Metal‐catalyzed carbenoid cascade reactions involving a C–H insertion/annulation — applications in the synthesis of carbo- and heterocycles

Bhat, Aabid H. (2023) Metal‐catalyzed carbenoid cascade reactions involving a C–H insertion/annulation — applications in the synthesis of carbo- and heterocycles. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Cascade reactions have gained significant importance in the pursuit of efficient and elegant synthetic chemistry. These processes offer environmental friendliness, atom economy and enable the synthesis of highly complex molecules. This thesis covers the general topic of tandem reactions based on metallocarbene insertion into C–H bonds and subsequent trapping of carbanion intermediate via annulation chemistry in a cascade manner to access various hetero- and carbocyclic frameworks. Three related projects illustrate this strategy; the last project is based on the pericyclic cascade strategy. In Chapter 2 of this thesis, a Rh(II)-catalyzed acceptor/acceptor diazo carbene insertion/annulation strategy will be discussed. A series of N-alkylated indoles contain an alkyne electrophile were prepared for this study. These indoles were reacted with diazo reagents under Rh(II) catalysis to achieve tandem C(sp²)–H carbene insertion and subsequent Conia-ene annulation for the synthesis of pyrroloindoles. Chapter 3 of this thesis discusses a Cu(II)-catalyzed C(sp²)–H insertion/Michael annulation cascade between α-diazocarbonyls and appropriately functionalized indoles containing alkynyl-ester electrophiles to access a variety of fused indole scaffolds in a stereoselective manner. Advancements of this reaction manifold to include alkenyl-esters as electrophiles were also explored allowing access to a range of new indole frameworks. By extending the reaction protocol to donor/acceptor diazocarbonyls, an additional synthetic value was achieved. Chapter 4 of this thesis presents a preliminary study on the Rh(III)-catalyzed pyrimidine-directed C–H activation of indole, followed by coupling with Meldrum's acid-derived α-diazocarbonyls through a migratory carbene insertion pathway. The resulting intermediate, upon the elimination of acetone and carbon dioxide, undergoes a Dieckmann condensation with a pendant ester moiety, leading to the formation of a carbazole core. The progress made in this study, as well as the planned future work, regarding the application of this novel reaction in the synthesis of various carbazole-based natural products, will be discussed in detail. Finally, Chapter 5 of this thesis discusses a pericyclic cascade towards the synthesis of citridone A and tersone D natural products. The key transformation involves a domino Knoevenagel condensation between branched conjugated dienals and pyridone-type 1,3-dicarbonyl substrates followed by an oxa-6π electrocyclic ring-closure cascade to construct a cyclopenta[b]furopyridone framework. This project was completed in collaboration with the Rivera Group of Rosario Institute of Chemistry-IQUIR and for simplicity, only our total synthesis efforts will be discussed.

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