Halogens ortholithiation

Phosphine oxides are similar excellent orf/zo-directors which have seen only limited use so far. The iodide 123, for example—a precursor of a new class of bisphosphine ligands—can be made by cooperatively-directed ortholithiation of the phosphine oxide 122, itself derived by halogen-metal exchange from 121 (Scheme 53) . 

Chlorobenzene is lithiated more slowly and cannot be lithiated completely at temperatures where benzyne formation is slow. With 1,2,3,4-tetrachlorobenzene 165, MeLi leads to ortholithiation f-BuLi, on the other hand, leads to halogen-metal exchange (Scheme 83). ... 

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 . 

The competition between ortholithiation and alternative reactivity—a- or lateral lithi-ation for example, or halogen-metal exchange—has been quantified in only a few cases, and where such issues of chemoselectivity arise they are mentioned in the sections on these topics. 

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