Exploring the Chemistry of Quinones for Accessing Valued Oxygen and Nitrogen Heterocycles

Abstract

Chapter 1: A Conspectus on the Reactivity of Quinone Derivatives and Strained Rings for Accessing Diverse Nitrogen and Oxygen Heterocycles Heterocycles are the prevalent structural motifs present in many natural products, enzymes, vitamins, and exhibits a variety of biological properties. In our routine life, we actually deal with so many medicinally and naturally abundant molecules in different ways that shows the importance of various heterocycles. For example, cosmetic products, polymers, and pharmaceuticals constitute a variety of fused oxygen containing compounds. Also, the oxacycles possess many pharmacological properties like anti-tumor, anti bacterial, anti-fungal and anti-oxidant. In present times, their wide range of application in pharmaceutical and medicinal chemistry has provided an extensive area for research in the synthetic field. Owing to their enormous importance in medicinal, agrochemical and industrial areas, it has become crucial to construct more heterocycles from the different reaction partners to meet the demand of the future. Therefore, an extensive study on the different methods towards the synthesis of an array of heterocyclic compounds is necessary by employing the efficient and straightforward approaches from readily available precursors. In this direction, quinones and their analogues are the prevalent structural motifs that represent an important class in the variety of biological active natural products and pharmaceuticals. Therefore, in order to construct functionalized heterocycles different routes has been showcased in this chapter by using quinones as one of the precursors along with another partner substrate. Also, other than quinones, urea derivatives and strained rings have also proved substantial reacting partners for the synthesis of nitrogen as well as oxygen heterocycles. This chapter describes the use of all these potential precursors to design the diverse methodologies for the development of valued heterocyclic scaffolds. The aim of the thesis and the investigations carried out during the doctoral training are outlined in the form of different chapters as follows. Chapter 2: Vinylogous Aza-Michael Addition of Urea Derivatives with p-Quinone Methides Followed by Oxidative Dearomative Cyclization: Approach to Spiroimidazolidinone Derivatives Imidazolidin-2-ones and its analogues are ubiquitous structural motifs found in natural products, pharmaceuticals, and other biologically active compounds. They often possess a broad range of biological activities such as antitumor, antibiotic, and anti-hypertonic. These N-containing heterocycles show versatile utility as useful structural synthons in organic synthesis. Amid the various spirocyclic scaffolds in drug discovery, spiroimidazolidinone is a promising structural motif. Consequently, continuous efforts have been made towards the synthesis of this type of spirocyclic molecules. On the other hand, it is worth considering that the cyclohexadienones are also the prevalent core structure found in many bioactive natural products and have gained considerable importance due to their abundance in pharmaceuticals. Hence, incorporation of spiroimidazolidinone and cyclohexadienone in one frame can be proved beneficial for medicinal chemists. During the past few years, p-quinone methides (p-QMs) have emerged as one of the most desirable components to access spiro-cyclohexadienones. In literature, p-QMs have been mainly known for their role as vinylogous Michael acceptors in various 1,6- conjugate addition reactions. Aromatization of the cyclohexadienone moiety is the main driving force for these types of conjugate addition reactions. However, the spirocyclization reactions of p-QMs are comparatively less explored due to the requirement of the dearomatization of the reaction intermediate. This chapter demonstrates the reactivities of p-QMs and urea derivatives as building blocks towards the construction of spiro imidazolidinones. The reaction of p-quinone methides with urea derivatives in the presence of a base results in the formation of 1,6-conjugate addition product in 90% yield which further on treatment with hypervalent iodine reagent renders the spiro-imidazolidinones in 65% yield. The optimization studies discovered DBU as the base for the conjugate addition product and PIDA as an efficient reagent for the cyclization step in order to construct spiro-imidazolidinones. The transformation exhibited wide substrate scope in terms of both the substrates. In the follow up chemistry, spiro-imidazolidinone were subjected to debenzylation which afforded the N-hydroxy urea ring attached cyclohexadienone and corresponding structures are used for metalloenzyme inhibition activities. Chapter 3: Accessing Complex Tetrahydrofurobenzo-Pyran/Furan Scaffolds via Lewis-Acid Catalyzed Bicyclization of Cyclopropane Carbaldehydes with Quinone Methides/Esters Benzannulated oxacycles, especially benzannulated [6,5]- and [5,5]- fused oxygen heterocycles, represent a highly privileged class of structural motifs in a variety of bioactive molecules and natural products. Xyloketals, isolated from mangrove fungus, comprising the tetrahydrofurobenzopyran unit, is engaged in the treatment of several neurological disorders like Alzheimer’s