SYNTHESIS OF MULTIFUNCTIONAL HETEROCYCLIC SYSTEMS THROUGH DOMINO REACTIONS

Abstract

The thesis entitled “Synthesis of multifunctional heterocyclic systems through domino reactions” is divided into three chapters, viz. (i) Introduction, (ii) Objectives, Results and Discussion, and (iii) Experimental. This thesis describes rapid and efficient protocols for the synthesis of novel heterocycles such as alkyl/aryl sulfide derivatives of coumarin, and dihydrobenzofuran via domino reaction and [3 + 2] cycloaddition reaction of alkenyl p-benzoquinones which were generated by oxidative demethylation of alkenyl dimethoxy arenes by using cerium(IV) ammonium nitrate as an oxidizing agent. We have also calculated Fukui functions for alkenyl p-benzoquinone to support the observed regioselectivity obtained from the nucleophilic addition. Further, we have established conceptually novel approach to generate nitrogen and oxygen containing heterocycles, for example, fused-pyrroles and naphthofurans by the treatment of aroylmethylidene malonates with benzoxazinones and -naphthols. Chapter 1: Introduction In the first chapter of the thesis, the synthetic aspects of heterocyclic compounds relevant to the research work are discussed. To conclude the chapter, literature describing investigations and development of heterocyclic compounds is presented. The field of organic chemistry has progressed intensely over the past decades, and present reaction methodologies deal with novel and effective strategies for the preparation of multifunctional heterocyclic compounds. Heterocycles play an important role in the design and discovery of new physiologically and pharmacologically active compounds. In recent years, synthesis of novel polyheterocyclic compounds has been at the forefront of today’s research. The formation of C–C, C–S, C–N and C–O bond is very essential for the synthesis of heterocyclic compounds. Domino reactions exemplify green approaches for the production of polyfunctionalized complex molecules by endorsing multiple bond-formations in a onepot process. Domino reactions are highly efficient and have environmental advantages as they generate molecular complexity in less number of steps. Various reactions of benzoquinones and aroylmethylidene malonates and synthesis of heterocycles such as viii coumarins, biarylsulfides, dihydrobenzofurans, naphthofurans and multisubstituted pyrroles are depicted in this chapter. Chapter 2: Objectives, Results and Discussion This chapter deals with the objectives, results and discussion, which is divided into five sections. 2.1 Domino reaction of alkenyl p-benzoquinones with alkyl/aryl thiols In this section, the synthetic aspects of novel alkyl/aryl sulfide derivatives of coumarin are presented. We have developed a novel, efficient and mild methodology towards the synthesis of alkyl/aryl sulfide derivative of coumarins via reaction between novel alkenyl p-benzoquinones and thiols. This protocol involved the formation of C–S and C–O bonds through domino reaction. This mild and catalyst-free approach delivered biarylsulfides in good to excellent yields. The reaction proceeded smoothly with good substrate scope. Scheme 1: Domino reaction between alkenyl p-benzoquinones and thiols. 2.2 [3 + 2] Cycloaddition of alkenyl p-benzoquinones with olefins This section deals with harnessing the reactivity of alkenyl p-benzoquinones with styrenes. We have discussed an efficient and mild approach towards the synthesis of dihydrobenzofurans via [3 + 2] cycloaddition between alkenyl p-benzoquinones and olefins. Dihydrobenzofurans are very important motifs and are found in various natural products and biologically important compounds. This protocol works under Lewis acid conditions to ix deliver bicyclic products with a plethora of functional groups regioselectively. The yields of these reactions are noteworthy. Scheme 2: [3 + 2] Cycloaddition reaction between alkenyl p-benzoquinones and substituted styrenes. 2.3 Synthesis of functionalized pyrrolobenzoxazinones Aroylmethylidene malonates are useful precursors for the formation of various heterocyclic compounds. Several aroylmethylidene malonates have been synthesized and performed their reactions with benzoxazinone derivatives. Benzoxazinone compounds have wide chemistry and they have been found in biologically and pharmacologically important compounds. An efficient, novel and mild approach for the synthesis of pyrrolobenzoxazinones has been developed. This transition metal promoted domino protocol with aroylmethylidene malonates and benzoxazinones has been successfully established to afford the title compounds in good to excellent yield under mild reaction conditions. FeCl3 is used as a promoter for this transformation to deliver pyrrolobenzoxazinones with high efficiency and excellent functional group tolerance. The synthesized pyrrolobenzoxazinone contain pyrrole as well as benzoxazine motiffs, which have an important role in biological field. x Scheme 3: Synthesis of fused pyrroles. 2.4 Synthesis of -substituted aryl ketones Encouraged by the results obtained from the reaction between aroylmethylidene malonates and benzoxazinones, the scope of aroylmethylidene malonates has been further extended. Consequently, a rapid, efficient metal-free and environmental-friendly approach has been established for the formation of -substitited aryl ketones under mild reaction condition with electron-rich arenes. This iodine mediated reaction ensues under solvent-free and aerobic conditions to deliver products in good yields. Scheme 4: Synthesis of -substituted aryl ketones. 2.5 Synthesis of functionalized naphthofuran derivatives In continuation of the above domino protocols a rapid and efficient method for the synthesis of naphthofuran derivatives has been developed. Aroylmethylidene malonates reacted with -naphthol and its derivatives to afford tricyclic products in good to excellent yields. This protocol sustains a wide range of functional groups tolerance in providing the desired products with low catalyst loading. xi Scheme 5: Domino reaction between aroylmethylidene malonates and naphthols. Chapter 3: Experimental The third chapter details the methods for preparation of compounds. Also the chapter includes all physical and spectroscopic data such as MP, IR 1H NMR, 13C NMR, 2D NMR and mass spectral data to characterize the synthesized compounds.