Aryl bromides, halogen-metal exchange

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 . 

Compounds containing two halogen atoms will undergo halogen-metal exchange and cyclisation provided that the cyclisation step is faster than the second halogen-metal exchange. This is the case if both are iodine, or if one is iodine and the other bromine, or if one is a vinyl or aryl bromide or iodide. 

Regiospecific aryl ketone synthesis. Negishi et al. have reported a regio-specific synthesis of aryl ketones from aryl bromides in which the new C—C bond is specifically at the carbon atom that originally was substituted by bromine. Thus the aryllithium compound (2) is prepared by halogen-metal exchange this reacts with a trialkylborane to form a lithium aryltrialkylborate (3). The reac-... 

Aryl—alkyl coupling. The reaction of aryl bromides with alkyllithium compounds in ether results mainly in halogen—metal exchange. However, when THF is used as solvent aryl bromides react with primary alkyUithiums (1 hr., 25°) to give the cross-coupled products in 50-70% yields ... 

On the other hand, quinolinyl nucleophiles as the quinolinylzinc derivatives presented in the following example have been prepared by the in situ transmetallation of quinolinyllithium salts realized by direct halogen-metal exchange of 6-bromo quinoline derivative. The zinc salt was allowed to react with several aryl bromides, affording clean Negishi reactions for the formation of 6-substituted derivatives, which are potent inhibitors of steroid 5a reductases of types 1 and 2 ... 

Parham, W. E., Jones, L. D. and Sayed, Y. 1975. Four- to seven-membered ring annulation of aryl bromides bearing ortho side chains having an electrophilic moiety, accomplished by halogen-metal exchange and subsequent nucleophilic ring closure. J. Org. Chem. 40 2394-2399. 

The title reactions offer a possibility for exchanging the halogen atom in aryl halides (Hal = Cl, Br, I) first with a metal (MgHal, Li) and then with an electrophile. It is generally easier to introduce bromine than chlorine or iodine into aromatic compounds. Accordingly, functionalizations of aryl bromides are the preparatively most important examples of the title reaction. 

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