SYNTHESIS AND CHARACTERIZATION OF FLAVONE, COUMARIN, IMIDAZOLE AND ISOXAZOLE DERIVATIVES USING NOVEL CATALYSTS

Abstract

The thesis entitle “Synthesis and Characterization of Flavone, Coumarin, Imidazole and Isoxazole Derivatives Using Novel Catalysts” is divided into five chapters. The present work is aimed to synthesize flavone, coumarin, imidazole, and isoxazole derivatives via novel catalysts under mild reaction conditions. Designed the novel coumarin and indanone based ligands for the cross-coupling reactions to synthesize 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles via dihydroquinolines as a novel oganocatalyst. Developed a new one-pot methodology for the synthesis of 4-hydroxycoumarin-based 1,5- diketones and effective cyclization to unexpected 3,4-dihydropyridines. Further, synthesized novel flavone and coumarin based isoxazoles in one-pot mediated by PhI(OAc)2 under mild reaction conditions, and their antibacterial activity is also studied. All the synthesized compounds are characterized using standard analytical techniques like IR, 1H-NMR, 13CNMR, GC-MS, HRMS etc. The thesis has been divided into five chapters for further transparency and clarity and elaborated as follows: CHAPTER-1 Introduction The first chapter describes the introduction of flavones, coumarin, imidazole, isoxazole, cross-coupling reactions and their synthetic methodology. Flavone, a sub-class of flavonoid compounds is a secondary metabolite of plants which plays important role in various biological activities such as anti-inflammatory, anti-oxidant, anti-tumor, anti-microbial, anticytotoxic, anti-allergic and anti-estrogenic activities. Coumarin belongs to a group of important oxygen containing benzopyran-2-ones, generally isolated from plants and shows verities of biological activities such as anti-inflammatory, anti-cancer, anti-viral, anti-oxidant, antimicrobial, anti-coagulant etc. Transition metal catalysis has become an essential tool in modern synthetic organic chemistry, of the transition metals, palladium has emerged as the most widely utilized over the past few decades (Figure 1). Figure 1: Bioactive compounds containing flavone, coumarin, imidazole and isoxazole. ii The importance of Pd in the synthesis is evident from the massive number of name reactions in connection with this field. Isoxazole and imidazole compounds are important class of nitrogen and oxygen containing heterocycles, widely distributed in natural and synthetic molecules because of diverse range of biological activities. CHAPTER-2 Part A: Coumarin Based Novel Ligands in the Suzuki-Miyaura and Mizoroki-Heck Cross-Couplings under Aqueous Medium Mohammed Waheed, Naseem Ahmed.* Tetrahedron Lett. 2016, 57, 3785-3789 In this chapter, we have developed an array of novel, efficient, air and moisture stable coumarin based ligands (L1-L5) for the Suzuki-Miyaura and the Mizoroki-Heck cross-coupling reactions under aqueous medium. The catalyst L1/Pd(OAc)2 system was observed to be an efficient catalyst for the cross-coupling reactions in various aryl halides under mild reaction conditions. We successfully applied this methodology for the coupling of aryl chloride with arylboronic acid in good yields (Scheme 1). These products were fully characterized on the basis of their spectral analysis 1H-, 13C-NMR, GC-MS and HRMS. Scheme 1: Coumarin based ligands in the Suzuki-Miyaura and the Mizoroki-Heck crosscoupling reactions. Part B: Pd/Indanone Based Ligands: An Efficient Catalyst System for Ullmann-type, Suzuki-Miyaura and Mizoroki-Heck Cross-Coupling Reactions with Aryl Tosylates and Aryl Halides Mohammed Waheed, Naseem Ahmed.* Synthesis. 