Nucleophilic Substitution of fluoride

These reactions are complicated further by the pronounced tendency of some alkyl fluorides to undergo /3-elimination, especially in protic solvents (strong hydrogen-bond formation with fluoride) and in the presence of vicinal electron-withdraw- 

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Fluoropyridines form valuable starting materials for a range of disubstituted pyridines because, after lithiation, nucleophilic substitution of fluoride (sometimes via the N-oxide) can be used to introduce, say, N or O substituents as in 191 and 192 (Scheme 96). Subsequent annelations can allow complex polycyclic heteroaromatics to be constructed. ... 

Intramolecular nucleophilic substitution of fluoride by heteroatoms can also lead to tricyclic systems such as dibenzofuran90 and acridinone91 derivatives (Eqs. 21 and 22). 

The alkylation process possesses the advantages that (a) a wide range of cheap haloalkanes are available, and (b) the substitution reactions generally occur smoothly at reasonable temperatures. Furthermore, the halide salts formed can easily be converted into salts with other anions. Although this section will concentrate on the reactions between simple haloalkanes and the amine, more complex side chains may be added, as discussed later in this chapter. The quaternization of amines and phosphines with haloalkanes has been loiown for many years, but the development of ionic liquids has resulted in several recent developments in the experimental techniques used for the reaction. In general, the reaction may be carried out with chloroalkanes, bromoalkanes, and iodoalkanes, with the reaction conditions required becoming steadily more gentle in the order Cl Br I, as expected for nucleophilic substitution reactions. Fluoride salts cannot be formed in this manner. 

The reaction with 4-nitrophenol and pentafluorophenol in the presence of KF-18-crown-6 has been investigated. Pentafluorophenoxide anion was found to be a better leaving group [82JFC(20)439]. Alkali metal fluorides on graphite can act as catalysts for nucleophilic substitution of pentafluor-opyridine [90JFC(46)57]. 

Most recent syntheses of fluorinated benzothiazoles make use of nucleophilic substitution. Potassium fluoride in acetonitrile converted 40 into the 2-fluoro derivative (R = 6-nitro) in 99% yield. When the solvent was dimethylformamide the 2-dimethylamino derivative was formed instead [80JCS(P1)2358], and similar behavior was reported earlier (77BSF171). 

Besides radical additions to unsaturated C—C bonds (Section III.B.l) and sulfene reactions (see above), sulfonyl halides are able to furnish sulfones by nucleophilic substitution of halide by appropriate C-nucleophiles. Undesired radical reactions are suppressed by avoiding heat, irradiation, radical initiators, transition-element ion catalysis, and unsuitable halogens. However, a second type of undesired reaction can occur by transfer of halogen instead of sulfonyl groups283-286 (which becomes the main reaction, e.g. with sulfuryl chloride). Normally, both types of undesired side-reaction can be avoided by utilizing sulfonyl fluorides. 

Aiyl fluorides and iodides cannot be prepared by direct halogenatlon. The cyano group cannot be Introduced by nucleophilic substitution of of Aromatic chlorine in chlorobenzene but cyanobenzene can be easily obtained from diazonium salt. 

Compared to homoaromatic and aliphatic substitutions, nucleophilic substitutions with fluoride ion or of heteroaromatic derivatives have not been... 

The radiosynthesis of p F]FDG is based on the nucleophilic substitution of a modified mannose precursor with [ F]fluoride used as the nucleophilic reagent (Fig. 3). 

Furthermore, Marshall et al. developed the extractable MBF tracer 7 -[ F] fluoro-6, 7 -dihydrorotenone (p F]FDHR) [72]. p F]FDHR is a derivative of the neutral and lipophilic lead compound rotenone that binds to the complex I of the mitochondrial electron transport chain [73-76]. It was prepared from 7 -tosyl-oxy-6, 7 -dihydroroten-12-ol (DHR-ol-OTos) in two steps. After nucleophilic substitution of DHR-ol-OTos with p F]fluoride, the intermediate was oxidized with manganese dioxide to yield the target compound [ F]FDHR (Fig. 11). 

By nucleophilic substitution of a sulfonate by fluoride ions. This reaction also proceeds with inversion of the configuration. ... 

For further reactions including displacement of the sulfonyl group with a labelled fluorine atom, see refs 191-193. The next homolog, tetraethylammonium fluoride has been also used for nucleophilic substitution of sulfonates. 3 /f-(Tosyloxy)-5 a//-androstan-l 7-one (7) on refluxing with tetraethylammonium fluoride in acetone yields 3a-fluoro-5a//-androstan-l 7-one (8) in 78% yield.194... 

