Ortholithiation acidity

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. 

To summarize the amides are most suitable for the formation, by ortholithiation, of condensed heterocycles and polycyclic aromatics (in which subsequent rings are formed by intramolecular attack on the amide group). In other cases the removal of the amide group may be problematic, though if carboxylic acids, aldehydes or hydroxymethyl-substituted compounds are required, alternative amide substituents may be used. 

These reactions have been used in the synthesis of aikaioids such as corydalic acid methyi ester 502 (Scheme i95). Isoiated from Corydalis incisa, 502 is derived from a proposed biosynthetic intermediate in the route to the tetrahydroprotoberberine aikaioids. The 1,2,3,4-tetrasubstituted ring of 502 demands control by an ortholithiation strategy, and the synthetic route proposed by Clark and Jahangir employs a lateral lithiation of 503 and addition to an imine as the key disconnection at the centre of the molecule. 

The amide 504 may be made by ortholithiation of benzodioxolane 505, though a higher-yielding preparation starts from 1,2-dihydroxybenzoic acid 506. OrthoUthiation of 504, directed by the tertiary amide group, is straightforward, and gives the alkylated amide 503 (Scheme 196). 

This chemistry can be very powerful, since the amide product itself offers further possibilities for functionalisation by lithiation. The synthesis of the natural product ochratoxin A (section 9.1) illustrates this point. Two successive ortholithiations of carbamate 210 are used first to introduce one amide group and then a second, by anionic ortho-Fries rearrangement. The symmetrical diamide 211 can be allylated and then cyclised in acid, with concomitant hydrolysis of the second amide and deprotection of the phenol to yield a known intermediate... 

N-activation by BF3 can be used to promote ortholithiation of pyridine itself,318 319 though not quinoline and isoquinoline. Temporary formation of a pyridine-hexafluoroacetone adduct 366 achieves the same result.320 Complexation of pyridine by chromium tricarbonyl also makes the ring protons sufficiently acidic to be removed by LDA.321... 

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... 

Coordination of the chromium tricarbonyl group onto an arene enhances the kinetic acidity of the aryl C—bonds. In order to avoid nucleophilic attack of the organolithium reagent onto a CO ligand, the reaction has to be run at low temperature. The reaction is regioselective as ortholithiation is observed with arene substituted by OCH3, F, Cl. 

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