2017, 49, 4372-4382 In this section, we have developed efficient air and moisture-stable indanone-based ligands and successfully applied them to Ullmann type, Suzuki-Miyaura, and Mizoroki-Heck cross-coupling reactions with aryl tosylates as well as aryl halides. This methodology can be used to couple various aryl tosylates and aryl halides with a range of coupling partners in high iii yields under mild conditions (Scheme 2). These products were fully characterized on the basis of their spectral analysis 1H-, 13C-NMR, GC-MS and HRMS. Scheme 2: Indanone-based ligands in Ullmann type, Suzuki-Miyaura and the Mizoroki-Heck cross-coupling reactions. CHAPTER-3 An Efficient Synthesis of 2,4,5-Trisubstituted and 1,2,4,5-Tetrasubstituted Imidazoles Using Dihydroquinolines as Novel Organocatalyst Mohammed Waheed, Naseem Ahmed,* Meshari A Alsharif, Mohammed Issa Alahmdi, Sayeed Mukhtar. ChemistrySelect. 2017, 2, 7946-7950. In this chapter, we have developed a new, simple, efficient and environmentally benign one-pot multicomponent methodology for the synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles catalyzed by dihydroquinoline based novel organocatalysts in refluxed ethanol. We have successfully applied this methodology for aromatic aldehydes and amines. The key advantages of this method are simplicity of operation, easy work-up and purification of compounds by recrystallization only in high product yields (Scheme 3). These products were fully characterized on the basis of their spectral analysis 1H-, 13C-NMR, GC-MS and HRMS. Scheme 3: One-pot multicomponent synthesis of 2,4,5-trisubstituted and 1,2,4,5- tetrasubstituted imidazoles catalyzed by dihydroquinoline. iv CHAPTER-4 One-pot Synthesis of 1,5-Diketones from 3-Acetyl-4-hydroxycoumarin and Effective Cyclization to Unexpected 3,4-Dihydropyridines Mohammed Waheed, Naseem Ahmed,* Meshari A Alsharif, Mohammed Issa Alahmdi, Sayeed Mukhtar. Org. Biomol. Chem. 2018, 16, 3428-3437 In this chapter, we have developed a new one-pot methodology for the synthesis of novel 4-hydroxycoumarin-based 1,5-diketones via aldol condensation, and Michael addition in the presence of L-proline in good to excellent yields under mild reaction conditions. These new 1,5-diketones were easily cyclized to the unexpected and extremely stable 3,4-dihydropyridines effectively and selectively, which could not be easily further oxidized to tetra-substituted pyridines. One pot, high yields, shorter reaction times, cheap starting materials, mild reaction conditions, easy work-up and purification of the products are the key advantages of this protocol (Scheme 4). These products were fully characterized on the basis of their spectral analysis 1H-, 13C-NMR, HRMS and X-ray single crystal. Scheme 4: One-pot synthesis of novel 4-hydroxycoumarin-based 1,5-diketones and unexpected cyclization to 3,4-dihydropyridines. CHAPTER-5 PhI(OAc)2-Mediated One-Pot Synthesis and their Antibacterial Activity of Flavone and Coumarin Based Isoxazoles under Mild Reaction Conditions Mohammed Waheed, Naseem Ahmed,* Meshari A Alsharif, Mohammed Issa Alahmdi, Sayeed Mukhtar. ChemistrySelect. 2019, 4, 1872-1878 In this chapter, we have developed a new, simple, efficient and environmentally benign onepot methodology for the synthesis of novel flavone and coumarin based isoxazoles via in-situ formation of nitrile oxide in the presences of PIDA in good to excellent yields under mild reaction conditions. We have successfully applied this methodology for O-propargyl flavones/coumarin containing heterocyclic ring such as furan and thiophene as well as 7-O-propargyl coumarin and 4-O-propargyl coumarin. We also developed one-pot synthesis of flavone based isoxazole catalyzed by hypervalent iodine (III) but reaction took longer time and less product yield as compared to PIDA. Cheap starting materials, shorter reaction time, one-pot, high yields, mild reaction conditions, easy work-up and purification of v compounds by recrystallization is the key advantages of this protocol. Various derivatives have been tested for their antibacterial activity, and high values of MIC were observed for these compounds (Scheme 5). Scheme 5: Synthesis of novel flavone and coumarin based isoxazoles mediated by PhI(OAc)2.