Finkelstein reaction

The rearrangement with ring contraction probably is the most important synthetic application of the Favorskii reaction it is for example used in the synthesis of steroids. Yields can vary from good to moderate. As solvents diethyl ether or alcohols are often used. With acyclic a-halo ketones bearing voluminous substituents in a -position, yields can be low a tcrt-butyl substituent will prevent the rearrangement. 

Tetrahedron Lett. 1981, 1733-1736. 

The synthesis of alkyl halides from alkyl halides is called the Finkelstein reaction  

For preparative use it is necessary to shift the equilibrium in favor of the desired product. This may for example be achieved by taking advantage of different solubilities of the reactants. 

With primary alkyl halides 1 the Finkelstein reaction proceeds by a Sn2-mechanism. An alkali halide is used to deliver the nucleophilic halide anion  

During the endgame of the total synthesis of the stemona alkaloid (-)-stenine, Y. Morimoto and co-workers utilized the Finkelstein reaction to prepare a primary alkyl iodide from a primary alkyl mesylate. The mesylate was prepared from the corresponding primary alcohol with MsCI/EtsN. The resulting primary alkyl iodide was used in the subsequent intramolecular N-alkylation to construct the final perhydroazepine C-ring of the natural product. 

In the laboratory of J. Zhu, the synthesis of the fully functionalized 15-membered biaryl-containing macrocycle of RP 66453 was accomplished. One of the key steps in their approach was Corey s enantioselective alkylation of a glycine template with a structurally complex biaryl benzyl bromide. This benzyl bromide was prepared from the corresponding benzyl mesylate via the Finkelstein reaction using lithium bromide in acetone. 

The marine sesquiterpene nakijiquinones were synthesized and biologically evaluated by H. Waldmann et al. The core structure of the natural product was assembled via a reductive aikyiation of a bicyclic enone with tetramethoxybenzyl iodide. This aryl iodide was obtained in a two-step procedure treatment of the corresponding 1,2,4,5-tetramethoxybenzene with HBr/paraformaldehyde/AcOH followed by the Finkeistein reaction to replace the bromide with iodide. 

The key step in D. Kim s total synthesis of (-)-brefeldin A was an intramoiecuiar nitriie-oxide cycioaddition. In order to prepare the substrate for this cycioaddition, a doubie Finkeistein reaction was performed first an alkyl tosylate was replaced with iodide then the iodide was exchanged with a nitrite ion to afford the desired alkyl nitro compound. 

Sn2 displacement of one alkyl halide with another halide. 

An abnormal Finkelstein reaction Smith, W. B. Branum, G. D. Tetrahedron Lett. 1983, 22, 2055. 

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These substances accelerate the reaction, and their effectiveness increases in the order given. This suggestion was questioned by Pocker, who found that the effects of such added substances were not directly proportional to their concentrations and could easily be explained by macro effects on the solvent character. He also found that common-ion effects were small in the reaction, the effect of added 1-methylpyridinium bromide was negligible, and that there was no evidence for surface catalysis on the walls of the vessel. There is an exact parallel between the relative rates of the Finkelstein reactions... 

Of preparative importance is the substitution of chloride or bromide or iodide, since the more reactive alkyl iodides are better substrates for further transformations. Alkyl iodides often are difficult to prepare directly, which is why the conversion of readily accessible chlorides or bromides via a Finkelstein reaction is often preferred. 

Secondary or tertiary alkyl halides are much less reactive. For example an alkyl dichloride with a primary and a secondary chloride substituent reacts selectively by exchange of the primary chloride. The reactivity with respect to the Finkelstein reaction is thus opposite to the reactivity for the hydrolysis of alkyl chlorides. For the Finkelstein reaction on secondary and tertiary substrates Lewis acids may be used," e.g. ZnCla, FeCls or MesAl. 

Alkyl fluorides can be prepared by the Finkelstein reaction. The fluoride anion is a bad leaving group the reverse reaction thus does not take place easily, and the equilibrium lies far to the right. As reagents potassium fluoride, silver fluoride or gaseous hydrogen fluoride may be used. 

FinkelStein reaction with sodium iodide is followed by acylation of heptane-3,5-dione to complete the synthesis of arildone (55). ... 

Scheme 3b). It is instructive at this point to reiterate that the furan nucleus can be used in synthesis as a progenitor for a 1,4-dicarbonyl. Whereas the action of aqueous acid on a furan is known to provide direct access to a 1,4-dicarbonyl compound, exposure of a furan to an alcohol and an acid catalyst should result in the formation of a 1,4-diketal. Indeed, when a solution of intermediate 15 in benzene is treated with excess ethylene glycol, a catalytic amount of / ara-toluenesulfonic acid, and a trace of hydroquinone at reflux, bisethylene ketal 14 is formed in a yield of 71 %. The azeotropic removal of water provides a driving force for the ketalization reaction, and the presence of a trace of hydroquinone suppresses the formation of polymeric material. Through a Finkelstein reaction,14 the action of sodium iodide on primary bromide 14 results in the formation of primary iodide 23, a substance which is then treated, in crude form, with triphenylphosphine to give crystalline phosphonium iodide 24 in a yield of 93 % from 14.

Halide exchange, sometimes call the Finkelstein reaction, is an equilibrium process, but it is often possible to shift the equilibrium." The reaction is most often applied to the preparation of iodides and fluorides. Iodides can be prepared from chlorides or bromides by taking advantage of the fact that sodium iodide, but not the bromide or chloride, is soluble in acetone. When an alkyl chloride or bromide is treated with a solution of sodium iodide in acetone, the equilibrium is shifted by the precipitation of sodium chloride or bromide. Since the mechanism is Sn2, the reaction is much more successful for primary halides than for secondary or tertiary halides sodium iodide in acetone can be used as a test for primary bromides or chlorides. Tertiary chlorides can be converted to iodides by treatment with excess Nal in CS2, with ZnCl2 as catalyst. " Vinylic bromides give vinylic iodides with retention of configuration when treated with KI and a nickel bromide-zinc catalyst," or with KI and Cul in hot HMPA." ... 

Fig. 5 Marcus plot of electron transfer reductions of alkyl halides, as contrasted with archetypal SN2 substitution processes (Finkelstein reactions, circled see Eberson,...

Figure 6.2 GL-PTC for the continuous-flow Finkelstein reaction in the gas phase.

Allqrl iodides are often prepared by the reaction of alkyl chlorides/ bromides with Nal in dry acetone. This reaction is known as Finkelstein reaction. 

Subsequently, a copper-catalyzed cross-coupling [with substoichiometric amounts of copper(l) iodide and N,N -dimethylethylenediamine (DMEDA)] between aryl halides and sulfoximines was developed [52]. In this case, both aryl bromides and aryl iodides reacted well. For the conversion of the former substrates an in-situ copper-catalyzed aryl Finkelstein reaction [53] had to be performed first, as shown in Scheme 2.1.1.22 for the preparation of 64 starting from bromobenzene (62). 

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