Ortholithiation coordination

Coordination to strongly orf/zo-directing groups is responsible for the regiochemistry of some other reactions which do not involve ortholithiation. For example, while the electron-withdrawing nature of the oxazoline would be expected to direct the addition of the organolithium nucleophile to benzyne 11 towards the meta position, the major product that arises is the result of addition at the ortho position to give 12 (Scheme 1). ... 

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. 

Addition of a lithiated secondary amine to an aldehyde both protects the aldehyde from attack by RLi and turns it into an ortholithiation directing group. The best lithioamines for this purpose are A-lithio-A-methylpiperazine 53, iV-lithio-iV,iV,iV -trimethylethylene-diamine 56 and Al-lithio-Al,0-dimethylhydroxylamine 58 , which optimize the opportunity for coordination of BuLi to the intermediate alkoxide (54) (Scheme 27) . ... 

Sulphones are similar in some ways even more acidifying, and with a powerful ability to coordinate, but less likely to be attacked at S. As with sulphoxides, lithiation a to S competes, and ortholithiation is useful only with sulphones lacking a-protons. After lithiation, the removal of sulphones can sometimes be accomplished by transition metal-catalysed reduction or substitution (Scheme 47) °. 

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. 

There are a number of other reports of difficulties in ortholithiation when further coordination sites are present molecules containing more than one strong coordinating substituent frequently require numerous equivalents of alkyUithium for lithiation . 

In sulfoxides, sulfur s weak acidifying effect is enhanced, and the oxygen atom introduces a powerful coordination effect in contrast with sulfides, sulfoxides are very powerful directors of both ortholithiation and a-lithiation. Ortholithiation is possible with aryl sulfoxides lacking an a-proton, but since sulfoxides suffer from the disadvantage of being electrophilic at sulfur, diaryl sulfoxides must be lithiated with lithium amide bases rather than... 

The powerful ability of trigonal (sp2) nitrogen to coordinate to lithium229 means compounds of general structure 267 may be ortholithiated, provided addition to C=N can be avoided. 

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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