Halogen-metal exchange aryl halides

Annulation of aryl halides with ortho side chains bearing a pendant electi ophilic moiety via treatment with an organolithium reagent, involving halogen-metal exchange and subsequent nucleophilic cyclization to form 4- to 7-membered rings. 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

Both diethyl (3-pyridyl)borane and diethyl (4-pyridyl)borane are readily accessible from 3-bromopyridine and 4-bromopyridine, respectively, via halogen-metal exchange and reaction with triethylborane [29-32], The two pyridylboranes have been coupled with a variety of aryl and heteroaryl halides, as exemplified by the coupling of diethyl (3-pyridyl)borane and 2-nitrophenylbromide to form phenylpyridine 39 [30, 31]. 

The equilibria mean that n-BuLi can be used to form organolithiums from aryl halides at low temperature (the subsequent reaction of ArLi with the BuX formed in the exchange is slow6) r-BuLi will form organolithiums from primary alkyl halides.7 The formation of secondary organolithiums by halogen-metal exchange is difficult,9 and reductive lithiation is usually preferable. 

The first alkyne cyclisations, from 377, 379 and 381, predate the early alkene cyclisations by a couple of years these three date from 1966173 and 1967,174 and illustrate the favourability of both exo and endo-dig cyclisation. All three generate benzylic vinyllithiums (378, 380 and 382), and both aryl (377, 379) and alkyl halides (381) are successful starting materials. Similar organomagnesium cyclisations were described at about the same time.175 However, it is not clear in these reactions how much of the product is due to participation of radicals in the mechanism - alkylbromides undergo halogen-metal exchange with alkyllithiums via radical intermediates (chapter 3).176 If it really is an anionic cyclisation, cyclisation to 378 is remarkable in being endo. Endo-dig anionic cyclisations are discussed below. 

When Me3SiSnBu3 is treated with CsF, the fluoride anion should coordinate to the silyl group and not the stannyl group to produce a hypervalent silicate, and as a result, a stannyl anion would be generated.282 The stannyl anion reacts with vinyl iodide to produce a vinyl anion via a halogen-metal exchange and it reacts with the carbonyl group intramolecularly (Equation (113)). Aryl halides or allyl halides are also used in similar cyclizations.283,284... 

Organolithiums can also remove halogen atoms from alkyl and aryl halides in a reaction known as halogen-metal exchange. Look at this example and you will immediately see why. 

Aromatic substitution, The reagent (1) reacts with aryl halides by halogen-metal exchange as the initial step to give (CH3)3SnAr. ArH is formed when proton donors are present. 

Intramolecular cyclisation following halogen-metal exchange in the benzonitrile derivatives 25 provides a route to xanthones and thioxanthones. Incorporation of a second aryl halide function into the benzonitrile substrate allows an anionic cascade ring-closing sequence and the formation of pentacyclic xanthene derivatives 26 <03JOC4091>. 

When an aryl or alkenyl halide (RX) is treated with an alkyllithium compound (R Li), halogen-metal exchange can take place. The Li and X swap places to... 

Aryllithiums. Halogen-metal exchange to form an aryllithium from aryl halides was first demonstrated by Gilman and co-workers1 and has since been shown to be relatively independent of the type of substituents.2 This exchange has been used in a general synthesis of benzocyclobutenes and of isoquinolines.3... 

Procedures for preparation of phenylsodium and vinylsodium from the halides have been described. These procedures involve slow addition of the halide to finely divided dispersions of sodium metal. In this way, the halide concentration is kept low. Since aryl and vinyl halides are relatively unreactive toward displacement, halogen-metal exchange is faster than Wurtz coupling. The organic derivatives of the higher... 

A very useful reaction of commercially available organolithiums such as butyllithium or the even more basic t-butyllithium is halogen-metal exchange the reaction is particularly suitable for alkenyl or aryl halides ... 

Dibromosubstituted dipyridylethene 83 was prepared in 67 % yield from the known 2,6-dibromo-3,5-dimethylpyridine. This compound can be converted very conveniently into a variety of derivatives 84 through the halogen-metal exchange and the consequent reaction with electrophiles or through one of many cross-coupling reactions involving aryl halides [91] (Scheme 32). 

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