Synergistic Catalysis: a new tool for Cycloaddition Reactions – CycloSyn

This project heavily relies on experimental work chemical reactions are performed at the Ecole Polytechnique facilities.
Screening techniques are used for catalysts, solvents and reactions conditions. Nuclear Magnetic Resonance and Mass Spectroscopy experiments are routinely used to analyse newly formed compounds.

The reactivity of oxyallylcations, formed in situ from a-tosyloxyketones, has been investigated. Unfortunately, in the presence of several stable -1,3 heteroatomic dipoles, the expected six-membered heterocycles could not be observed. These negative results prompted us to turn our attention towards other all-carbon 1,3-dipoles precursors: 2-indolylmethanols. Using an enantioselective acidic catalysis, a (3+3) cycloaddition has been developped in the presence of nitrones and the corresponding oxazinanes were isolated with good enantiomeric excess.

The chemistry of transition-metal stabilized oxyallylcations and azaoxyallylcations have been tackled using cyclic enol carbonates as test substrates. In the presence of various electrophilic and nucleophilic partners, we have not been able to detect the expected cycloadducts and this objective has been set aside at the moment. We turned our attention towards allylic carbonates derived from 2-methylenepropane-1,3-diol. In the presence of a palladium(0) catalyst, these substrats are known to act as oxygenated -1,4 dipoles. Unlike oxyallylcations, these intermediates bear an additional methylene group between the pi-ally moity and the nucleophilic oxygen atom. In the presence of electrophilic azadienes, an efficient (4+4) cycloaddition afforded eight-membered rings oxazocines in good yields. DFT calculations allowed us to understand the absence of (4+2) cycloadducts in these transformations.

The interesting results obtained using 2-indolylmethanols as all-carbon 1,3-dipoles precursors prompt us to pursue our investigations in this field.
A new project aiming to access nitrogenated six-membered rings involving a Pd(0)/Ag(I) synergistic-catalyzed (3+3) cycloaddition of activated vinylcyclopropanes has recently led to promising results when using a stable 1,3-dipolar partner and this study will be pursued in 2021.

Liu, X.; Scuiller A.; Cordier, M.; Archambeau, A. Poster Journées de Chimie Organique 2019, Palaiseau (Best Poster Prize)

Academic and industrial researchers are in charge to drive the advancement of our society while keeping in mind the sustainability of our planet. In this context, our research proposal aims to develop unprecendented and eco-friendly reactive pathways towards biologically relevant N-heterocycles. The main goal of this project is to develop broad access these structure through the investigation of original (3+3) cycloaddition reactions relying on the remarkable synthetic potential of synergistic catalysis. This original strategy employs two different catalysts designed to independently generate two activated intermediates, lowering the energetic barrier for the formation of a coupling product. The exploratory aspects of this work will allow us to overcome the kinetic issues associated with this strategy by careful selection of the two catalysts.