Fluorination Balz-Schiemann reaction

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. 

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. 

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). 

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... 

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>. 

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. 

Diazotization procedures. Widely used for the production of aromatic fluorine is the Balz-Schiemann reaction. The approach involves diazotization of the aniline and isolation of the insoluble tetrafluoroborate salt, followed by decomposition under heating conditions (Fig. 32). Initially introduced in 1927 [137,138], it did not achieve commercial utility until the mid-1980s. A modification of the Balz-Schie-mann reaction involves replacing the tetrafluoroborate with other counterions such as a fluorine anion [139],... 

H. Suschitzky, The Balz-Schiemann reaction, Advances in Fluorine Chemistry 4 (1965) 1-27. 

Aromatic fluorination chemistry has a remarkably long history, and the first successful synthesis of aryl C-F bonds was reported in 1870 [22], Significant developments in the area in the early part of the 20th century included the discovery of Balz-Schiemann reaction [23,24] involving diazotization of an aromatic amine in the presence of tetrafluoroboric acid and the reaction scheme is shown in Fig. 4. The above reaction produces large quantities of waste (such as NaBF4,... 

Regioselectively fluorinated heteroaromatic compounds can be obtained on transformation of amino groups using the classical Balz-Schiemann reaction (65MI1 71JA3060) or modified routes. When a solution of suitably protected 2-amino- and 4-amino-DL-histidines in 50% fluoroboric acid are treated with sodium nitrite and subsequently photolyzed, the 2-fluoro- and 4-fluoro-DL-histidine derivatives are obtained (73JA4619, 73JA8389) (Scheme 7). 

Since dialkyltriazenes were first used in aromatic fluorination by Wallach, ° many fluoroaro-matic compounds have been obtained in high yield by the decomposition of 3,3-dialkyl-l-aryl-triazenes with various fluorides in acidic media (see Vol. ElOa, p 725fT). Aryltriazenes are a potential source of aryldiazonium salts under controlled, mild, acid conditions. Therefore, this replacement (Route A) can be considered as a type of Balz-Schiemann reaction (see Section... 

The photochemical Balz-Schiemann reaction has been used for the preparation of interesting fluoroarenc pharmaceutical agents, such as ring-fluorinated tyraminc and dopamine derivatives (Table 9. entries 1-3), and 2-, 5-, and 6-fluoronorepinephrine precursors (entries 4 and 5), from the corresponding nitroarenes. 

Selective introduction of fluorine into an aromatic ring is often achieved by thermal decomposition of diazonium fluoroborates, which is called the Balz-Schiemann reaction (Scheme The scope of... 

In the laboratory of D.A. Holt, the synthesis of a new class of steroid 5 -reductase inhibitors was undertaken. They found that unlike the steroidal acrylates, steroidal A ring aryl carboxylic acids exhibit greatly reduced affinity for rat liver steroid 5 -reductase. The tested steroidal A ring carboxylic acids were synthesized from estrone in one example, fluorine was incorporated into the 4-position of estrone via the Balz-Schiemann reaction. 

The synthesis of 7-azaindoles is a challenging task and there are few efficient routes to substituted derivatives. In the laboratory of C. Thibault, the concise and efficient synthesis of 4-fluoro-1/-/-pyrrolo[2,3-jb]pyridine was achieved. The fluorination was carried out using the Balz-Schiemann reaction. The aromatic amine precursor was prepared via the Buchwald-Hartwig coupling of the aryl chloride with A/-allylamine followed by deallylation. The diazonium tetrafluoroborate intermediate was generated at 0 C and it decomposed spontaneously in 48% HBF4 solution to afford the desired aromatic fluoride. 

Suschitzky, H. The Balz-Schiemann reaction. Advan. Fluorine Chem. (M. Stacey, J. C. Tatlow, and A. G. Sharpe, editors. Butter-worths)... 

The Balz-Schiemann reaction for the introduction of fluorine into an aromatic nucleus involves forming the amine, then the diazonium fluoborate, which in turn decomposes into an aromatic fluoride (104,106,107). One of the reviews (104) of this reaction gives tables of the compounds prepared by this method. 

One of the earliest means of introducing fluorine selectively into specific positions of aromatic compounds is the Balz-Schiemann reaction [77] which dates back to the 1920s. An isolated arene diazonium tetrafluoroborate is thermolyzed at up to 120 °C to yield the corresponding fluoroaromatic compound. Because of the infamously hazardous nature of isolated diazonium salts the scope of the classical variant of the Balz-Schiemann reaction was limited to the small scale. The high exothermicity of the reaction is most conveniently controlled by diluting the diazonium salt with a solid inert medium such as sea sand. In addition to the danger to the experimenter, the reproducibility of the reaction yield is quite poor. 

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