SCHIEMANN Fluorination

Scheme 2.29 Balz-Schiemann fluorination of aryl diazonium tetrafluoroborates. A recent variant works in 70% HF-pyridine, avoiding isolation ofthe explosive diazonium salt [77-79].

Fluorinated and iodinated derivatives are usually prepared by halogen exchange reactions, although the Baltz-Schiemann reaction has been applied to the synthesis of 2-fluoroquin-oxaline (66JHC435>. 

The Schiemann reaction seems to be the best method for the selective introduction of a fluorine substituent onto an aromatic ring. The reaction works with many aromatic amines, including condensed aromatic amines. It is however of limited synthetic importance, since the yield usually decreases with additional substituents present at the aromatic ring. 

The Balz-Schiemann reaction continues to attract attention, with much of it generated by the interest in fluoroquinolones, e.g., (7), which is a potential antibacterial. Two approaches to its synthesis are possible—introduction of fluorine prior to or post ring construction. Decomposition of the tetrafluoroborate salt was unsuccessful, whereas the PF6 salt (8) gave only a poor yield (84JMC292). A more successful approach was the introduction of F into the pyridine nucleus prior to formation of the 1,8-naphthyridine ring (84JHC673). A comparison of decomposition media showed that cyclohexane was the best with regard to yield and time. 

Photochemical modification of the Balz-Schiemann reaction has enabled fluorine-containing biologically important molecules e.g., imidaz-... 

On the basis of these redox potentials it seems likely that direct electron release to the benzenediazonium ion takes place only with iodide. This corresponds well with experience in organic synthesis iodo-de-diazoniations are possible without catalysts, light, or other special procedures (Sec. 10.6). For bromo- and chloro-de-di-azoniations, catalysis by cuprous salts (Sandmeyer reaction, Sec. 10.5) is necessary. For fluorination the Balz-Schiemann reaction of arenediazonium tetrafluoroborates in the solid state (thermolysis) or in special solvents must be chosen (see Sec. 10.4). With astatide (211At-), the heaviest of the halide ions, Meyer et al. (1979) found higher yields for astato-de-diazoniation than for iodo-de-diazoniation, a result consistent with the position of At in the Periodic System. It has to be emphasized, however, that in investigations based on measuring yields of final products (Ar-Hal), the possibility that part of the yield may be due to heterolytic dediazoniation is very difficult to quantify. 

The classical method for replacing a diazonio group by fluorine is the Balz-Schie-mann reaction (Balz and Schiemann, 1927) in which the arenediazonium tetrafluoro-borate is heated without a solvent. Although it gives fairly good yields in the majority of cases, it can lead to difficulties. These have been discussed by Wulfman (1978,... 

For the introduction of fluorine into aromatic and heteroaromatic compounds the photolytic fluoro-de-diazoniation sometimes has advantages compared with the corresponding thermal dediazoniation (Balz-Schiemann reaction, see Sec. 10.4). For aromatic substrates the reaction was studied by Rutherford et al. (1961), Christie and Paulath (1965), Petterson et al. (1971), and Becker and Israel (1979). Hexafluorophos-phates sometimes give better yields than tetrafluoroborates (Rutherford et al., 1961). In analogy to Balz-Schiemann reactions in solution (Fukuhara et al., 1987), photolytic fluoro-de-diazoniations of benzene derivatives with electron-withdrawing substituents give lower yields. 

For this reason, industrial fluorinations of aromatics are performed by other routes, mostly via the Schiemann or Halex reaction [54, 55]. As these processes are multi-step syntheses, they suffer from low total selectivity and waste production and demand high technical expenditure, i.e. a need for several pieces of apparatus. 

Fluorine substituents can also be introduced via diazonium ions. One procedure is to isolate aryl diazonium tetrafluoroborates. These decompose thermally to give aryl fluorides.106 Called the Schiemann reaction, it probably involves formation of an aryl cation that abstracts fluoride ion from the tetrafluoroborate anion.107... 

Halo-de-diazoniations are a series of reactions in which the replacement of the dia-zonio group changes from a heterolytic de-diazoniation in the case of the fluorination (Balz-Schiemann reaction) to transition metal-catalyzed chlorination and bromination (Sandmeyer reaction) and finally to iodination and astatination where no catalyst is necessary due to the favorable redox potentials of I and At- (I- E° = 1.3 V). 

Balz, G. Schiemann. G. Ber. Dtsch. Chem. Ges. 1927, 60, 1186. Gunther Schiemann was bom in Breslau, Germany in 1899. In 1925, he received his doctorate at Breslau, where he became an assistant professor. In 1950, he became the Chair of Technical Chemistry at Istanbul, where he extensively studied aromatic fluorine compounds. 

