title: Alkali-Metal Alkoxide Mediated Activation of Organozinc and Organomagnesium Reagents for Arene Functionalisation
Creators: name: Judge, Neil, Roland
Publisher: name: Universität Bern
Year: 2024
Subjects: subject: 540 Chemistry
subject: 570 Life sciences; biology

description: This thesis explores the use of alkali-metal alkoxides as additives for the activation of organomagnesium and organozinc reagents towards arene functionalisation focussing on two cornerstone reaction in organic synthesis, namely metal/halogen exchange and deprotonative metalation. Approaching this area from a more metal-focussed perspective, the work collected in this thesis not only aims at advancing the synthetic applications of these heterobimetallic combinations for regioselective functionalisation of arenes but also to advance the understanding on the constitution of the key organometallic species involved in these transformations, providing valuable mechanistic understanding that can then be used for further rational design. Essential analytical tools to carry out this research have been advanced NMR spectroscopic analysis as well as X-ray crystallographic studies which have help to shed light on the unique activating effects mediated by alkali-metal alkoxides in these main group bimetallic systems. Chapter 2 explores the use of mixed alkyl/alkoxy lithium magnesiates for atom economical Mg/Br exchange under mild conditions, displaying remarkable levels of chemo- and regioselective control. Spectroscopic and structural mapping allowed for a deeper understanding of the hidden reaction pathways as well as revealing a novel bimetallic derivative of the Schlenk equilibrium. Chapter 3 focuses primarily on how the nature of the alkali-metal and alkoxide ligand used effects the reactivity of these mixed alkyl/alkoxy magnesiates towards bromoarenes. These studies revealed that subtle changes to these parameters had quite drastic consequences on the Mg/Br exchange ability of the bimetallic reagents but also on the constitution of the metalated intermediates formed in the reaction. Moving from metal/halogen exchange to deprotonative metalation, Chapter 4 reveals how the addition of two molar equivalents of KOtBu to Zn(TMP)2 (TMP = 2,2,6,6-tetramethylpiperidide) transforms this mild zinc bis-amide base to a powerful metalating agent able to perform facile regioselective zincation of a wide range of sensitive fluoroarenes. Structural authentication of the intermediates post Zn-H exchange demonstrates activation of both TMP groups to form a range of higher order bis-aryl potassium zincates which are further functionalized in electrophilic interception reactions. While several intermediates have been isolated and structurally characterized, showing a remarkable stability at room temperature, these compounds can still engage into C-C bond forming processes such as Negishi cross-couplings and Cu catalysed allylations. Chapter 5 extends this methodology to reveal the true metalating power of this bimetallic mixture, able to perform challenging regioselective zincations of non-activated arenes such as benzene, ferrocene, and naphthalene. Complex redistribution patterns of the metalated intermediates, induced by alkoxide additives, are unveiled through spectroscopic and crystallographic studies. Interestingly for these less activated substrates there is a clear alkali-metal effect, with only KOtBu being able to enhance the metalating power of Zn(TMP)2. Finally, a “cleave and capture” decomposition pathway of this strong base in THF has been uncovered, allowing for the isolation of an unusual potassium zincate complex containing a zincated 1,3 butadiene fragment resulting from the synergic cleavage of THF which is used as a solvent in these reactions.