The nucleophilic addition of organomagnesium/lithium reagents to aldehydes and ketones has long enabled the synthesis of valuable alcohol derivatives; however, these types of transformations are often plagued by poor functional group tolerance and require harsh reaction conditions. The direct coupling of carbonyls and alcohols with aryl halides is an appealing alternative to access secondary alcohol products. However, this necessitates a formal C-H bond activation which is not well established in the literature. Chapter 1 provides a detailed literature background of the transition metal-catalyzed functionalization of carbonyls and alcohols. The work discussed in Chapter 2 of this thesis demonstrates the addition of aryl halides to aryl and aliphatic aldehydes and alcohols providing secondary alcohol products in moderate to high yields. Key to the success of this transformation was the implementation of underexplored and readily synthesized 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligands. Chapter 3 extends the methodology established in chapter 2 and aims to get a preliminary understanding of the application and mechanism of the reaction described above. For this purpose, pharmaceutically relevant isatin substrates are derivatized, providing access to substitution at the 3-position. Coupling isatins with aryl halides yields 3-aryl-3-hydroxy-2-oxindole products which are scaffolds for many natural product derivatives. Through high-throughput experimentation (HTE), we were able to discover that 1,2-addition at the carbonyl position of isatins is highly compatible with our established system and led us to develop a modest scope as well as gain useful mechanistic insights for this coupling.

Faculty of Science School of Chemistry 0100505x jzeevaart@csir.co.za / The application of homogenous transition metal catalysis to the arylation of enolates to develop new synthetic procedures which are more environmentally benign, atomefficient and economically viable than current methods was the motivation behind the current work. The specific choice of molecules with an aromatic group in the a- position of a ketone, carboxylic acid, amide or other electron-withdrawing group arose from the fact that many natural products, pharmaceutical actives and synthetic intermediates contain such a substructure while the syntheses of these substructures are often cumbersome. The application of homogenous catalysis to various types of enolates was explored and in the process several developments were achieved and discoveries made. These included the use of inorganic bases under phase transfer conditions for the Heck reaction of acrylic acid as well as the synthesis and application of phosphine and phosphite ligands in the Heck reaction of acrylic acid esters. The successful use of low palladium loadings (as low as 0.01mol%) in the arylation of diethyl malonate using aryl chlorides and the application to the synthesis of ketoprofen and phenobarbital was demonstrated. The novel application of palladium catalysis to the arylation of methanesulfonamides and the first example of a bromoindole derivative as the aryl halide partner in an enolate arylation reaction was demonstrated. Ligand-free palladium catalysed phenylation of pinacolone followed by Baeyer Villiger oxidation led to a proposed novel synthetic route to tert-butyl esters of 2-arylacetic acids. The palladium and copper catalysed arylation of acetoacetate esters, with in situ decarbonylation, provided a different route to 2-arylacetic acid esters which are useful in the preparation of non-steroidal anti-inflammatory compounds.

A thesis presented in the University of the Witwatersrand for the degree of Doctor of Philosophy / AC 2018

Functionalizing arenes and heteroarenes has been an active area of research since the 19th century, due to the presence of these molecular structures in many industrially important sectors. A tremendous amount of research has been published in achieving these chemical transformations using stoichiometric reagents and transition metal-catalyzed reactions. However, challenges still remain. An alternative and comparable methodology to metal-catalyzed reactions to overcome the drawbacks will advance this particular area of research is desirable. Hypervalent iodine compounds offer a promising approach to metal-free arylation reactions. These mild, air and moisture stable compounds have showed significant success as non-toxic and metal-free reagents for the arylation reactions. In particular, unsymmetrical diaryliodonium salts offer functionalization of complex arene structure in an efficient and sustainable pathway. A base-mediated coupling reaction for the metal-free synthesis of alkyl-aryl ethers by using unsymmetrical diaryliodonium salts and aliphatic alcohols is described. This method shows broad substrate scope with respect to both of the coupling partners to produce industrially useful alkyl-aryl ethers in moderate to excellent yields. The reaction is operationally simple, proceeds at mild temperature, and is atom-economical. Sustainability and synthetic utility of this reaction is demonstrated by the use of unsymmetrical aryl(mesityl)iodonium salts as the arylating agents. A limitation of poor reactivity of electron rich unsymmetrical diaryliodonium salts was overcome by designing 2nd generation conditions and using trimethoxy benzene (TMP) as the auxiliary group. Additionally discovery and development of an efficient method to access highly functionalized arynes from unsymmetrical aryl(mesityl)iodonium tosylate salts is presented. The aryne intermediates are generated by ortho C-H deprotonation of aryl(mesityl)iodonium salt with an amide base and subsequently trapped in a cycloaddition reaction with furan in moderate to good yields. Selective iodonium moiety elimination is discussed and the effect of auxiliary and temperature to reduce the regioisomeric ratio is demonstrated. Finally, additional coupling partner including benzyl azide and aliphatic amines are presented to show further utility of this methodology. Also, mechanistic investigations leading to the moderate reactivity of some electron rich unsymmetrical diaryliodonium salts is discussed.

