SUSTAINABLE APPROACHES FOR CONSTRUCTING C–C AND C–S BONDS IN ORGANIC SYNTHESIS

Abstract

Climate change has become a major concern for countries across the globe as the environment catastrophe manifests itself in the form of drought, cyclones, floods, etc in different parts of the world. While governments are busy framing rules & policies to limit the damage to environment, industries are also adopting strategies which can lead to more sustainable development. Chemicals, used across the industries, can pave the way for developing new eco-friendly products which can be manufactured using less resource and, thus, result in carbon footprint reduction. The importance of carbon–carbon and carbon–sulfur bonds has grown over the past few years particularly in the pharmaceutical and agrochemical industries. Therefore, the development of new methods for the construction of these bonds is a very attractive research area. As part of this thesis, investigations were carried out to develop simple, efficient, economic, sustainable and promising protocols for the construction of carbon–carbon and carbon–sulfur bonds leading to variety of molecular entities of relevance for biological activity and material applications. The thesis has been divided into eight chapters. Chapter 1 of the thesis places in perspective literature background and developments, so that the work embodied in Chapters 2– 8 may be better appreciated and at the end, copies of 1H NMR and 13C NMR spectra of selected compounds are provided. Chapter 1 of this thesis presents evolution of organic synthesis, green and sustainable chemistry and its utilization in the development of new synthetic methodologies. Also discussed are endeavors focused on developing methods for Carbon–Carbon and Carbon– Sulfur bonds that are devoid of explosive attributes. The developments in domino organic synthesis using quinones are presented in brief. In addition, use of green chemistry in pharmaceuticals is also described at the end of this chapter. Chapter 2 is concerned with the waste-free synthesis of diarylmethyl thioethers, which constitute an important category of compounds of relevance in pharmaceutical and biological chemistry. It is shown that the rapid synthesis of symmetrical diarylmethyl thioethers (SDAMTs) and unsymmetrical diarylmethyl thioethers (unSDAMTs) in high to quantitative yields promoted by inexpensive and eco-friendly BF3·OEt2 by simple stirring of readily ______________________________________________________________________Abstract ii available thiols and diaryl carbinols at room temperature via dehydrative SN1 reaction (Scheme 1). Metal-free conditions, broad substrate scope with diverse substitution patterns, large-scale preparation, high atom economy and operational simplicity are noteworthy features of this economic synthetic process. Scheme 1: Synthesis of symmetrical and unsymmetrical diarylmethyl thioethers. Chapter 3 deals with the metal-free dehydrative coupling reaction of p-quinols to diaryl carbinols. The product hydroquinones are versatile chemicals with significant applications in cosmetics, photography, dyes and variety of pharmacologically important agents contain hydroquinone moiety and shown to have anti-oxidant, anti-cancer and other bioactivities. The reaction proceeds through iodine catalyzed alkyl(aryl) transfer-aromatization alkylation domino (ATAAD) approach. Our sustainable synthesis of branched hydroquinones involves simple stirring of pquinols with diaryl carbinols at room temperature using eco-friendly molecular iodine as a catalyst under mild reaction conditions. This metal-free and base-free approach provided the novel class of alkylated hydroquinones in good to excellent yields in short reaction time with high atom economy. This protocol required simple work-up procedure. The developed ATAAD approach expanded the scope of symmetrical/unsymmetrical diaryl carbinols bearing substituents of different electronic nature and a variety of p-quinols. Large-scale preparation of branched hydroquinone demonstrated the clear and practical utility of this efficient domino process (Scheme 2). ______________________________________________________________________Abstract iii Scheme 2: Synthesis of branched hydroquinones. Chapter 4 explores in situ generated superacid BF3·OH2-promoted alkyl(aryl) rearrangement of p-quinols leading to branched hydroquinones with diaryl carbinols which an extension of the results of Chapter 3. Inspired by the results of chapter 3, we wondered if alkyl(aryl) transferaromatization alkylation domino (ATAAD) reactions could be performed with in situ generated catalyst in the same pot to create same molecular entities. As part of our ongoing interest in the generation of sustainable protocols, we envisaged that superacid BF3·OH2 would encourage intramolecular alkyl(aryl) rearrangement of p-quinols and activation of diaryl