REGIOSELECTIVE SYNTHESIS OF OXINDOLE-BASED POLYHETEROCYCLES

Abstract

The thesis entitled “Regioselective synthesis of oxindole-based polyheterocycles” is divided into three chapters, viz. (i) Introduction, (ii) Objectives, Results and Discussion, and (iii) Experimental. We have developed novel green approaches for the regioselective synthesis of oxindole based polyheterocycles by employing diverse oxindole based starting materials. The protocols involves FriedelCrafts, domino and SN1 reactions. We have synthesized arene substituted oxindole, benzo-fused oxindoles, lactone embraced oxindoles, and multisubstiuted pyrrole heterocycles by treating a series of 3-alkylidene oxindoles with various nucleophiles as precursors. Further, we have constructed 3,3-disubstituted oxindoles by the sulfenylation reaction of 3-hydroxy bisindoles. We have performed theoretical investigations to comprehend the regioselectivity and chemical reactivity observed in the sulfenylation reaction of 3-hydroxy bisindoles by using different methods on Gaussian 09 suite programs. Chapter 1: Introduction Oxindoles are distinguished scaffolds in natural products as well as in pharmaceutical lead compounds. Their interesting biological properties and valuable contribution in the synthesis of drugs prompted synthetic chemists to build novel oxindole derivatives and for their utilization in different transformations to construct biologically potent structures/molecules under various conditions. Also, the development of environmental friendly protocols were considered as most significant approaches in organic synthesis. The goal of green synthesis involves precluding the use of toxic solvents minimizing the waste generation, excluding the use of metal-additives, obviating column chromatography techniques for purification, and achieving step and atom economy. Regioselectivity exemplifies as an essential feature in designing an efficient synthetic strategy. In fact, factors such as the nature of the functional groups already installed into the molecule, reagents and reaction conditions, affect the regioselectivity of reactions and a perfect tuning of all factors, results in the selective construction of particular regioisomers. Hence to design regioselective routes are essential for the success of organic reactions. x Chapter 2: Objectives, Results and Discussion This chapter deals with the objectives, results and discussion which are divided into four sections. 2.1. Regioselective reactions of electron-rich arenes with 3-ylidene oxindoles We have successfully demonstrated BF3•OEt2-mediated novel and regioselective synthesis of a series of arene substituted ylidene oxindoles from 3-alkylidene oxindoles and arenes under mild conditions. The protocol was compatible with various electron-rich arenes. The methodology led to the facile synthesis of various potentially biologically active 2,3-difunctionalized benzofuran and lactone embraced products by employing phenols and ylidene oxindoles as starting materials under same conditions (Scheme 1). Scheme 1: FriedelCrafts reactions of 3-ylide oxindoles and electron-rich arenes. 2.2. Regioselective synthesis of multisubstiuted pyrrole polyheterocycles A highly regioselective iodine-mediated cascade reaction for the synthesis of multifunctional polyheterocyclic systems was developed by treating 3-(2-oxo-2- arylethylidene)-oxindoles with 1,4-benzoxazinone. The polyheterocycles are skillfully xi embraced with oxindole, pyrrole, and coumarin scaffolds, which are well-known for their enriched biological activity. The current approach worked under mild reaction conditions. The reaction afforded a single product, and no rotameric and keto-enol isomeric products were formed. The method was environmentally benign and atom-economical, and the only side product of this reaction was water. This protocol obviates the purification techniques such as column chromatography for the isolation of the products. The products were isolated by decantation of the solvent or by recrystallization. The reaction proceeded through interand intramolecular C−C and C−N bond formation. The current protocol was also scalable (Scheme 2). Scheme 2: Cascade reaction between 3-ylidene oxindoles and 1,4-benzoheterocyles. 2.3. BF3•OEt2-promoted synthesis of pyrrole-oxindole hybrids We have established BF3•OEt2-mediated efficient, regioselective approach for the synthesis of novel polyheterocyles by employing methyleindolinones and  -enamine esters as starting materials under metal-free and mild conditions. The salient features of this regioselective method are short reaction time, operational simplicity, and products are free from rotamers and keto-enol tautomers (Scheme 3). xii Scheme 3: Domino reaction of 3-ylidene oxindoles with  -enamine esters. 2.4. Regioselective C-3 functionalization of 3-hydroxy bisindoles with thiols A novel, efficient and unprecedented green protocol for the formation of C–S bonds has been developed under metal-free conditions. We have accomplished an instant and efficient p-TSA·H2O-catalyzed sulfenylation reaction of 3-hydroxy-3-(indol-3-yl)indolin-2-one derivatives. This highly regioselective approach provided C-3 functionalized products in excellent yield, and this methodology was found compatible with both aromatic and aliphatic thiophenols having electronic and steric divergence as well as diverse functional groups. Sulfenylation reaction was performed at room temperature in green solvent with minimal catalyst load. The protocol proceeded with the involvement of quasi-antiaromatic- 2H-indole-2-one ring intermediate (Scheme 4). Scheme 4: Sulfenylation reaction of 3-hydroxy bisindoles. xiii 2.5. Theoretical investigations on sulfenylation reaction of 3-hydroxy bisindoles The experimental results obtained in the sulfenylation reaction of 3-hydroxy bisindoles were supported by scrupulous theoretical calculations, to comprehend the regioselectivity and chemical reactivity observed in the thiolation reaction of 3-hydroxy bisindoles. We have calculated electrophilic Fukui function (fk +) and Mulliken atomic spin density for all the atoms of transient quasi-antiaromatic-2H-indole-2-one species generated after the dehydration of 3-hydroxybisindole by using different methods in both gas and aqueous phases with Gaussian 09 suite of programs. The data harnessed after the evaluation of electrophilic Fukui functions displayed largest Fukui values (fk +) for C-3 atom of quasiantiaromatic- 2H-indole-2-one cationic species in both gas and aqueous phases. The electrophilic Fukui values and Mulliken atomic spin density (MASD) values evaluated for the transient cationic species justified the attack of thiols at C-3 position of hydroxy bisindoles and comprehend the regioselectivity observed in the sulfenylation reaction of 3- hydroxy bisindole exclusive formation of C-3 sulfenylated products. The SN1 pathway of sulfenylation reaction of 3-hydroxy bisindole followed was also justified by employing theoretical calculations. Chapter 3: Experimental The third chapter provides experimental procedures in detail along with physical and spectroscopic data such as MP, yield, 1H and 13C NMR and mass spectral data.