Thesis advisor: James Morken / Boronates are extremely useful in synthesis due to the ability of carbon-boron bonds to be transformed into carbon-oxygen, carbon-nitrogen, or carbon-carbon bonds stereospecifically. This makes the stereoselective construction of carbon-boron bonds especially useful. The development of transition-metal catalyzed diboration of alkenes gave synthetic organic chemists a way to quickly make not one, but two carbon-boron bonds in a stereoselective fashion. However, there are many drawbacks to transition-metal catalysis, such as high cost of catalysts and chiral ligands, and air and moisture sensitivity of catalysts. These issues, in addition to difficulties in removing trace amounts of metal contaminants from reaction products have prevented transition-metal-catalysis from being used on the industrial scale. Discussed in this thesis are two different methods for stereoselective, transition-metal-free diboration of alkenes developed by the Morken group. Also discussed is the pioneering work in the area of transition-metal-free diboration done by the Fernández group, which inspired these methodologies. / Thesis (BS) — Boston College, 2016. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Chemistry.

Indiana University-Purdue University Indianapolis (IUPUI) / Aromatic rings are universal motifs in natural products, pharmaceuticals, agrochemicals, and wide variety of organic materials. Aromatic halides are widely used as synthetic precursors in all these applications. Therefore, tremendous effort has been devoted to activate aryl halides in the past decades. The common methods to activate aryl halides require the use of transition- metals either in the form of Grignard reagents or through the use of transition-metal catalysis. Over the past decade, photoredox catalysis has attracted significant attention as a cogent tool to develop greener synthetic processes and enable new molecular activation pathways under mild conditions. The most common of these approaches uses a photoredox/nickel dual catalytic cycle. While this technology has greatly expanded the toolbox of organic chemists, this method still requires expensive rare-metal-based catalyts. Herein, we present a series of visible light-induced methods that are transition-metal-free. These new base-promoted transformations and their mechanistic work will be discussed in the following order: We will first present our discovery that the dimsyl anion enables visible-light-promoted charge transfer in cross-coupling reactions of aryl halides. This work was applied to the synthesis of unsymmetrical diaryl chalcogenides. This method has a broad scope and functional group tolerance. An electron-donor-acceptor (EDA) complex between a dimsyl anion and the aryl halide is formed during the reaction and explains the observed aryl radical reactivity observed. Then, a visible-light-induced borylation and phosphorylation of aryl halides under mild conditions was developed. Inspired by the mechanistic breakthroughs observed in the previous work. The mechanism of this reaction also involves an aryl radical that is presumed to be formed also via an EDA complex. In other work, a photo-induced phosphonation of ArI using N,N- diisopropylethylamine (DIPEA) and trialkyl phosphites was developed. This method uses very mild conditions, which allowed the preparation a wide variety of functionalized aromatic phosphonates derivatives, including natural products and medicinal compounds. Finally, a photochemical amination of amides was developed via a C(sp 3 )–H bond functionalization process under visible light irradiation. This reaction showed good functional group compatibility without the use of external radical initiators, strong oxidants, or heat source. An EDA complex between N-bromophthalimide and LiOtBu is formed during the reaction.

Organoboron compounds are highly valued synthetic intermediates due to their diverse array of reactivity, which is often utilized in the synthesis of valuable organic molecules. For this reason, there is significant interest in the development of novel borylation protocols, especially those whose products are suitable for further synthetic transformations towards valuable classes of compounds. Research in organoboron synthesis has been geared heavily toward transition metal-catalyzed addition to double and triple bonds, though an increasing number of publications detail transition metal-free borylation techniques involving substrate-mediated activation of a diboron reagent. This dissertation describes the author's contributions to the development of both a transition metal-catalyzed diboration and a transition metal-free protoboration. A transition metal-free diboration of alkynamides is described in Chapter 1 which uses the unsymmetrical, differentially protected diboron reagent, pinBBdan. The method installs both boron moieties in a regio- and stereoselective fashion. The products have synthetic value because they are shown to have chemoselectivity in downstream cross-coupling reactions; chemoselectivity is made possible by to the significant difference in Lewis acidity of the pinacol and diaminonapthalene-protected boron centers. This method allows for facile synthesis of tetrasubstituted alkenes with a set geometry about the double bond. A protoboration of allenes employing a Cu(II) catalyst under aqueous and atmospheric conditions is described. Though Cu(I)-catalyzed allene protoboration is well-described in the literature, this is the first report of an analogous Cu(II)-mediated process. The selectivity of the reaction is ligand-controlled, and moderate to good regioselectivities and yields can be achieved through use of a triphenylphosphine as ligand. The method is an environmentally friendly and facile means by which to borylate a challenging cumulated substrate. / Ph. D. / Organoboron compounds are valuable because of their ability to undergo a wide variety of chemical transformations, and they are often used as intermediates in the synthesis of challenging target molecules. In order for this reactivity to be exploited, methods must exist for the efficient synthesis of the desired boron-containing compound. This dissertation describes the author’s contributions to the development of two new methods by which to synthesize organoboron products. The first method involves installation of two differently ligated boron moieties onto an alkynamide substrate to produce a single, uncommon trans isomer as product. A synthetic application of these diboration products is described. The second method involves installation of a single boron moiety into allenes. Though the same overall transformation has been achieved in the literature with use of highly air-sensitive catalysts and organic solvents, the described method entails use of air-stable CuSO4 as catalyst and water as solvent. Therefore, the method is operationally simple and environmentally friendly relative to previously described methods.

