Development of novel metal-free based pot-economy approaches to 3,3-disubstituted 2-oxindoles, pyridines and related compounds

Abstract

This thesis presents research into the development of a novel metal-free based one-pot protocol for the efficient synthesis of a novel class of diversely substituted pyridine, 3,3-disubstituted oxindole and spirooxindole scaffolds in a mild, and environment-friendly manner from easily accessible starting materials. The first chapter describes the general introduction for the synthesis and applications of 3,3-disubstituted oxindoles, spirooxindoles and substituted pyridines with historical background and synthetic protocols documented for the synthesis of an aforesaid class of derivatives through different synthetic modifications. The second chapter illustrates an efficient diastereoselective synthesis of 3,3-disubstituted oxindoles via double SN2′ reaction of cyclic N-sulfonyl ketimines with isatin-derived MBH carbonates in the presence of a catalytic amount of DABCO at room temperature. This allylic alkylation reaction generates very quickly (5-10 min) a wide range of 3,3-disubstituted oxindoles in good to excellent yields (76-96%) with excellent diastereoselectivities (up to ≤ 99:1 dr), which are flanked by a cyclic imine and an acrylate moiety at the C3 position. Chapter three devises a unique, experimentally simple, eco-friendly and metal-free based domino route for the facile synthesis of an exciting class of functionalized tri-and tetrasubstituted pyridines having a synthetically useful ester, aroyl or phenolic moiety. The reaction proceeds through a [3+3] cyclization reaction between cyclic N-sulfonyl ketimines and several Morita- Baylis-Hillman acetates of nitroolefins as 1,3-bielectrophiles under MW irradiation promoted by DABCO or DBU as organobase. This unprecedented sequential reaction affords good to high yields of the aforementioned aza-heterocycles under mild conditions with a tolerance of several compatible functional groups. Chapter four demonstrates the development of a unique, one-pot, two-step sequential reaction of 4-methyl N-sulfonyl ketimines with MBH carbonates derived from acrylates catalyzed by DABCO (20 mol%), followed by aromatization using DBU (1.2 equiv) as an organobase in an open-flask. This smart, metal-oxidant-free C–C/C–N bond-forming process leads to an array of functionalized nicotinates possessing an interesting phenolic moiety at the C6 position in good to high yields. Chapter five describes a unique, mild, organo-base-promoted eco-friendly method for synthesizing a novel class of symmetrical and unsymmetrical 2,4,6-trisubstituted pyridines having a sterically hindered phenolic moiety at the C4 position of the pyridine ring. This C–C and C–N bond-forming reaction occurs between various vinyl-substituted p-QMs as 3C units (C6– C7–C8) for pyridine synthesis and a group of 5-membered cyclic sulfamidate imines in the presence of 1.5 equiv of DABCO at 60 ℃ in 2- MeTHF under open atmosphere. Moreover, a series of control studies revealed that the reaction proceeds via a regioselective 1,6-conjugate addition, followed by elimination-6π-aza-electrocyclization-aerial oxidation sequence. Interestingly, this conjugate addition-initiated cyclization reaction applies to a wide range of substrates and provides good to high chemical yields of the title compounds with an exceptional functional group tolerance. The final chapter of this thesis focuses on the conclusion and future outcomes of the developed protocols accomplished during the entire course of works.