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

Abstract

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.

Meta-metallation of N,N-dimethylaniline: Contrasting direct sodium-mediated zincation with indirect sodiation-dialkylzinc co-complexation

“…While the metallation reaction remains an essential tool for constructing substituted aromatic compounds [1–2], the quest for new improved reagents capable of selectively abstracting hydrogen from organic substrates continues. Routinely, organolithium reagents have been employed for this purpose with the high electropositivity of lithium affording polar, reactive C δ− –Li δ+ bonds proficient in metallating C–H bonds in organic, especially aromatic and heteroaromatic, compounds [3–5].…”

Funktionalisierung von Aryllithium‐Regioisomerengemischen durch selektive Abfangreaktionen mit Zirconocendichlorid

“…[2] Gewçhnlich stellt das Vorhandensein einer dirigierenden Gruppe die Lithiierung in der ortho-Position sicher,i mF all von unsymmetrischen Substraten von Typ 1 kann allerdings ein Gemisch der regioisomeren Aryllithiumverbindungen 2 und 3 erhalten werden. [3] Die Bildung solcher Gemische erschwert die Anwendungen in Synthesen ungemein. Das Problem fehlender Regioselektivität kçnnte mçglicherweise durch eine bevorzugte Tr ansmetallierung eines der beiden Regioisomere 2 und 3 gelçst werden.…”

Bromine–lithium exchange: An efficient tool in the modular construction of biaryl ligands

“…Polar organometallic chemistry [33–35] allows the performance of highly selective reactions. Therefore, it seemed to us the ideal tool to reaching this goal.…”

“…Although this reaction was reported by C. S. Marvel in 1927 [40], G. Wittig [41] and H. Gilman [42–44] were the first to apply it in organic synthesis in the late thirties. Since then, this reaction has been considered as a mature method lacking both appeal and surprise [33], and only new applications of this reaction or mechanistic studies have been reported [30,32–33 45–55]. However, in the last few years, the halogen–metal permutation has recaptured its former role as one of the most important and versatile methods in organic synthesis.…”