Development of synthetic strategies towards quinoline-4carboxamide and fused-diaza heterocycles via annulations of oxime acetate
Creators: name: ANDHAVARAM, Ramaraju
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 340503
subject: Organic chemical synthesis

description: The extensive literature survey reveals that nitrogen containing heterocyclic frameworks have significant importance in the field of medicinal, pharmaceutical and industrial applications. To achieve these motifs, researchers have found oxime and its derivatives as handy substrates. Oxime acetates are versatile building blocks widely applied in organic synthesis, exclusively for the construction of N-heterocycles. Easy handling, ready accessibility and potential to generate an imine in situ by a reducible N-O bond are the three distinct features that impart the building block status to O-acyl oximes. Further, oxime acetate plays a dual role as both the reactant and oxidant in transition metal-catalysed oxidative C-H functionalizations. This phenomenon is called an internal oxidant, and it is an emerging tool in C-H activation of aromatic or olefin moieties, where this function acts as an oxidizing directing group.

Chapter I of this thesis briefly summarises the literature on the importance of heterocycles and the synthesis of diverse N-heterocycles through various strategies from different precursors. In the past decades, oxime acetate-based chemistry was extensively explored in organic synthesis to construct diverse nitrogen containing heterocyclic scaffolds using transition metal catalysis in two pathways: i) transition metal-catalysed Csp2-H bond activation and ii) transition metal-catalysed Csp3-H bond activation.

Chapter II illustrates a copper-catalysed mild domino rearrangement strategy for the direct access of substituted quinoline-4-carboxamides through the coupling reaction of O-acyl oximes with isatins. This reaction proceeded through the cleavage of N-O bond and ring expansion of isatin via cleavage of C-N bond in the presence of molecular oxygen as the oxidizing agent. Diversely substituted quinoline-4-carboxamides were obtained in moderate to good yields under mild reaction conditions. Compared with other available methods for the synthesis of quinoline-4-carboxamides, the present method is highly efficient and easy to operate with high atom-economy. Moreover, inexpensive and environmentally benign molecular oxygen was used as the oxidant.

Chapter III describes a copper-mediated chemo-selective intermolecular [3+2] cyclization of promptly accessible ketoxime acetate with 2-aryl-3-ethoxycarbonyl-pyrroline-4,5-dione for the synthesis of novel functionalized pyrrolo[2,3-b]pyrroles. The present protocol is highly efficient, atom-economical, using less expensive copper catalyst. The reaction proceeds through the cleavage of N-O bond and the formation of C-N and C-C bonds. This direct and operationally convenient protocol provided good functional group compatibility to afford the products in good yields. The formation of pyrrolo[2,3-b]pyrrole derivatives is confirmed by single X-ray crystallography.

Chapter IV consists of new approach for the synthesis of nitrogen-based heterocycles from oxime acetate. In continuation of work from Chapter III, copper-catalyzed synthetic strategy for direct access to multi-substituted pyrrolo[1,2-a]pyramidin-4-ones by the coupling of oxime acetate and ethyl-5-(2-ethoxy-2-oxoethylidene)-4-oxo2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylate has been developed. The reaction proceeds by the cleavage of N-O bond and ring expansion of 4-oxo-2-phenyl-4,5-dihydro-pyrrole derivatives through the cleavage of C-C bond and followed the formation of C-C &amp; C-N bond.

Overall, the oxime acetate substrates were successfully utilized for the development of novel synthetic strategies towards the synthesis of diverse azaheterocycles such as quinoline-4-carboxamide, pyrrolo[2,3-b]pyrroles and pyrrolo[1,2-a]pyramidin-4-ones via copper catalysis. Chapter V outlines the conclusion for each study and suggests future direction of this aza-hetero-cyclic chemistry.