Aromatic rings are universal motifs in natural products, pharmaceuticals, agrochemicals, and wide variety of organic materials. Aromatic halides are widely used as synthetic precursors in all these applications. Therefore, tremendous effort has been devoted to activate aryl halides in the past decades. The common methods to activate aryl halides require the use of transition-metals either in the form of Grignard reagents or through the use of transition-metal catalysis. <br>Over the past decade, photoredox catalysis has attracted significant attention as a cogent tool to develop greener synthetic processes and enable new molecular activation pathways under mild conditions. The most common of these approaches uses a photoredox/nickel dual catalytic cycle.<br>While this technology has greatly expanded the toolbox of organic chemists, this method still requires expensive rare-metal-based catalyts. Herein, we present a series of visible light-induced methods that are transition-metal-free. These new base-promoted transformations and their mechanistic work will be discussed in the following order:<br>We will first present our discovery that the dimsyl anion enables visible-light-promoted charge transfer in cross-coupling reactions of aryl halides. This work was applied to the synthesis of unsymmetrical diaryl chalcogenides. This method has a broad scope and functional group tolerance. An electron-donor-acceptor (EDA) complex between a dimsyl anion and the aryl halide is formed during the reaction and explains the observed aryl radical reactivity observed.<br>Then, a visible-light-induced borylation and phosphorylation of aryl halides under mild conditions was developed. Inspired by the mechanistic breakthroughs observed in the previous work. The mechanism of this reaction also involves an aryl radical that is presumed to be formed also via an EDA complex. In other work, a photo-induced phosphonation of ArI using N,N-diisopropylethylamine (DIPEA) and trialkyl phosphites was developed. This method uses very mild conditions, which allowed the preparation a wide variety of functionalized aromatic phosphonates derivatives, including natural products and medicinal compounds. Finally, a photochemical amination of amides was developed via a C(sp 3 )–H bond functionalization<br>process under visible light irradiation. This reaction showed good functional group compatibility without the use of external radical initiators, strong oxidants, or heat source. An EDA complex between N-bromophthalimide and LiOtBu is formed during the reaction.

No description available.

The thesis entitled “Design and Development of Metal-Free Cross Dehydrogenative Coupling Reactions for the construction of C-S, C-O and C-C bonds” is divided into three Chapters. Chapter 1 is presented in five parts, which reveals the cross dehydrogenative coupling (CDC) strategies for the C–S bond forming reactions through C–H functionalization strategy using heterocyclic thiols and thiones. Chapter 2 presents tetrabutyl ammonium iodide (TBAI) catalyzed chemoselective α-aminoxylation of ketones with N-hydroxyimidates using TBHP as oxidant under cross dehydrogenative coupling (CDC) strategy. Chapter 3 describes a transition metal-free Minisci reaction for the acylation of isoquinolines, quinolines, and quinoxaline. Chapter 1 Iodine Promoted C-S Bond Forming Reactions using Dimethyl Sulfoxide as an Oxidant Chapter 1 reveals the utility of cross dehydrogenative coupling (CDC) reactions for the formation of C–S bonds by employing C–H functionalization strategies.1 The direct functionalization of C–H bonds to form C–C and C–X (N, O, S and P) bonds using metal-free reaction conditions is an interesting research topic in recent years.2 Use of dimethyl sulfoxide as an oxidant is emerging as one of the research topics of great interest and utility.3 Heterocyclic thiols and thiones are important precursors for synthesizing a variety of pharmaceuticals and biologically active compounds.4 Therefore it is useful to develop CDC reactions using heterocyclic thiols and thiones as precursors. In this chapter, we describe CDC reactions of heterocyclic thiols and thiones for the sulfenylation of ketones, aldehydes, α, β unsaturated methyl ketone derivatives, pyrazolones, enaminones and imidazoheterocycles using DMSO as an oxidant Chapter 1: Part 1 Iodine Promoted Regioselective α-Sulfenylation of Carbonyl Compounds using Dimethyl Sulfoxide as an Oxidant: In this chapter, a rare regioselective C–H sulfenylation of carbonyl compounds with heterocyclic thiones and thiols have been described using iodine and dimethyl sulfoxide as reagents. Thus, dimethyl sulfoxide (as an oxidant) and stoichiometric amount of iodine have been used for the sulfenylation of ketones using heterocyclic thiones. Whereas the sulfenylation of ketones with heterocyclic