Synthesis of Oxazolidin-2-ones by Oxidative Coupling of Isonitriles, Phenyl Vinyl Selenone, and Water

Reaction of alkyl isocyanides, phenyl vinyl selenone, and water in the presence of a catalytic amount of Cs2CO3 afforded oxazolidin-2-ones in good yields. This unprecedented heteroannulation process created four chemical bonds in a single operation with the isocyano group acting formally as a polarized double bond and phenyl vinyl selenone as a latent 1,3-dipole. The phenylselenonyl group played a triple role as an electron-withdrawing group to activate the 1,4-addition, a leaving group, and a latent oxidant in this transformation.

Copper-catalyzed transformations of carboradicals generated by electrochemical and photochemical methods: oxidative amination and polyfluoroarylation

Xiangli Yi

Organic radicals are highly active species that can undergo various transformations. Electrochemistry and photochemistry are efficient methods for the generation of these species of high energy, through single electron transfer processes under mild conditions. These methods have been frequently used to form various carboradical intermediates, for example, via the addition of N-centered radicals to alkenes (Section 1.4). Copper is a versatile transition metal that can transform carboradicals for the formation of various chemical bonds (Section 1.6). Combining electrochemistry or photochemistry for the generation of carboradicals with the copper-catalyzed carboradical functionalization will potentially lead to a large chemical space of useful organic reactions. So far, this intersection of electrochemistry or photochemistry with copper chemistry is still highly underdeveloped. In this thesis, we have developed three useful reactions, testifying the practicability of this concept.In Chapter 2, we describe an intramolecular oxidative amination reaction by integrating electrochemical oxidation with Cu catalysis. Electrochemical oxidation facilely generates N-radical from N-H for the intramolecular cyclization to double bonds, and then the resultant carboradicals are transformed into a new double bond via copper-catalyzed oxidative elimination (Section 1.6.1). A wide range of 5-membered N-containing heterocycles bearing a pendant, functionalizable alkene moiety can be synthesized under mild conditions. Mechanistic studies revealed that direct oxidation on the electrode couldn't efficiently convert primary and secondary alkyl radical intermediates into alkenes, and that the assistance of copper was indispensable.In Chapter 3, an intermolecular oxidative amination reaction of unactivated alkenes by integrating photoredox with Cu catalysis is described. This method relied on photochemical reduction of a hydroxyamine derivative to generate amidyl radical which then adds to unactivated alkenes. The obained carboradicals are trapped by the copper catalyst to form allylic amines. The reaction exhibited a broad scope and excellent tolerance for functional groups including highly polar groups. In Chapter 4, we report a decarboxylative coupling reaction of aliphatic acids with polyfluoroaryl nucleophiles by integrating photoredox with copper catalysis. A set of polyfluoroaryl zinc reagents were prepared and applied to the coupling. The aliphatic esters of N-hydroxyphthalimide (NHPI esters) were transformed into alkyl radicals by photoreduction. Then, the trapping of the radical by the copper catalyst and subsequent reductive elimination render the alkyl polyfluoroarenes as products. This method allows the installation of polyfluoroaryls with variable F-content (2F -5F) and F-substitution patterns on primary or secondary alkyl groups, with good compatibility of functional groups. In summary, this thesis demonstrates the combination of electrochemistry and photochemistry with copper catalysis to construct useful synthetic methods. Considering the diversity of radicals that could be generated by electrochemical and photochemical methods, and the versatility of copper catalyzed functionalization of carboradicals, we believe that this combination has far more potential than these three reactions.

EPFL2021

Rh-catalyzed C-H Bond Heteroarylation with Hypervalent Iodine Reagents and Pd-Catalyzed Tethered Functionalizations of Carbon-Carbon Multiple Bonds.

