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Chemistry of Multiynes for the Synthesis of Functionalized Arenes

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Title: Chemistry of Multiynes for the Synthesis of Functionalized Arenes
Author(s): Karmakar, Rajdip
Advisor(s): Lee, Daesung
Contributor(s): Gevorgyan, Vladimir; Mohr, Justin T.; Mankad, Neal P.; Cho, Hee Yeon; Lee, Daesung
Department / Program: Chemistry
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): Multiynes, Functionalized Arenes
Abstract: This thesis consists of two main parts, Part I and Part II. The eight chapters in Part I cover various reactivity and applications of arynes generated via the hexadehydro Diels-Alder (HDDA) reactions of bis-1,3-diyne substrates, whereas the two chapters in Part II are devoted to describe an unprecedented benzannulation reaction of 1,3,8-triynes. Below are brief outline of each chapter. Chapter 1 provides an overview of the history and mechanism of thermal HDDA reactions to generate short-lived aryne species followed by various trapping reactions. In addition, described herein is modulating the reactivity of aryne intermediates by silver-catalysts to achieve unique reactivity. In chapter 2, intramolecular type-I ene reactions of arynes are discussed. The study of thermal vs metal-catalyzed reactions shows that the metal catalysts do not have much impact on the efficiency of the ene reaction. Rather, structural elements in the substrates such as the presence of heteroatom in the tether mainly determine the productivity. By judiciously placing a beneficial structural element, various medium-sized rings were generated. With the knowledge of type-I ene reaction in Chapter 2, macrocycles formation was explored in Chapter 3. After initial investigation of type-I ene reactions for macrocyclization, type-II ene reaction was studied with a broad range of substrates, which revealed that the efficiency of the reaction depends on the ring-size as well as the structural features of the tether. While the yield of the macrocyclic products drops with the ring-size, as large as 48-member ring was generated in reasonable yield. Chapter 4 describes an unprecedented dearomatization of arylsulfonamides mediated by aryne intermediates that are generated from a ynamide tethered unsymmetrical bis-1,3-diyne. The structural requirement for this dearomatization is the presence of an alkene moiety suitably tethered to the aryne framework. DFT-based mechanistic study indicates that the aryne behaves as a 1,2-dicarbene, which interacts with the tethered alkene to form cyclopropyl carbene followed by the remaining carbene with the arene moiety of the arylsulfonamide thereby providing dearomatization products. In Chapter 5, the regioselectivity for nucleophile trapping of differently substituted arynes is discussed. High regioselectivity of nucleophile addition was observed with arynes generated from symmetrical tetraynes containing two terminal silyl substituents and ynamide-tethered unsymmetrical tetraynes bearing the corresponding alkyl substituents, providing nucleophile addition mainly at the ortho position to the silyl or the alkyl group. On the other hand, nucleophile addition to the aryne species generated from symmetrical bis-1,3-diyne turned out less selective. It was also found that that the regioselectivity of nucleophile addition depends on not only the steric and electronic nature of the aryne but also the nature of nucleophiles. In Chapter 6, the nucleophile trapping study in Chapter 5 was extended to the synthesis of phenol and α-halophenol derivatives using silver trifluoroacetate, as a hydroxy surrogate. The addition of silver trifluoroacetate onto an aryne generates a putative organosilver intermediate that can be quenched with a proton or trapped by halogen electrophiles such as N-halosuccinimides. Depending on the nearby substituent, the trifluoroacetate moiety may remain intact or hydrolyzed by silica gel during column chromatography to furnish substituted phenol derivatives. Chapter 7 presents a ruthenium alkylidene-catalyzed hydrohalogenation of arynes whereby a variety of chloro-, bromo-, and iodoarenes are synthesized by trapping an aryne species with solvents such as CHCl3 and CH2Cl2 or other halogenated hydrocarbons like CH2Br2, and CH2I2, Mechanistic study proves that both the hydrogen and the halogen are transferred from these halogenated hydrocarbons to the aryne intermediate. A synthetic utility of the halogenated products is demonstrated by a formal synthesis of herbondole B. Also, in Chapter 8, the utility of arynes generated via HDDA reactions was demonstrated for the synthesis of phosphodiesterase inhibitor selaginpulvilin C and D. In Chapter 9, an unprecedented benzannulation of 1,3,8-triynes with spontaneous nucleophile incorporation is presented. The structural requirement for this reactivity is the presence of propargylic hydrogens capable of an initial intramolecular ene reaction to generate allene-enyne intermediate. The position of nucleophile incorporation depends on the electronic nature of the substituent on the terminal carbon of the diyne moiety. With silyl- and aryl-substituents oxygen-based nucleophiles add onto the newly formed aromatic ring or at the benzylic position respectively. Computational and experimental study reveals the stepwise mechanism of the reactions. This benzannulation is extended to the synthesis of trifluoromethylthiolated arenes by using silver trifluoromethylthiolate as the nucleophile, which is discussed in Chapeter 10.
Issue Date: 2017-05-04
Type: Thesis
Date Available in INDIGO: 2017-10-31
Date Deposited: August 201

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