ACID MEDIATED DOMINO TRANSFORMATIONS: ONE-POT SYNTHESIS OF HETEROCYCLIC AND CARBOCYCLIC COMPOUNDS

Pedireddi, Niharika and G, Satyanarayana (2018) ACID MEDIATED DOMINO TRANSFORMATIONS: ONE-POT SYNTHESIS OF HETEROCYCLIC AND CARBOCYCLIC COMPOUNDS. PhD thesis, Indian Institute of Technology Hyderabad.

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Abstract

Organic chemistry deals with bond cleavage and bond forming reactions during the course of achieving target compounds. In organic synthesis, construction of CC or Cheteroatom bond is considered to be of paramount interest. Development of strategies towards synthesis of various annulated products has been a vital part of synthetic chemistry. The ring/cyclic structures are very essential, due to their prominent presence in various naturally occurring compounds. Dating back to the early times in synthesis, ring forming and annulation reactions have been very widely reported. To name a few, Diels-Alder reaction, Nazarov cyclization, Robinson annulation, Paal-Knorr synthesis, ring closing metathesis (RCM) have been some of the versatilely modified and employed reactions to afford the ring systems. In addition, closing the tethered chains into rings, locks particular atoms into specific stereochemistry and chirality engendering unique complexity and three-dimensional shapes. Furthermore, the cyclic compounds, due to their structural features and biological significance, comprise a majority of biomolecules involved in the functioning of living organisms and synthetic molecules (e.g., drugs, herbicides, etc.). The traditional methods of synthesis have endured a gradual evolution in the course of discovering more effective, efficient and environmentally benign approaches. Sustainable research has turned into a core concern in contemporary organic synthesis. To address this, multistep reaction sequences are performed in an effective single reaction vessel to accomplish the synthesis of the targets. Domino or one-pot transformations have emerged to facilitate the multiple bond construction in a single reaction vessel. These reactions are also termed as cascade reactions, pseudo domino strategies, and tandem catalysis. Several advantages are attributed to such processes as they avoid the isolation of intermediate species and reduce the waste generation. This results in minimizing the solvent usage and resources. Also, these methods save time and energy and ultimately increase the efficiency of the synthetic process. Various emerging domains of organic chemistry like transition metal catalysis, acid catalysis, pericyclic reactions, have utilized the domino processes, to facilitate effective construction of bonds resulting in formation of various heterocyclic/carbocyclic products with a high degree of complexity. One-pot pathways have been well documented in synthetic organic chemistry. Although, one-pot transformations are known from a long time, Tietze et al, broadcasted their significance in the early 90’s. Even before this, reports on domino transformations were prevalent. For example, Gassman et al developed a one-pot synthetic strategy, for the synthesis of substituted indoles from anilines, by clubbing three steps into a single reaction vessel for the synthesis of variedly substituted indoles. Complex natural product syntheses have also been boosted by employing the one-pot methods, as the key transformations. In this context, Hayashi et al synthesized ‘Tamiflu’, a neuraminidase inhibitor, for the treatment of type A and type B human influenza, by combining a nine-step process into a noteworthy three “one-pot” operations. Even from an industrial perspective, the synthesis of the key intermediates in one-pot protocols are highly demanded and economically advantageous. Merck laboratories reported a four step one-pot preparation of 7-hydroxyquinoline starting from 3-N-tosylaminophenol, in fair yields. Apart from these classical illustrations, there have been tremendous elaborations in single-pot applications, especially in mimicking the biosynthesis. The research group of Johnson developed the biomimetic synthesis of progesterone, while Nicolaou et al employed a one-pot process, for the synthesis of endiandric acid. In view of the recent modifications emerging in this broad domain of synthetic organic chemistry, domino transition metal mediated reactions, non-conventional techniques and alternative approaches have been evolved. Also, in particular, the acid mediated domino reactions have gained popularity as a vital development in organic synthesis era. In continuation of our research interests in the development of domino transformations, either through transition metal catalysis or acid mediated reactions, herein, in this thesis, some versatile one-pot synthetic methodologies for the synthesis of heterocyclic, spiro heterocyclic and carbocyclic compounds, have been described. The thesis is divided into five chapters, describing the acid mediated or catalyzed one-pot strategies, for the synthesis of heterocyclic as well as carbocyclic compounds. The first chapter deals with the efficient domino one-pot dual bond formation, for the synthesis of dihydrocoumarins starting from phenols and cinnamic acid esters. While the second chapter presents the accomplishment of novel spirolactones upon the reaction of phenols with alicyclic esters. The third chapter describes a concise approach towards the chemoselective synthesis of fused tricyclic ketones through domino intramolecular dual CC bond formation. Synthesis of 3-aryl-1H-indenes and regioselective benzyl styrenes has been discussed in chapter four. Finally, chapter five comprises the synthetic protocol, for the synthesis of indenes bearing a quaternary carbon atom.

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