Please use this identifier to cite or link to this item: http://localhost:8081/xmlui/handle/123456789/14864
Title: SYNTHESIS OF PYRAZOLES BY DIAZA-NAZAROV CYCLIZATION AND FUNCTIONALIZED SULFONES
Authors: Aegurla, Balakrishna
Keywords: Nazarov Cyclization;Hetero Cycles;Bonds Formation.;Carbon-Heteroatom Bond Construction
Issue Date: 2018
Publisher: I.I.T Roorkee
Abstract: The thesis entitled “Synthesis of pyrazoles by diaza-Nazarov cyclization and functionalized sulfones” is divided into three chapters, viz. (i) Introduction, (ii) Objectives, Results and Discussion, and (iii) Experimental. We have developed novel and rapid protocols for the synthesis of pyrazoles, vinyl sulfones, -keto sulfones and nuclephilic substitution of -keto sulfones-derived -hydroxy sulfones. The pyrazoles were synthesized from in situ generated benzaldehyde hydrozone with acetphenone derivatives by using environmentally benign and inexpensive molecular iodine. We have also carried out theoretical studies on diaza-Nazarov-type 4-elctrocyclization (DAN) leading to pyrazoles by using B3LYP/6-311G** theory to better understand the experimentally observed regioselectivity of DAN cyclization. Chapter 1: Introduction Nazarov cyclization reaction is emerged as one of the most privileged techniques for the construction of 5-membered carbo- and hetero-cycles since its revelation. This 5- membered carbo- and hetero-cycles are prevalent structural motif in several natural products and pharmaceutically active compounds. Owing to its importance, various elegant approaches have been developed for target 5-membered carbo- and hetero-cyclic compounds; among them, Nazarov-type cyclization reaction is one of the most versatile and efficient methods for C–C and C–N bonds formation. Carbon-carbon and carbon-heteroatom bond construction (C–N, C–S) is an essential quest for the development of novel and efficient chemical building blocks in present research scenario. Due to the significance of carbon-heteroatom bond generation, specifically C–S bond forming reactions have gained huge attention in synthetic community. Gneerally sulfones, thioethers are the most common skeletons in sulfur containing drugs which are useful for the treatment of leprosy, dermatitis herpetiformis, and tuberculosis. Scientists have also determined various therapeutic activities of sulfone containing compounds including antibacterial, antifungal, antimalarial, cysteine protease inhibitor, antivi HIV, anti-proliferative, anti-cancer, protein phosphatase methylesterase-1 inhibitors, thyroid receptor antagonist. Because of the potential applications of organosulfur compounds numerous protocols has been established for C–S bond construction during the last few decades. Chapter 2: Objectives, Results and Discussion This chapter deals with the objectives, results and discussion which are divided into four sections. 2.1. Synthesis of pyrazoles via diaza-Nazarov (DAN) cyclization and theoretical investigation In this section, unprecedented iodine-mediated diaza-Nazarov (DAN) type cyclization for the construction of substituted pyrazoles from easily available starting materials via an enamine–iminium ion intermediate is described. The oxidative cyclization worked under green conditions with remarkable regioselectivity. This one-pot, efficient and operationally simple three-component intramolecular regioselective DAN cycliza-tion displayed a wide range of substrates scope. The dichotomy of reaction pathways has been explored with density functional theory in the gas phase and solution phase. Of the possible 1,5-, 1,6-, and 1,7- electrocyclizations, the DAN cyclization, i.e., the 1,5-pathway offers lowest activation energy barrier supporting our experimental observations. (Scheme 1). Scheme 1: The diaza-Nazarov cyclization for the synthesis of polysubstituted pyrazoles. 2.2. Synthesis of pyrazoles via denitrative-imino-diaza-Nazarov (DIDAN) cyclization A novel, efficient and unprecedented green methodology for the construction of pyrazoles has been established from easily accessible, in situ generated benzaldehyde hydrozone with -nitro carbonyl derivatives through denitrative imino-diaza-Nazarov vii (DIDAN) cyclization in the presence of iodine as powerful catalyst in EtOH. The corresponding aryl pyrazoles are obtained in high to excellent yields. A catalytic amount of inexpensive and non-toxic iodine drives the reaction and no exclusion of air and use expensive ligands is required (Scheme 2). Scheme 2: The denitrative imino-diaza-Nazarov cyclization for the synthesis of disubstituted pyrazoles. 2.3. Synthesis of vinyl sulfones and hydrosulfonylation of chalcones A facile iodine/tert-butyl hydroperoxide (TBHP)-mediated protocol has been developed for the formation of C(sp2)–SO2 and C(sp3)–SO2 bonds through radical pathway and ionic pathway, respectively. The denitrative sulfono functionalization (DNSF) of - nitrostyrenes with arylsulfonyl hydrazides under solvent-free and base-free conditions is described. The DNSF process appears to proceed through an addition–elimination pathway. The sulfonylation of olefins that contain electron-withdrawing groups was also examined under solvent-free conditions which afforded the corre- sponding alkenyl sulfones through the elimination of HI from the -sulfonyl-iodo intermediate. The hydrosulfonylation of chalcones and -nitrostyrenes proceeded in the presence of an organic base in acetonitrile through a sulfa-Michael addition (Scheme 3). viii Scheme 3: Metal-free sulfonylation of -unsaturated systems by using sulfonyl hydrazides. 2.4. Synthesis of sulfonylpropane derivatives by dehydrative substitution of - hydroxysufones The first dehydrative C- and S-alkylation by nucleophilic substitution of - hydroxysufones with arenes and thiophenols is reported. This study represents elegant and ecological concept to construct C−C and C−S bonds for novel and unsymmetrical 1,1- and 3,3-branched propanes. The -hydroxysufones underwent BF3·OEt2 mediated dehydrative arylation and thiolation at room temperature and elimination at 40 oC. The nucleophile attack occurs on the less hindered phase of planar benzylic carbocation to furnish the title compounds in good diastereoselectivity (Scheme 4). Scheme 4: Dehydrative C- and S-alkylation: Access to highly substituted 1- sulfonylpropanes.
URI: http://localhost:8081/xmlui/handle/123456789/14864
Research Supervisor/ Guide: Peddinti, R.K.
metadata.dc.type: Thesis
Appears in Collections:DOCTORAL THESES (chemistry)

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