Diaryliodonium salts offer potential as novel reagents for arylation chemistry. An overall goal and successful outcome of this work has been to further understanding of diaryliodonium salt chemistry by developing practical methods that enable chemists more convenient access to these reagents, for the purpose of reaction development. To this end a robust and convenient preparation method has been developed and resulted in novel commercially available diaryliodonium salts. The remainder of the work described, has focused on understanding the parameters important to diaryliodonium mediated arylation and has resulted in a solid framework that multiple future development efforts can build upon. A strategy adopted throughout this work was to use multivariate methodologies such as Design of Experiments (DoE). Applicable chapters show the results of optimization studies that were carried out using DoE, during the course of this work. Additionally, the desire to further realize the potential that DoE has to offer inspired of a search for parameters to study fundamental reactivity. Chapter 2 details the development of a practical diaryliodonium salt synthesis that is convenient, facile, and economical. A detailed procedure is also included and was drafted to the requirements for publication in the journal Organic Synthesis. Finally, limitations and future directions of the method are discussed. Chapter 3 describes studies aimed at understanding the role of the counter anion; a very practical counter anion screening method is presented. Future directions are discussed and include detailed characterization of diaryliodonium salts by NMR. Chapter 3 also describes a practical, scalable, and rapid salt exchange method developed during this work. Chapter 4 describes the results obtained in studying an azidation reaction via solubility parameters. All Supporting Information, including characterization data and experimental details, are provided in Chapter 5.

The regioselectivity in Pd(0)-catalyzed direct arylation of pyrrole, thiophene, and indole can be improved by blocking some of the reactive sites with a chloride group, leading to increased yields of the desired regioisomers. Competition experiments and computational studies show that the blocking group also activates the substrates toward arylation. Due to the activated nature of chlorinated heteroaromatics, rare and sought after regioisomers, such as 3-arylthiophenes, can be obtained under mild conditions in good yields. Chlorine-bearing thiophenes arylated at C3 and C4 have the potential to undergo controlled regioregular polymerization under conditions developed in the field of polythiophene chemistry. Mechanistic studies support the hypothesis that the arylation of the substrates under investigation likely proceeds via the CMD transition state.

The regioselectivity in Pd(0)-catalyzed direct arylation of pyrrole, thiophene, and indole can be improved by blocking some of the reactive sites with a chloride group, leading to increased yields of the desired regioisomers. Competition experiments and computational studies show that the blocking group also activates the substrates toward arylation. Due to the activated nature of chlorinated heteroaromatics, rare and sought after regioisomers, such as 3-arylthiophenes, can be obtained under mild conditions in good yields. Chlorine-bearing thiophenes arylated at C3 and C4 have the potential to undergo controlled regioregular polymerization under conditions developed in the field of polythiophene chemistry. Mechanistic studies support the hypothesis that the arylation of the substrates under investigation likely proceeds via the CMD transition state.