carbinols for nucleophilic substitution leads to branched hydroquinones. It illustrates an efficient and ecofriendly approach to the coupling of p-quinols with diaryl carbinols promoted by superacid BF3·OH2 which is generated in situ from BF3·OEt2 (Scheme 3). The crucial role of moisture in the generation of superacid BF3·OH2 has been investigated in details. Our green protocol involves the simple stirring of p-quinols with diaryl carbinols using BF3·OEt2 in open atmosphere at room temperature, leading to branched hydroquinones. This clean process does not require any quenches and tedious work-up procedure. The current ______________________________________________________________________Abstract iv protocol offers valuable alternative to the activation of p-quinols for a variety of reactions that can find applications in the field of green synthesis. Scheme 3: Superacid BF3·OH2 water catalyzed synthesis of branched hydroquinones. Chapter 5 describes the functionalization of hydroquinones because functionalized hydroquinones are of immense chemical and biological interest and evoked as a separate class of compounds over the past few decades. Based on our growing interset in quinone chemistry we have developed an efficient method for the synthesis of benzylated hydroquinones by the reaction of monosubstituted hydroquinones with benzhydrols under the influence of simple and inexpensive p-toluenesulfonic acid monohydrate (PTSA) in water (Scheme 4). Scheme 4: Benzylation of hydroquinones with benzhydrols. The procedure is operationally simple, and the reactions occur within 1 hour, leading to benzylated products in high yields. This process allows an ecologically and economically favourable chemical production with minimization of waste and water as only by-product. This ______________________________________________________________________Abstract v method is remarkable in light of the fact that benzylation of hydroquinones with benzhydrols does not require any organic solvents and reaction occurred effectively in aqueous medium. Chapter 6 deals with Hexafluoroisopropanol (HFIP)-promoted expeditious synthesis of thioesters from thiols and acyl halides. Hexafluoroisopropanol (HFIP) is known as “magic solvent” that has been utilized within literature for a wide range of synthetic transformations. Herein, we present HFIP as new highly active catalyst for the rapid synthesis of thioesters which is an important class of acyl donors in organic synthetic chemistry. This protocol involves an unprecedented HFIP induced activation of acyl halides that facilitates nucleophilic substitution reaction with readily available thiols, thus enabling the synthesis of a range of thioesters in an efficient manner (Scheme 5). Almost all reactions were clean and provided the desired products in good to quantitative yields. It has also been demonstrated that HFIP can be recovered and used for other occasions in synthetic chemistry and be equally as good at catalyzing the synthesis of thioesters as the store bought material. Scheme 5: HFIP-catalysed synthesis of thioesters. In chapter 7, we present metal-free, base-free and halogen-free protocol for the Scarbonylation of thiols with parent acids by using eco-friendly and inexpensive methanesulfonic anhydride (MSAA) under solvent-free conditions. A variety of thiols were successfully coupled with a range of acids and provided the thioesters (Scheme 6) in good to excellent yields. In view of excellent atom economy and stable attribute of this reagent, the present transformation shall prove to be ideal thiocarbonylation reaction in general under neat conditions. Moreover, Large-scale preparation of thioester illustrated the practical utility of this economic synthetic process. ______________________________________________________________________Abstract vi Scheme 6: MSAA-promoted synthesis of thioesters from acids and thiols. Chapter 8 deals with direct arylation of benzhydrols with arenes to construct the polyarylated alkanes which are privileged architectural units frequently found in biologically active compounds and natural products. Our work focuses on the development of an unprecedented reagent combination for metal-free synthesis of a variety of compounds. It is hypothesized that use of fluoroalcohols as efficient reaction media would allow the activation of the hydroxy functionality of benzylic alcohols through hydrogen-bonding, could progress the direct arylation via dehydrative nucleophilic substitution. Proof-of-concept for this approach focused on the reaction between benzhydrols and variety of arenes and heteroarenes. This waste-free methodology offers the variety of polyarylated alkanes in high yields. Most importantly, this work demonstrates the synthesis of bis-benzylated arenes by excess use of benzhydrols and the products are quite difficult to obtain from the reported methods