In order to use the potentiality of the Balz Schiemann reaction and to increase the specific radioactivity, the tetrafluoroborate anion was substituted for the tetrachloroborate. The fluorination of p-toluidyl diazonium tetrachloroborate. 

The Balz-Schiemann and Wallach reactions The Balz-Schiemann reaction (the thermal decomposition of an aryl diazonium salt. Scheme 46) was for many years the only practical method for the introduction of a fluorine atom into an aromatic ring not bearing electron-withdrawing substituents. This reaction, first reported in the late 1800s, was studied in fluorine-18 chemistry as early as 1967 [214]. It involves the generation of an aryl cation by thermal decomposition, which then reacts with solvent, nucleophiles or other species present to produce a substituted aromatic compound. Use of fluorine-18-labelled... 

HF—Amine Complexes Complexes of fluorhydric acid (HF) with pyridine or alkyl amines (Et3N, Et2NH) are often utilized as reagents in nucleophilic fluorination reactions such as the opening of oxiranes," the bromofluorination of double bonds in the presence of NBS, or the diazotation/fluorination of amines with sodium nitrite (the Balz-Schiemann-like reaction) (Figure 2.1). ... 

Aromatic fluorination involves analogous methods to those used in the aliphatic series. The most utilized methods are electrophihc fluorination (F2, N— F reagents) and nucleophilic fluorination through the Balz-Schiemann reaction (diazotation in the presence of fluoride ion). This latter method is of prime importance in industry. When the aromatic ring is activated by one or several electron-withdrawing groups, the... 

In most of cases, the fluorine atom(s) or the CF3 group(s) is borne by aromatic rings. Synthesis of these compounds for the optimization of hits as well as for parallel synthesis is done using the numerous fluoro aromatic or heterocyclic compounds that are commercially available. These latter compounds generally come from aromatic fluorination or trifluoromethylation reactions (especially the Balz-Schiemann reaction) and from heterocyclization reactions. However, fluoroaliphatic chains and fluorofunctionalities are more and more present, because of their pharmacological properties. Some examples are given in this section. 

Two routes to the electrophilic fluorination of pyrrolo[2,3-3]pyridine A -oxide lead to the 4-fluoro derivative. The Balz-Schiemann reaction route, via a diazonium tetrafluoroborate salt, or a lithium/halogen-exchange reaction followed by quenching with an electrophilic fluorine source, generates the 4-fluoro product in moderate yields <20030L5023>. 

Meinert demonstrated that fluorination of pyridine at low temperatures gives the ionic salt N-fluoropyridinium fluoride, a compound that was reported to be explosive at 0°C (Fig. 59) [154]. However, direct fluorination of variously substituted pyridines is possible and good yields of the corresponding 2-fluoro-pyridines (Figs. 60 and 61) [155] are obtained, offering an attractive alternative to the usual halogen-exchange and Balz-Schiemann routes to these products. These reactions probably proceed via N-fluoropyridinium salts (Fig. 62) which are activated towards nucleophilic attack. 

Diazotization in the presence of boron trifluoride enables diazonium tetrafluoroborates to be isolated from the reaction mixture and purified. Subsequent controlled decomposition produces the required fluoroaromatic. Although explosion hazards and the toxicity of the isolated salts are significant concerns with this process, known as the Balz-Schiemann process, 4,4 -di-fluorobenzophenone (BDF. 6) has been prepared by this route as a monomer for the production of the engineering plastic poly(ether ether ketone) , or PEEK , by condensation with 1,4-dihydroxybenzene in the presence of potassium carbonate. BDF 6 is superior to its chlorine analog because in aromatic systems the nucleophilic displacement of fluorine is more facile than that of chlorine, leading to a shorter polymerization time and a better quality product containing less degradation impurities. 

Due to the corrosive and toxic nature of volatile hydrogen fluoride, the fluorodediazoniation of aromatic and heteroaromatic amines in anhydrous hydrogen fluoride (see Section 26.1.2.), though very efficient, inexpensive and easy to scale up, needs special apparatus and safety measures which are not always available in every laboratory. Thus, the Balz-Schiemann reaction remains the most popular way to substitute aromatic amino groups for fluorine on a laboratory scale. Moreover, special techniques have been developed during the last decade to control formation, storage and decomposition of arenediazonium tetrafluoroborates on a large scale. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

This technique has been applied to the synthesis of fluorinated dopamine and other compounds of biological significance Fluoroheterocycles such as fluoro-lmidazoles [35, 36] and fluoropyrazoles [37] can also be prepared by the photo Balz-Schiemann technique (equation 9) Photoohemically induced in situ fluoro dediazoniation can also be applied to arenediazonium fluorides in hydrogen fluo ride-pyridine media Thus, o-fluoroanisole is obtained in 73% yield at 20 °C after 18 h [35]... 

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