thiols required catalytic amount of iodine. This protocol offers a rare regioselective sulfenylation of (i) methyl ketones in the presence of more reactive α-CH2 or α-CH groups, and (ii) aldehydes under CDC method. A few representative examples are highlighted in Scheme 1.5 The application of this methodology has been demonstrated by synthesizing a few precursors for Julia-Kocienski olefination intermediates. Scheme 1. Iodine promoted rare regioselective α-sulfenylation of ketones and aldehydes Siddaraj , Y.; Prabhu, K. R. Org. Lett. 2016, 18, 6090 Chapter 1: Part 2 Regioselective Sulfenylation of α’-CH3 or α’-CH2 Groups of α, β Unsaturated Ketones using Dimethyl Sulfoxide as an Oxidant: In this chapter, an interesting regioselective sulfenylation of α’-CH3 or α’-CH2 groups of α, β unsaturated ketones using dimethyl sulfoxide as an oxidant and catalytic amount of aq. HI (20 mol %) as an additive has been described. This eco-friendly method uses readily available, inexpensive I2 or HI and DMSO. This methodology exhibits a high regioselectivity without forming Michael addition product in the presence of strong acid such as aq. HI or iodine, which is difficult to achieve under cross dehydrogenative coupling (CDC) conditions. Current methodology exhibits a broad substrate scope. A few examples are shown in Scheme 2.6 Scheme 2. HI and DMSO promoted α’-sulfenylation of α, β unsaturated ketones Siddaraju, Y.; Prabhu, K. R. (Manuscript submitted) Chapter 1: Part 3 Iodine Catalyzed Sulfenylation of Pyrazolones using Dimethyl Sulfoxide as an Oxidant: In this chapter, a sustainable and efficient strategy for the sulfenylation of pyrazolones has been described using metal-free conditions by employing DMSO as an oxidant and iodine as a catalyst. A variety of heterocyclic thiols, heterocyclic thiones and disulfides undergo C–H functionalization reaction with pyrazolone derivatives furnishing the corresponding sulfenylated products in short time. Most of the products are isolated in pure form without column purification. A few examples are presented in Scheme 3.7 Scheme 3. Iodine promoted sulfenylation of pyrazolones Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem. 2017, 15, 5191 Chapter 1: Part 4 Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: Sulfenylation of Enaminones using Dimethyl Sulfoxide as an Oxidant: In this chapter, synthesis of poly functionalized aminothioalkenes has been described using substoichiometric amount of iodine and DMSO as an oxidant. This metal-free methodology enables a facile sulfenylation of enaminones with heterocyclic thiols and thiones. This methodology is one of the simple approaches for the sulfenylation of enaminones under cross dehydrogenative coupling method. A few examples are highlighted in Scheme 4.8 Scheme 4. Cross-dehydrogenative coupling approach for sulfenylation of enaminones Siddaraju, Y.; Prabhu, K. R. J. Org. Chem. 2017, 82, 3084 Chapter 1: Part 5 Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: A Regioselective Sulfenylation of Imidazoheterocycles using DMSO as an Oxidant: In this chapter, a simple synthetic approach for the regioselective sulfenylation of imidazoheterocycles using iodine as a catalyst and DMSO as an oxidant under cross dehydrogenative coupling (CDC) reaction conditions has been demonstrated. This protocol provides an efficient, mild and inexpensive method for coupling heterocyclic thiols and heterocyclic thiones with imidazoheterocycles. This is the first report on sulfenylation of imidazoheterocycles with heterocyclic thiols and heterocyclic thiones under metal-free conditions. A few examples are shown in Scheme 5.9 Scheme 5. Cross-dehydrogenative coupling approach for sulfenylation of imidazoheterocycles Siddaraju, Y.; Prabhu, K. R. J. Org. Chem. 2016, 81, 7838 Chapter 2 Chemoselective α-Aminoxylation of Aryl Ketones: Cross Dehydrogenative Coupling Reactions Catalyzed by Tetrabutyl Ammonium Iodide: In this chapter, chemoselective α-aminoxylation of ketones with N-hydroxyimidates catalyzed by tetrabutyl ammonium iodide (TBAI) has been presented. The coupling reaction of a variety of ketones with N-hydroxysuccinimide (NHSI), N-hydroxyphthalimide (NHPI), N-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) using TBHP as oxidant has been investigated. This α-aminoxylation of ketones is chemoselective as aryl methyl ketones, aliphatic ketones as well as benzylic position are inactive under the reaction condition. A few examples are highlighted in Scheme 6.10 The application of this method has been demonstrated by transforming a few coupled products into synthetically useful vinyl phosphates. Scheme 6. Chemoselective α-aminoxylation of ketones with N-hydroxyimidates Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem. 2015, 13, 11651 Chapter 3 A Transition Metal-Free Minisci Reaction: Acylation