Balz—Schiemann route

Applications in agrochemicals [42, 43], pharmaceuticals [44,45], and positron emission tomography (PET) [46, 47, 48 49] have resulted in the resuscitation of the Wallach reaction The Wallach technique provides high-specific-activity F-radiolabeled aromatic fluoride for PET studies, in contrast to the low-specific-ac-tivity product by the Balz-Schiemann route... 

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. 

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>. 

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. 

A potentially very important use for HF Py was developed by Yoneda and coworkers, who used this complex as an efficient diazotization agent on route to various fluoroaromatics (equation 17). This variation of the old Balz-Schiemann reaction can be carried in chlorobenzene where HF Py is not soluble but the resulting soluble ArF enables a flow reaction to be devised31. This was successfully tested on various pyridines as well32 and, because of the reaction importance, its mechanism and kinetics were carefully studied33. 

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... 

In general, the Balz-Schiemann process involves the preparation of an insoluble arenediazonium ictrafluoroborate, either by aqueous diazotization of the corresponding arylamine with tetrafluoroboric add (Route A), or by addition of tetrafluoroboric acid or alkaline tetrafluoroborates to an aqueous solution of another previously formed arenediazonium salt (Route B). After filtration and drying, the diazonium tetrafluoroborate is decomposed to form the corresponding organo-fluorine compound. 

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. 

Physical constants of several partially fluorinated biphenyls (up to the 2,2, 3,4, -5,5, 6-heptafluoro-compound), obtained by a range of classical methods including the Friedel-Crafts, Ullmann, and Balz-Schiemann reactions, have been reported, and 1,8-difluoro- or 1,4,5-trifluoronaphthalene may be obtained by conventional routes (nitration, reduction, diazotization) from 1,8-diamino- or 1,5-difluoro-naphthalene, respectively. ... 

Diazonium salt chemistry provides a classic synthetic route to fluorinated arenes, the Balz-Schiemann reaction ... 

Historically, aryl fluorides were prepared by either Balz-Schiemann-type reactions or though the Halex process [70-75], Although a number of these procedures were quite successful, many of them required the use of toxic reagents or harsh conditions. To address these issues and provide practical routes to aryl fluorides, a host of alternative protocols have been developed [6, 76-78]. In addition to this work, a number of methods for the synthesis of aryl halides have been developed. The following sections will highlight several practical versions. 

A very important advance was made in 1927, with the disclosure24 by Balz and Schiemann of a new synthetic route (which has ever since been named after them) from an arylamine to an aryl fluoride. After diazotization in the normal way, the readily available tetrafluoroboric acid, or a tetrafluoroborate salt, was added to precipitate the insoluble diazonium tetrafluoro-borate salt. This was then dried and heated it decomposed (usually at 100-150°C) to give a good yield of the corresponding aryl fluoride. 

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