The high reactivity of di- and trinitrophenyl fluorides towards nucleophiles has been used for the arylation of various N-nucleophiles. A method was developed for the determination of N-terminal amino acids in peptides. Thus, nucleophilic attack of the amino acid nitrogen at Sanger s reagent (2,4-dinitrophenyl fluoride, 4), hydrolysis and subsequent analysis of the N-(2,4-dinitrophenyl)amino acid allows determination of the amino acid.162,163 Although this method has been replaced by more efficient procedures, it marked a milestone in the elucidation of peptide structures (Nobel Prize 1958). A variety of N-nuclcophilcs (no amino acids) which have been used in the nucleophilic substitution of 2,4-dinitrophcnyl fluoride is listed. 

The silyl group is widely used as an oxygen protecting group, because of the ease of its removal by nucleophilic substitution by fluoride anion. The protected phenols 0-(tert-butyldimethylsilyl)-/ -(bromomethyl)phenol (45) and 0-(tert-butyldimethylsilyl)-2,6-bis(bromomethyl)phenol (46) react rapidly with fluoride anion in water to form the corresponding phenols, which then break down to the ortho-quinone methide 41 (Scheme 21A) and the substituted ortho-quinone... 

Another nucleophilic center can also appear due to tautomerization of the unsaturated bonds induced by bases such as the fluoride ion. Thus the reaction of perfluoro-2-methylpent-2-ene with active methylene compounds, for example, acetylacetone, ethylacetoacetate, benzoylaceto-nitrile, and benzoylmethylperfluoroalkylketones in the presence of KF gives not only the products of nucleophilic substitution of fluorine... 

Nucleophilic substitution of the fluoride of fluorobenzenetricarbonylchromium by morpholine leads to phenylation of the nitrogen (Scheme 18) [27]. However, in the case of imidazole, substitution is effected only with the anion of the nitrogen base. 

The ability of crown ethers to bind selectively to particular Group IA and Group IIA metal ions, because of the relationship between hole size and metal ion radius, has led to considerable interest in them in relation to membranes (models for selective ion transport), antibiotics (similar polyether structure), organic synthesis [solubilization of inorganic reagents leading to milder routes for oxidation (122), nucleophilic substitution (123), fluoridation (90)] and extraction of alkali... 

Recently, the [ F](luorobcnzalciehyde 5 was obtained by nucleophilic substitution of the 2-formyl-A, A, A -trimethylbenzeneammonium trifluoromethanesulfonate precursor 4 using no-carrier-added [K/222] F as the [ F]fluoride source. The ammonium trifluoromethanesulfo-natc4 is obtained by quaternization of the dimethylamino compound 3. The [ F]fluorobcnz-aldehyde 5 is used in the preparation of interesting radiopharmaceutical a-metliyl-L-amino acids for positron emission tomography, as well as potential inhibitors of enzymatic functions. 

In the course of nucleophilic substitution of vinyl fluoride in azamethines by the perfluoro-phenyl group using triinethyl(perfluorophenyl)silane, the geometry of the starting azaalkene remains unchanged, possibly indicating stereospecificity of this reaction. 

Nucleophilic substitution of nitro [242, 243] and trimethylamnioniuni groups [244] by fluoride ion has been employed for the preparation of a number of fluoroaliphatic and fluoroaromatic substrates (Figure 3.49). 

The reaction of various substituted 2-fluorobenzonitriles 1 with guanidine carbonate affords quinazoline-2.4-diamines 2 in excellent yields. It is proposed that this cyclization reaction proceeds by the reversible addition of guanidine to the cyano function followed by nucleophilic displacement of fluoride. The reaction possesses considerable generality and is successful even when electron-donating groups are present at position 6 of the educt... 

A convenient method for preparing 2-fluoro- and 2,3-difluoroquinoxalines under mild reaction conditions is fluorination by nucleophilic substitution of one or more chlorine atoms on the heterocyclic ring using cesium fluoride activated by 18-crown-6. This procedure can be modified into a one-pot synthesis of 2-substituted 3-fluoroquinoxalines from 2,3-dichloroquinoxalines by subsequent nucleophilic substitution with various synthons containing a primary or secondary amino group, e.g. synthesis of compound 11 (R = morpholino X = H). 

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