Design and Synthesis of New Polyaromatic Scaffolds for Nano-Scale ApplicationsResumen: En la última década, el diseño y la síntesis de nuevos sistemas poliaromáticos han resultado de gran interés gracias a sus propiedades únicas y sus aplicaciones potenciales para la obtención de dispositivos electrónicos, y como precursores de fullerenos. Hemos estudiado el mecanismo que procede a través de la activación del enlace C-H en la reacción intramolecular de arilación directa catalizada por paladio, para la formación de sistemas biarílicos, demostrando que la reacción procede a través de la abstracción del protón asistido por la base. Aplicando condiciones optimizadas hemos preparado la molécula C60H24 que al ser irradiada da lugar a la formación del fullereno C60, mediante la reacción de arilación directa formando seis nuevos enlaces C-C en una única etapa. Además, en una colaboración interdisciplinar con físicos teóricos y experimentales, en el proyecto PicoInside, hemos participado en el diseño y la síntesis de moléculas poliaromáticas para su posterior aplicación como dispositivos electrónicos moleculares.Abstract:In the last decade, the design and synthesis of new polyaromatic scaffolds have attracted a broad interest due to their exceptional properties and their potential applications in material science like molecular electronic devices and as precursors of fullerene.Based in the intramolecular palladium-catalyzed direct arylation reaction we developed new procedures as reliable tools for the biaryl coupling through C-H activation. Insight mechanistic studies showed a proton abstraction mechanism assisted by the base rather than activation of aromatic systems towards electrophilic attack. Applying optimized reaction conditions, formation up to six C-C bonds, and in situ dehydrogenation, allows for the synthesis of C60H24, crushed fullerene in one single step that upon laser irradiation leads to C60 fullerene. Moreover, in an interdisciplinary collaboration with theoretical and experimental physicist, PicoInside project, we have participated in the design and synthesis of Y-shaped polyaromatic molecules required for single molecule electronic devices.

The Knoevenagel reaction is defined by the condensation of an aldehyde or ketone with a carbon nucleophile produced by the deprotonation of a methylene species whose acidity is dramatically increased by bonds to strongly electron withdrawing groups. Previously, our group developed an effective one-pot method for the preparation of 4H-chromenes using sodium borohydride reduction of the cyclized intermediates formed by the Knoevenagel condensation of malononitrile with salicylaldehydes in aqueous ethanol. In this study we outline the extension of these strategies to include 2’-hydoxyphenylketones as the starting material. Many of these compounds are also unique and were prepared by Friedel-Crafts acylation of phenols with acyl chlorides and/or Fries Rearrangement of the corresponding phenyl ester. The objective of this project has been to expand the application of the methods optimized in our lab for the simple and efficient formation of carbon-carbon bonds via the selective reduction of the alkylidene portion of the Knoevenagel reaction products. These methods have allowed for the production of several important classes of natural product-like compounds. Specifically, in this investigation, we have adapted these methods to the production of various 4-alkyl and 4-aryl substituted 3-amino-2-cyano-4H-chromenes. These types of molecules exhibit diverse pharmacological activity and have been shown to be potentially useful for the treatment of various diseases. A subset of the synthesized compounds will be submitted to Eli Lilly through their PD2 program. Further variation of substrates included the reaction of salicylaldehydes with ethyl cyanoacetate or cyanoacetamide which provided products unreported in the literature. Reactions with cyanoacetates gave the expected 3-carboethoxy(ester) functionalized 4H-chromene compounds. Products from cyanoacetamide were found to occur in open rather than cyclized forms. / Introduction and background literature -- Synthesis of 2'-hydroxyphenylketones -- Synthesis of 2-amino-3-cyano-4H-chromenes -- One pot method applied to salicylaldehydes with ethylcyanoacetate or cyanoacetamide. / Department of Chemistry

The regioselectivity in Pd(0)-catalyzed direct arylation of pyrrole, thiophene, and indole can be improved by blocking some of the reactive sites with a chloride group, leading to increased yields of the desired regioisomers. Competition experiments and computational studies show that the blocking group also activates the substrates toward arylation. Due to the activated nature of chlorinated heteroaromatics, rare and sought after regioisomers, such as 3-arylthiophenes, can be obtained under mild conditions in good yields. Chlorine-bearing thiophenes arylated at C3 and C4 have the potential to undergo controlled regioregular polymerization under conditions developed in the field of polythiophene chemistry. Mechanistic studies support the hypothesis that the arylation of the substrates under investigation likely proceeds via the CMD transition state.