C3 FUNCTIONALIZATION OF 2-OXINDOLE TOWARDS DRUGS AND NATURAL PRODUCTS USING METAL AND METAL-FREE APPROACHES

Abstract

Oxindole is an important scaffold in pharmaceutical drugs and natural products. These derivatives have received significant attention among synthetic chemists and biologists due to their broad range of synthetic applications and biological activity. Therapeutic application of 2-oxindole derivatives includes, anti-cancer, Aurora B Inhibitor, treatment of idiopathic pulmonary fibrosis (IPF), antiviral, and antimicrobial etc. Structurally, many drugs and natural products were often connected at the C3 position of 2-oxindole via C-C, C=C, C-N, and C-O bonds. Although considerable efforts have been made by several research groups for the construction of these oxindole derivatives, the following essential concerns still need to address, i.e, the use of expensive catalyst, the efficiency of transformations, use of genotoxic halogenated reagent, atom economy, environment benign and safer approach, multistep synthesis and use of toxic starting materials. Hence, the development of C-C and C=X bond either catalytic/non-catalytic method to functionalize 2-oxindole is immensely important in organic synthesis. Thus, the main focus of my research centered on the development of C-C, C=C, and C-O bond formation using a metal catalyst or metal-free reaction for the synthesis of C3-alkylated 3-hydroxyindolin-2-one, 3-(diphenylmethylene)indolin-2-one, 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones, and Spirooxindole 2H-Azirines derivatives. In the first chapter, I will present the various synthetic approaches for the 2-oxindole derivatives towards drugs and natural products. Next chapter will depict our synthetic strategy for C3-alkylated 3-hydroxyindolin-2-one and 2-substituted-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one derivatives from 2-oxindole/1-teralone by using less expensive, bench stable and easily available primary alcohols in the presence of Ru-NHC catalyst in a one-pot condition under the borrowing hydrogen concept. Furthermore, this method has been successfully and efficiently applied for the synthesis of 2-oxindole based natural products such as Donaxaridine in fewer steps. To support the mechanism, the crucial intermediate was confirmed by HRMS analysis. All the detailed investigations will be presented in the second chapter. In the third chapter, we developed Ru(II)-NHC catalyzed formation C=C bond at C3-position of 2-oxindoles by using secondary alcohols in the absence of an acceptor. A detailed experiment-based mechanism was reported for this transformation. To confirm the mechanism, we detected the dissociated ligand, hydride intermediate by using NMR spectroscopy and liberation of molecular hydrogen was confirmed by GC analysis. The biological activities of the synthesized 3-(diphenylmethylene)indolin-2-one derivatives were tested against the Plasmodium falciparum parasite. Next, we have developed a novel, straightforward, simple and efficient transition-metal-free approach for the exclusive synthesis of Z-3-(aminobenzylidene/aminoalkylidene)indolin-2-ones. Furthermore, in the synthetic application, we have developed base and additive-free fluorination using selectfluor and the C=C bond cleavage using CuI and environmentally benign O2. This addition reaction proceeded via two possible mechanisms and supported by SET experiment and HRMS analysis. All the details will be discussed in the fourth chapter. In the final chapter, we have also demonstrated a feasible and efficient approach for the synthesis of spirooxindole 2H-azirines via intramolecular oxidative cyclization of 3-(amino(phenyl)methylene)-indolin-2-one derivatives in the presence of I2 and Cs2CO3 under batch/ continuous flow. Furthermore, a serendipitous nucleophilic addition of Grignard reagent across the C=N of azirine and subsequent ring-opening afforded 3-(amino(phenyl)methylene)-indolin-2-one derivatives. In this thesis, we have illustrated the research findings in the establishment of “C3 functionalization of 2-oxindole towards drugs and natural products using metal and metal-free approaches”.