of Isoquinolines, Quinolines, and Quinoxaline: In this chapter, transition metal-free acylation of isoquinoline, quinoline and quinoxaline derivatives with aldehydes has been described by employing TBAB (tetrabutyl ammonium bromide, 30 mol %) and K2S2O8 as an oxidant under cross dehydrogenative coupling (CDC) reaction. This intermolecular acylation of electron-deficient heteroarenes provides an easy access and a novel acylation method of heterocyclic compounds. The application of this CDC strategy has been illustrated by synthesizing isoquinoline-derived natural products. A few representative examples are shown in Scheme 7.11 Scheme 7. CDC reactions of heteroarenes with aldehydes Siddaraju, Y.; Lamani, M.; Prabhu, K. R. J. Org. Chem. 2014, 79, 3856

Le motif biaryl contenant la pyridine représente une structure omniprésente dans la chimie organique et médicinale. Ainsi, le développement de méthodes fiables de synthèse est continuellement désiré. Traditionnellement, les cycles azotés biarylés sont efficacement synthétisés par des réactions de couplage croisé catalytique. Cependant, la pyridine peut être difficilement fonctionnalisée en position C-2 compte tenu de sa déficience en électrons. Cette propriété limite son utilisation en tant que partenaire nucléophile dans les réactions de couplage croisé. Par exemple, dans le couplage de Suzuki-Miyaura, l’acide 2-pyridyle boronique est connu pour son instabilité. À l’inverse, les organométalliques du 2-pyridyle sont peu réactifs pour faire des réactions de substitution aromatique électrophile. La synthèse des pyridines 2-substituées est par conséquent un défi qui reste difficile à relever. La première partie de ce mémoire est consacrée au développement récent des méthodes pour résoudre les problèmes de couplage avec des nucléophiles 2-pyridyles. En particulier, les approches classiques comme le couplage modifié de Suzuki-Miyaura, l’activation de liaison C-H des composés pyridinium N-activés, et l’arylation directe du cycle pyridine sont présentées. De plus, les approches alternatives qui utilisent la partie pyridine comme partenaire électrophile dans la réaction couplage avec les réactifs organométalliques sont également discutées. Dans la deuxième partie de ce mémoire, une méthode de couplage croisée entre des esters de sulfonate de 2-pyridyles et des organolithiens est rapportée. Une variété de pyridines 2-substituées a été synthétisées avec succès en faisant réagir des sulfonates de pyridine avec des organolithiens (aryl, alkane, heteroaryle lithium) à basse température. La méthode permet également de s’affranchir de l’utilisation d’un quelconque métal de transition. Des études mécanistiques montrent que le processus impliquant les composés lithiés s’apparente à une réaction de substitution nucléophile aromatique. Cependant, le mécanisme diffère lorsque la réaction met en jeu des réactifs de Grignard, où un processus de couplage entre deux ligands d’un intermédiaire σ-sulfurane peut être impliqué. / Biaryl compounds containing the pyridine moiety represent a ubiquitous structure in both organic and medicinal chemistry. Therefore, finding new and reliable approaches for their synthesis is still of interest. Traditionally, azine containing biaryls are efficiently synthesized via transition-metal catalyzed cross-coupling reactions. However, due to its π-deficient nature, pyridine cannot be easily functionalized at the C-2 position to serve as nucleophile partner. For examples, in the Suzuki-Miyaura cross-coupling reaction, 2-pyridyl boronates are well known for their instability. 2-Pyridyl organometallics undergo electrophilic aromatic substitution poorly. Thus, the synthesis of 2-substituted pyridines remains a challenging task. The first part of the thesis focuses on the recent methods to address the coupling issues of 2-pyridyl nucleophiles in cross-coupling reactions. Of note, the classical methods including Suzuki-Miyaura cross-coupling reactions, C-H activation of N-activated pyridinium species, and direct coupling reaction of pyridine are presented. Alternative approaches using the pyridine moiety as an electrophilic entity in the coupling with organometallic reagents are also discussed. In the second part of the thesis, a transition metal-free desulfinative cross-coupling reaction of 2-pyridyl sulfonates with organolithium reagents is reported. A variety of 2-substituted pyridines were successfully synthesized in good yields, by treatment of neopentyl 2-pyridyl sulfonates and phenyl 2-pyridyl sulfonate with aryl, alkyl, and heteroaryl-lithium reagents at low temperature. Mechanistic studies showed that the coupling reaction with lithium reagents undergoes an SNAr pathway. However, a ligand coupling process of a σ-sulfurane intermediate may be involved in the reaction with Grignard reagents to form the biaryl.