Ortholithiation deprotonation

Attempts to use intermolecular and intramolecular kinetic isotope effects (KIE s) to identify a complexation step during ortholithiation have so far been inconclusive. Both intramolecular and intermolecular KIE s for the deprotonation of 2 and 3 by s-BuLi... 

To summarize, ortholithiation is a reaction with two steps (complex-formation and deprotonation) in which two features (rate and regioselectivity of lithiation) are controlled by two factors (coordination between organolithium and a heteroatom and acidity of the proton to be removed). In some cases, some of these points are less important (acidity, for example, or the coordination step). The best directing groups tend to have a mixture of the basic properties required for good coordination to lithium and the acidic properties required for rapid and efficient deprotonation. 

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 . 

Ferrocene is best deprotonated by f-BuLi/f-BuOK in THF at 0 since BuLi alone will not lithiate ferrocene in the absence of TMEDA and leads to multiple lithiation in the presence of TMEDA. In the example in Scheme 134, a sulphur electrophile and a Kagan-Sharpless epoxidation lead to the enantiomerically pure sulphinyl ferrocene 278. The sulphinyl group directs stereoselective ortholithiation (see Section I.B.2), allowing the formation of products such as 279. Nucleophilic attack at sulphur is avoided by using triisopropylphenyllithium for this lithiation. 

The dimethylaminomethyl group must operate solely by coordination to Li, and it is assumed, as for ortholithiation, that the deprotonation takes place after the initial equilibrium formation of a BuLi-amine complex. 

Using deuterium labelling, we found that we could follow the detailed choreography of the deprotonation (Scheme 6).39 While some of the amide 11 was clearly deprotonated directly in the a (benzylic) position to give 21, a significant amount was ortholithiated first, to give 20 and the... 

These amides are a-lithiated because no other deprotonation can compete. With less hindered aromatic N,A-dimethylamides, a-lithiation still takes precedence over ortholithiation but the organolithium is immediately acylated by another molecule of amide. For example, LiTMP a-lithiates 46 even though ortholithiation could compete, but the product rapidly forms 47.7 With less readily lithiated groups on nitrogen (such as ethyl or isopropyl) ortholithiation (see section 2.3) takes over as the main reaction pathway. 

The greater acidity of lateral protons means that LDA can usually be used to remove them and hence much more electrophilic directing groups can be used for lateral lithiation than ortholithiation. Ethyl 2-methylbenzoate 427 is deprotonated at -78 °C by LDA but as soon as the product organolithium forms it adds to unreacted starting material to give dimeric products 428.392... 

Epoxides will also capture organolithiums formed by deprotonation, notably cyclopropyllithiums and ortholithiated tertiary amides. Ortholithiated amides cyclise regioselectively in a valuable route to benzofurans such as 142 and 143 and (less efficiently) benzopyrans 144.70... 

Making organometallicsby deprotonating aromatic rings ortholithiation... 

Here is an example where deprotonation occurs at a different site in two compounds identical except for a C-C bond closing a three-membered ring. The first is an ortholithiation of the type discussed in Chapter 9. 

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