Metallaelectro-Catalysis and Aryl Sulfonium Salts in Sustainable C–H Activations and Late-Stage Diversification
by Hendrik Simon
Date of Examination:2024-07-02
Date of issue:2024-09-17
Advisor:Prof. Dr. Lutz Ackermann
Referee:Prof. Dr. Konrad Koszinowski
Referee:Prof. Dr. Dietmar Stalke
Referee:Prof. Dr. Johannes C. L. Walker
Referee:Dr. Holm Frauendorf
Referee:Dr. Daniel Janssen-Müller
Persistent Address:
http://dx.doi.org/10.53846/goediss-10747
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Abstract
English
In the past decades, organic chemistry was dominated by functional group interconversions and cross-coupling chemistry. These techniques allowed the synthesis of a plethora of highly complex molecules and are established as indispensable tools in modern industrial chemistry. Unfortunately, problems with lengthy routes and waste management are still an unsolved issue, as pre-functionalization and byproduct generation are often unavoidable. However, the direct modification of C–H bonds as latent functional groups has gained more and more attention within the last years. The early findings employing often harsh reaction conditions and precious transition metals are successively replaced by mild reaction systems. Less expensive and less toxic catalysts based on cost efficient ruthenium, or earth-abundant 3d transition metals are on the rise and research on their broader application is needed. In the first part of this thesis, the unprecedented merger of metallaelectro-catalysis and remote C–H functionalization was realized by establishing a protocol, which allows for the metaselective bromination of diverse aryl N-heteroarenes. This strategy avoids the use of expensive electrophilic brominating reagents, which would lead to extensive waste formation. Instead, simple aqueous hydrobromic acid was used, thus generating dihydrogen as the sole byproduct. Furthermore, the ruthenaelectro-catalysis system led to the metabromination of the phenyl moiety of pyrazolyl arenes, whereas electrophilic brominating agents usually address the electron-rich pyrazole fragment. Second, the incorporation of pharmaceutical valuable heterocycles is a key challenge in medicinal chemistry and drug discovery. However, the introduction of interesting N-aryl triazoles and aryl tetrazoles in a late-stage fashion remained an unsolved problem. They are of particular interest as bioisosters for amides and carboxylic acids, respectively. We disclosed a ruthenium-catalyzed C–H functionalization of these entities employing aryl sulfonium salts as electrophilic coupling partners. The reaction system showed a broad functionalization group tolerance with diverse coupling partners. In this way, the incorporation of the triazole and tetrazole moiety in variety of different natural products, APIs, or crop protecting agents was viable. The third project dealt with the C–H arylation of azoles under copper-catalysis, which usually requires harsh reaction conditions with temperatures above 120 °C. The establishment of photochemistry allowed the reaction to occur at room temperature. Nevertheless, usually harmful high energy UV-C irradiation or the combination of blue LED irradiation and a precious metal photocatalyst are needed for this approach. The only additional photocatalyst-free approach is limited to benzoxazoles. We envisioned to fine-tune the photo redox properties of the copper catalyst by choosing a suitable ligand and combine it with the high reactivity of sulfonium salts to facilitate a photocatalyst-free C–H arylation of benzoxazoles and benzothiazoles at room temperature. Our approach proved to be highly timeefficient, with durations of 1 h up to only 10 minutes. Moreover, the re-isolation of the sulfurbased transfer reagent was possible so that a circular use of it is feasible and improves the overall sustainability. Fourth, we devised a reaction protocol for the C–H arylation of pyridine-N-oxides with aryl sulfonium salts. Under the optimized conditions employing our the standard substrate we achieved an excellent yield of 87%, using a bimetallic palladium(II)-silver(I)- system. The reaction can also operate avoiding silver additives, but with diminished yields. As a next step, further studies should now concern the exploration of the substrate scope. A special focus should be laid on the incorporation of the pyridine-N-oxide motif into API structures since a following reduction of the N-oxide can lead to medicinally highly relevant pyridine and piperidine derivatives.
Keywords: Organic Chemistry; C–H Activation; Electrochemistry; Photochemistry; Late-Stage Diversification; Catalysis; Sulfonium Salts
