The 2×3 Toolbox of Organometallic Methods for Regiochemically Exhaustive Functionalization

This Review describes a concept aimed at rational and maximal structure proliferation. To this end, simple aromatic or heterocyclic starting materials, often bulk chemicals, are converted into all regionisomerically possible polar organometallic intermediates (mostly lithiated species), which then may be combined with any of the countless electrophiles to provide attractive new building blocks, particularly functionalized derivatives. The practical implementation relies on a set (“toolbox”) of sophisticated recipes developed by mechanistically guided modification of the two most prominent exchange methods used for the generation of polar organometallic compounds: hydrogen–metal and halogen–metal interconversion. These mutant methods (“old methods in a new outfit”) amplify the existing options for organic synthesis by ensuring maximum regioflexibility. At the same time they offer new insight into factors that govern organometallic reactivity and provide hints on how to alter or finetune this reactivity judiciously. Like a wildcard in a card game, the introduction of a metal into aromatic or heterocyclic building blocks ensures a maximum of target flexibility in the synthesis (see scheme). It can be replaced with a wide range of electrophiles and thus offers a convenient access to virtually any functionalized derivative. The ultimate objective of this “toolbox” approach is not to miss any structural opportunity inherent in a new substituent pattern.