 

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... 

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