Nucleophilic halogen exchange

A. Introduction of Fluorine into a Heterocycle 1. Nucleophilic Halogen Exchange... 

Nucleophilic halogen exchange, using cesium fluoride and 18-crown-6 in tetrahydrofuran, gave high yields of 2-, 3-, and 2,3,-di-fluoroquinoxalines from the chloro analogues [87H)26)1215]. The Balz-Schiemann process has been used successfully to make 2-fluoro-quinoxaline (84MI8). 

Astatination by means of nucleophilic halogen exchange, occasionally with the help of catalysts, and electrophilic replacement via demetalation seem to have become the preferred techniques. Short synthesis and separation time together with the possibility of carrier-free preparation of labelled compounds are especially important factors, bearing in mind the short half-life of astatine isotopes and the requirement of high specific activity for chemical and biomedical investigations. 

Nucleophilic halogen exchange has been observed frequently with 2-and 4-halogenopyridines. The commonest reaction of this type is that of a 2- or 4-chloropyridine with hydriodic acid 819-20,... 

Numerous examples of the removal of halogen substituents during the saturation of the pyridine nucleus (p. 264) and the reduction of substituents attached to it (pp. 267, 284) have been recorded. In nucleophilic halogen exchange, reductive removal of a halogen substituent is sometimes caused by the use of hydriodic acid (p. 230). Hydriodic acid and phosphorus replace 2- and 4-halogen substituents selectively, Hydriodic acid and zinc with acid give similar results . 

Halogen exchange of F is usually with chloro compounds however, replacement of bromine has enabled fluorodiazirines to be obtained (83JA6513 86TL419). Diazirine (2) was previously obtained by a difficult route involving F2. The relative ease of access to (2) enables a carbene whose reactivity is intermediate between that of electrophilic ( CF2) and nucleophilic ( C(OMe)2) carbenes to be studied. 

Among the nucleophilic processes available for introduction of bromine to quinolines are reactions of the diazonium salts (87JHC181) and syntheses based on hydroxyquinolines or quinolones (91M935) (Scheme 36). The former processes are especially useful for making 5-, 6-, 7-, and 8-bromo derivatives. Halogen-halogen exchange reactions have also been reported, but they are not common. When perfluoroquinoline was heated... 

It is the metal catalyzed halogen exchange for haloarenes, that is to say the arylation of halides anions (chloride, bromide, iodide), acting as nucleophiles (Fig. 21). 

Two papers have appeared on the reactions of halogenophosphines with tervalent phosphorus compounds. In a detailed study of the reactions at 20 °C of a range of tertiary phosphines with phosphorus trichloride, dichlorophenylphosphine, and chlorodiphenylphosphine, it has been shown that, in general, 1 1 adducts are formed, provided that the tertiary phosphine is a good nucleophile. With diphenylchlorophosphine, for example, an adduct (18) is formed with dimethylphenylphosphine, but not with diphenylmethylphosphine, although the relative importance of steric and electronic factors remains to be established. The related reactions of phosphorus trichloride and of dichlorophenylphosphine are much more complex, and the initial crystalline products are not amenable to analysis. The reactions at 280 °C of a similar system have been shown to lead to halogen exchange, e.g. the conversion of (19) to (20). 

The protonation of the triplet jtjt state of 3-bromonitrobenzene is shown to be responsible for the acid-catalysed promotion of halogen exchange which follows a S y23Ar mechanism26 (equation 23). Cationic micellar effects on the nucleophilic aromatic substitution of nitroaryl ethers by bromide and hydroxide ions have also been studied27. The quantum efficiency is dependent on the chain length of the micelle. The involvement of counter ion exchanges at the surface of ionic micelles is proposed to influence the composition of the Stem-layer. 

The formation of C-O, C-S, C-N and C-C bonds by nucleophilic substitution is described in subsequent chapters. In this section the synthesis of haloalkanes by halogen-halogen exchange and related reactions are presented. 

Copper iodide acts as an efficient reagent for the nucleophilic displacement of 1-haloalkynes. It transforms 1-bromoalkynes (72) into 1-iodoalkynes (73) which, on further treatment with copper(II) bis(arenesulfinate), are converted into the corresponding alkynyl aryl sulfones (74). An electron transfer between 1-haloalkynes and copper(I) salts is believed to take place for the copper-assisted halogen-exchange reaction at the acetylenic carbon atom. 

More recently, 6-astatomethyl-19-norcholest-5(10)-en-3/S-ol (V) has been prepared rapidly, in high yield (60-70%), and at high specific activity by halogen exchange (At /I) in the presence of crown ethers. The crown ethers may fulfill a catalytic role by acting as specific cationic sinks, and thus facilitating rapid nucleophilic exchange. The product was identified by TLC with an Rp value very close to that of the iodinated derivative (95). 

Halogen exchange between an aryl carbanion and a haloarene is well established and occurs by nucleophilic substitution on the halogen substituent [154]. This pro-... 

We now turn to reagents which are important in context with the element/halogen exchange Compounds of the type 8 would be interesting reagents for nucleophilic halomethylation but are quite unstable due to carbene formation. Compound 9 would be an attractive synthetic equivalent for the synthons 8. As will be shown... 

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. 

Furthermore, the halofluorination method can also be modified to prepare vicinal difluorides by a one-pot two-step reaction. Halofluorination followed by nucleophilic halogen-fluorine exchange is carried out simply by adding silver(I) fluoride to a solution of the initially formed a-fluoro-/J-haloalkanes, effecting the exchange in situ202 203 (Table 12). 

Silver(I) fluoride dispersed on the surface of calcium fluoride demonstrates improved fluoride nucleophilicity for halogen exchange. Silver(I) fluoride/calcium fluoride is considerably more active than potassium or cesium fluoride dispersed on the surface of calcium fluoride.38... 

Halogen functionality in heteroaromatics undergoes a variety of transformations by nucleophilic substitution metal-halogen exchange, radical substitution, and cross coupling reactions. The connecting link between these processes and the DoM reaction is therefore a powerful tool in heterocyclic chemistry. 

---