University of Groningen
Harnessing the reactivity of alkenyl heteroarenes through copper catalysis and Lewis acids
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Publication date: 2018
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Lanza, F. (2018). Harnessing the reactivity of alkenyl heteroarenes through copper catalysis and Lewis acids. University of Groningen.
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Aromatic and aliphatic heterocycles are core structures in a number of biologically active molecules, drugs, and materials. Synthesis and functionalization of such scaffolds is a constant challenge in organic chemistry. Over the years an incredible amount of synthetic strategies, ranging from organocatalysis to cross coupling chemistry, till the most recent C-H activation, to address this issue have been developed. Nevertheless, the methodologies to introduce stereogenic centres in heterocycle-containing frames are still underdeveloped compared to their racemic counterparts or to those one yielding achiral molecules. Asymmetric strategies often make use of chiral auxiliary or enantioenriched reagents to achieve high degree of stereocontrol. The necessity to develop new asymmetric catalytic approaches to access relevant heterocyclic structures prompted us to embark this challenge. The results of our efforts in designing new methodologies to access chiral heterocycles and understanding the reaction mechanisms are herein described.
Chapter 2 describes the development of copper-catalysed conjugate addition of Grignard
reagents to alkenyl heteroarenes promoted by Lewis acids. According to the recent literature, introduction of carbon substituents on the β-position of such substrates with excellent results was achievable only employing expensive Pd or Rh catalysts. Moreover, the substituents were limited to aromatic molecules. Thanks to the substantial activation granted by BF3∙OEt2, the
scope has been extended also to linear, branched and functionalised aliphatic chains. Remarkably, the catalytic system delivers the desired products in high yields and excellent enantioselectivities.
Chapter 3 can be defined as a “spin off” of the previous chapter. Deeper investigations on a side
reaction encountered while developing the abovementioned catalytic system led us to an unusual one-pot protocol for enolate trapping. Despite its narrow scope, the process showed a remarkable chemo- and diastereoselectivity.
Also in this case BF3·OEt2 played a fundamental role reverting what would have been the
expected reaction order. Studies conducted using NMR spectroscopy linked the origin of this phenomena to the ability of the BF3∙OEt2 to bound selectively to benzoxazole scaffolds in
In Chapter 4 the results of the copper-catalysed alkylation of alkenyl pyridines are discussed. 4-Alkenyl and 2-alkenyl pyridines can be functionalised with this methodology. Despite in the process strong organometallic nucleophiles are involved, a remarkable functional group tolerance was displayed, even in presence of sensitive functional group like ester and cyano group.
The presence of reactive functional groups in the final product gave us the possibility to decorate further the heteroaromatic ring, accessing in this way high molecular complexity in few synthetic steps.
In Chapter 5 extensive NMR studies and tailored experiments have been conducted to disclose the reaction mechanism of the transformation described in the previous chapter. Characterization of Si-enolate intermediate suggests a mechanism in which formation of a Cu(III) species is involved, as already suggested for the Cu-catalysed conjugated addition to enones and enoates. Evaluation of size, strength and counterion effect of different Si-based Lewis acids showed undoubtedly that the role of the LA is not confined exclusively to the activation of the substrate, but it is also involved in the enantiodiscriminating step. All the information collected gave us the chance to delineate a plausible catalytic cycle for this transformation.