disease. Alboatrin, a phytotoxic metabolite, is responsible for vascular-wilt disease in alfalfa, whereas aflatoxins bearing the tetrahydrofurobenzofuran units are well-known for their carcinogenicity, toxicity, and antimitoticity. Owing to their unique structure and intriguing activity in biological systems, the construction of such complex structural motifs with multiple stereogenic centers has always been a challenging task for the synthetic fraternity, and consequently, the reports on the synthesis of these frameworks are still rare and underexplored. However, a few methodologies demonstrating the synthesis of benzofused six-five and five-five oxygen tricycles have been reported in recent years. Over time, donor-acceptor cyclopropane carbaldehydes have emerged as versatile synthons for the diverse hetero/carbocyclic synthesis. In this regard, our group has significantly explored the strain-driven reactivity of aryl-substituted cyclopropane carbaldehydes (ACC) towards heterocyclic synthesis via Lewis-acid or metal-free activation of the cyclopropane ring. At the same time, quinone derivatives have also acquired enormous attention for their electrophilic nature towards assembling densely functionalized molecules. Quinone methides and quinone esters are widely known to act as four- and three-atom contributors for accessing intriguing heterocyclic systems. As part of our efforts and inspired by our previous results, we anticipated that the electrophilic dipolar reactivity of quinone derivatives and the in-situ ring expansion of ACC could be used in synergy for a possible bicyclization process. In this chapter, we disclosed a straightforward one-pot synthesis of tetrahydrofurobenzopyran and tetrahydrofurobenzofuran systems via an in-situ ring-expansion of the cyclopropane carbaldehydes followed by a [2+n] cycloaddition with the quinone derivatives. After careful screening of the conditions, we established our standard conditiond where BF3.OEt2 is an efficient catalyst for the synthesis of benzofused six-five oxacycles and Sc(OTf)3 is an effective catalyst for the synthesis of benzofused five-five oxacycles with good yields. To our delight, the transformation was compatible with variety of cyclopropane carbaldehydes and quinone methides as well as quinone esters and furnished the product in moderate to good yields. Moreover, the tetrahydrofuranobenzopyran derivative was easily transformed to 3,9a-dihydro-2H-furo[2,3-b]chromene, which is also an essential component in many biological scaffolds. Chapter 4: Switchable Reactivity of Cyclopropane Diesters towards (3+3) and (3+2) Cycloadditions with Benzoquinone Esters Heterocyclic compounds are privileged structural motifs that have been found as an important core in many natural products. Particularly, oxygen-containing heterocyclic frameworks are widely known for their biological and pharmaceutical activities. However, benzopyran derivatives often possess antitumor, antibiotic and antioxidant properties. Due to their inherent biological properties, chromans have acquired immense attraction in medicinal and organic chemistry. Furthermore, the benzopyran moiety is also a part of PPARγ and PPARα/γ agonists. These PPARs play a very crucial role in the control of different pathological disorders, like hyperlipidaemia, obesity, type 2 diabetes, neurodegenerative and cardiovascular diseases. In addition, bioactive benzopyran scaffolds are used as neuroprotectors in various neurological disorders such as Alzheimer’s disease. Over the time, donor-acceptor cyclopropanes (DACs) have appeared as one of the most versatile building blocks for the synthesis of various carbo- and heterocycles. Due to the presence of vicinal donor and acceptor groups and high ring strain in the cyclopropane, the cleavage of the carbon-carbon bond occurs effortlessly. These 1,3 zwitterionic species exhibit several transformations like ring opening, rearrangements, ring expansion, and cycloaddition reactions. Also, these activated cyclopropanes undergo many rearrangement reactions, most commonly the in-situ generation of styryl malonates. Interestingly, these styryl malonates can further be a part of cycloaddition reactions by using a suitable reaction partner. Our group has significantly utilized the strain driven reactivity of DACs for a variety of annulation and cycloaddition reactions to synthesize valuable heterocycles. In this context, we delineate a catalyst-controlled cycloaddition reaction of DACs; a source of 1,3-zwitterionic species as well as 2-styryl malonate by fine-tuning of Lewis acid with the same reaction partner (quinone esters) to furnish densely functionalized five- and six-membered oxacycles. The optimization studies identified that InCl3 (10 mol %) was the most effective Lewis acid for the (3+3) cycloaddition. On the contrary, (3+2) cycloaddition was successfully carried out using In(OTf)3 (20 mol %) in dichloromethane in good yields. The control experiments were also performed in order to prove the mechanism. The desired product was also encountered at the gram scale in moderate yields. Further, in the follow up chemistry, the final product was subjected to the methylation of the phenolic hydroxyl group using methyl iodide and base. Also, the treatment of final product with DIBAL-H resulted in the formation of tetrahydro-2H-pyrano[3,4,5-de]chromene scaffolds.