Ashis Kumar Das

Transition metal-catalyzed C-H activation is a powerful tool for the synthesis of organic building blocks, materials, and natural products. Over the last decade, directing-group-assisted metal-catalyzed C-H functionalization has attracted increasing interest as a means to target specific C-H bonds. Moreover, a large variety of electrophiles has been employed in this kind of processes. In this thesis, we describe a novel C-6 selective C-H heteroarylation of pyridine-2-ones using indoleBX reagents as coupling partners under Rh(I)-catalysis. The reaction worked efficiently also with other analogous heterocyclic substrates and with a quinoline-N-oxide. We were able to obtain 6-(indol-3-yl)pyridinone and 8-(indol-3-yl)quinolone after cleavage of the directing group or rearrangement of the N-oxide moiety. 1,2-Amino alcohols are important structural motifs in organic chemistry that can be observed in natural products, pharmaceutically and biologically active molecules. The palladium-catalyzed difunctionalization of C-C multiple bonds has been broadly investigated as an efficient strategy to access such substructures. This transformation has been reported using either Pd(0)/Pd(II) or Pd(II)/Pd(IV) catalytic cycles, in which the nucleophilic functionalization of a putative Pd(II)-alkyl intermediate is achieved prior to beta-hydride elimination. As a further topic of this thesis, we developed new methods for the synthesis of amino alcohols whereby the Pd-catalyzed difunctionalization of alkynes and alkenes was combined with the tethering approach previously established in our laboratories. We first investigated the Pd-catalyzed enantioselective hydroalkoxylation of propargylic amines. The latter were tethered in situ with a trifluoroacetaldehyde hemiacetal. Best results were obtained with commercially available DACH-Phenyl Trost ligand. Aryl iodides were required as an additive in catalytic amount for successful outcome. A large variety of chiral oxazolidines were obtained in good to excellent yields and ee, followed by a diastereoselective reduction to give protected enantioenriched amino alcohols. A possible mechanism for this transformation relies on a Pd(0)/Pd(II) catalytic cycle involving oxidative addition of aryl iodide with a subsequent oxypalladation/protodemetallation (or reductive elimination) reaction. This is necessary to generate the active complex, not as the start of a cross-coupling event. The use of a commercially available DACH-Ph Trost ligand to produce high enantioselectivity in an unprecedented DYKAT process was critical to success.The Pd-catalyzed amino acetoxylation of cinnamyl alcohols was next taken into consideration towards the synthesis of valuable amino diol derivatives. In this case, preformed substrates were used, where the alcohol moiety was tethered to N-nucleophilic groups. Conditions involving Pd(II)/Pd(IV) catalysis and employing PIDA as a strong oxidant were employed. The use of this hypervalent iodine reagent was key to the success of the transformation. Amino acetoxylated products were obtained in moderate to good yields and dr. The scope of this reaction remains mostly limited to cinnamyl derived substrates. The reaction conditions did not tolerate substituents on the alpha, beta, and gamma positions of the allylic chains. Alkyl chain containing unsaturated alcohols delivered Aza-Wacker-type products.

EPFL2022

Molecular Engineering of Electrode Surfaces for Electrocatalysis

Patrick Eduard Alexa

Electrocatalysts play an important part on the route towards environmental friendly energy sources. They support modern technologies like fuel cells to move further away from the utilization of fossil fuels and the resulting CO2 emission into our atmosphere. The main principle of such energy conversion technologies is to store chemical energy within chemical bonds and to release it as electric energy to fulfill the energy demand of today's society. However energy conversion chemistry in such technologies requires catalysts in order to be effective by providing an alternative reaction pathway that lowers activation energies and maximizes the energy output. Providing suitable catalyst surfaces requires a fundamental knowledge of the interaction of reactants and reaction intermediates with the catalyst surfaces. This concern is addressed in this thesis by fabricating specifically tailored molecular components on metal surfaces, which act as organic/inorganic hybrid electrodes for various energy conversion reactions in electrocatalysis. Characterizing the electrode surface is crucial in order to identify active sites of the catalyst. The molecular structure is investigated by surface sensitive techniques, such as STM and XPS in combination with a home-build transfer system, which enables electrode fabrication in UHV and electrocatalytic experiments in a liquid environment. A detailed characterization of organic polymer components on electrode surfaces is obtained by combining experimental data with MD simulations. The morphology of polymer networks can be successfully mimicked and depending on the chemical composition and the structure, spatial correlations on short length scales are reported. Hybrid electrodes with organic polymer co-catalysts reveal an increased catalytic activity for the HER by providing suitable docking sites that act as catalytic active sites. Reactants and reaction intermediates are stabilized via hydrogen bonding, which results in a higher catalytic turnover. The specific designed structure of the organic co-catalyst helps to identify a fraction of the reaction mechanism and highlights the importance of molecular components in electrocatalysis. The utilization of organic units on electrocatalysts provides also an excellent opportunity in order to use single metal atoms as catalysts. Engineering large pi-systems has no significant impact on the ORR activity, while the distance between active sites and the underlying electrode are crucial for enhancing the catalytic activity. A significant factor in using molecular components in electrocatalysis is the stability of the organics. Using electrografting allows to design organic/inorganic hybrid electrodes with covalent bonds between the molecular component and the metal substrate. Attaching empty porphyrin molecules to substrates introduces a powerful technique in molecular engineering, since empty porphyrin cycles can be metallized with various metal centers that can act as electrocatalysts for different electrochemical reactions. In summary, this thesis provides multiple engineering aspects, which are useful in designing molecular components on metal electrodes for energy conversion. Such hybrid catalyst surfaces are capable of improving the catalytic activity and allow to study the mechanism of catalytic reactions. Implementing organic components provides new routes for tailoring novel materials, which deliver new insight into the complex field of electrocatalysis.

EPFL2020