Fluorinations electron rich aromatic compounds

BF3 Et20 reacts with fluorinated amines to form salts which are analogous to Vils-meier reagents, Arnold reagents, or phosgene-immonium salts (Eq. 77) [131]. These salts can be used to acylate electron-rich aromatic compounds, introducing a fluorinated carbonyl group (Eq. 78). 

In aromatic systems, oxazolines can have three different functions (Fig. 4). Firstly, they can be used as protecting groups for carboxylic acids. Secondly, they activate even electron-rich aromatic systems for nucleophilic substitution. Fluorine or alkoxy groups in the ortho position can be substituted by strong nucleophiles such as Grignard reagents. Thirdly, when biaryl compounds with axial chirality are synthesized in these reactions, oxazolines can induce the formation of only one atropisomer with excellent selectivity. These three qualities were all used in the synthesis of 20, a precursor of the natural product isochizandrine [10]. 

The electrophilic fluorine of AcOF was also used for aromatic fluorinations. Activated aromatic compounds produced mainly the ortho fluoro derivatives in yields of up to 85%267. The dominant ortho substitution was a result of the addition of AcOF across the most electron-rich region of the aromatic ring. A subsequent spontaneous elimination of AcOH restored the aromaticity, but in cases where this was not possible the resulting cyclohexa-diene reacted very rapidly with the reagent and tars were obtained. Only in certain cases and with careful monitoring could the corresponding adducts be isolated (equation 151.)... 

The direct nucleophilic substitution of electron-rich phenol ethers using hypervalent iodine oxidants in the presence of Lewis acid or fluorinated alcohols and involving aromatic cation-radical intermediates was originally developed by Kita and coworkers in 1994 [362], Since then this procedure with some variations has been extensively applied by Kita and other researchers for various oxidative transformations. In the intermolecular mode, this reaction (Scheme 3.122) has been utilized for the preparation of the products 298 from N3, AcO , ArS, SCN , 3-dicarbony 1 compounds and other external nucleophiles [320]. The oxidative coupling reaction in the intramolecular mode provides a powerful synthetic tool for the preparation of various... 

More than a third part of all the described principal syntheses of pyrimidines bearing fluorinated alkyl at C-4 atom commences from fluorinated p-dicarbonyl compounds 699. The chemistry of these bis-electrophiles was reviewed recently [411, 412] therefore, their preparation is not discussed herein. This synthesis of pyrimidines is fairly general (Table 34) it allows for introducing aliphatic, alicyclic and aromatic p-diketones (Entries 1-10), p-ketoesters (Entries 11-16), and cyclic P-ketoamides (Entry 17). Presence of some functional groups, such as additional ester moiety (Entry 15), is more or less tolerated, whereas increasing steric hindrance results in lowered yields of the products (Entry 10). A scope of conunon NCN binucleophiles include amidines (Entries 1, 11, 12, 17), (thio)urea and its derivatives (Entries 2-4), guanidines (Entries 5,16) and biguanides (Entry 6). Electron-rich amino heterocycles e.g. aminoazoles and even 2,6-diaminopyridine) are excellent NCN binucleophiles for the principal synthesis of fused pyrimidine derivatives (Entries 7-10, 13-15). 

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