Thesis advisor: James P. Morken / The first highly enantioselective diboration of unfunctionalized terminal alkenes has been developed using a platinum-phosphonite complex. This transformation produces versatile 1,2-bis(boronate)esters that can manipulated chemoselectively to generate a pletheroa of enantioenriched structural motifs. When combined with an appropriate palladium catalyst, the diboration product undergoes an efficient alkyl boron cross-coupling with aryl and vinyl electrophiles producing a wide range of enantioenriched homobenzylic and homoallylic boronates. Alternatively, when the 1,2-bis(boronate)ester diboration product contains an adjacent Z-olefin (derived from diboration of cis-1,3-dienes), allylation to aldehydes can be achieved delivering the syndiastereomer of product exclusively with excellent chirality transfer. Notably, the products obtained from the two described reactions contain an additional boronate moiety, which can be further functionalized through known carbon-boron bond transformations. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Some interesting, biologically active natural products have been found to contain poly-azole fragments within their core. These fragments are linked through the 2- position of one azole and the 4-position of its neighbour. Decarboxylative cross-coupling methodology may provide a route to these desired linked azoles through cross-coupling of azole-4-carboxylic acids with azole-2- halides or with azoles containing no substitution at the 2-position. Investigations into the silver-mediated decarboxylation, and subsequent coupling potential, of thiazole and oxazole-4-carboxylic acids are reported. Methods towards the synthesis of novel chlorinated thiazole and oxazole acids and their precursors are also described. A method to successfully couple these acids to aryl iodides has been developed and the scope of this reaction extended to a variety of functionalised azole-4-carboxylic acids. Attempts to extend this methodology and combine the decarboxylative coupling with CH activation of a second azole are also described.

Organometallic compounds derived from tin, boron, and zinc, have been used extensively in transition metal-catalysed cross-coupling, and continue to hold status as the go-to reagents to form new carbon-carbon bonds. Recently, organosilicon compounds have emerged as an attractive alternative to these established reagents, benefitting from low toxicity, low cost, and general ease of handling. While the fundamental reactivity of arylsilane reagents (Ar-SiR3) is well known, their role in transition metal-catalysed reactions is generally less well studied. This thesis comprises an investigation into the effect of ortho-substitution of these arylsilane reagents, and specifically, their application in gold-catalysed direct arylation. In Chapter 2, the transmetalation of these reagents to gold(III) is assessed using a combination of in situ reaction monitoring coupled with kinetic simulations. This allowed a scale of reactivity to be constructed for a range of structurally diverse arylsilanes, and uncovered that more sterically hindered arylsilanes actually exhibit accelerated rates of transmetalation. In Chapter 3, the reactivity of ortho-substituted arylsilanes in gold-catalysed arylation is addressed. The majority of arylsilanes tested in the previous chapter were found to be unable to undergo coupling, despite the viability of transmetalation having been demonstrated. Slight modification of the ortho-substituent, to incorporate a tethered ligand, was found to have a dramatic effect on reactivity, and allowed the coupling of a variety of substrates. The nature of the ligand, as well as the substitution of the tether was found to have a significant impact on the rate of coupling. Chapter 4 describes the way in which the reactivity of ortho-substituted arylsilanes might be exploited in a 'Catch and Release' protocol for catalyst recovery. This aims to combine the established benefits of homogeneous and heterogeneous catalysis to offer an alternative to current methods of catalyst recycling in industrial chemistry. A number of different 'Catch and Release' mechanisms were considered, and the validity of the concept was demonstrated in a monophasic system.

Since its discovery in 1979, the Suzuki-Miyaura (SM) reaction has become one of the most widely utilised tools for carbon-carbon bond formation. The palladium catalysed coupling of an organoboron and organohalide compounds proceeds through a three-stage mechanism of oxidative addition, transmetalation and reductive elimination. The transmetalation of boronic acids to a palladium(II) complex has been widely studied. However, very little is known about the transmetalation of boronic esters, which are commonly used as an alternative to unstable boronic acids. Whether these species undergo direct transmetalation or prior hydrolysis to the boronic acid under SM conditions remains unknown. This research aimed to elucidate the mechanism of this cross-coupling process. Initial results under typical SM conditions created a biphasic reaction, promoted by the inorganic base and solvent composition, and showed that the boronic esters and corresponding boronic acid couple at the same absolute rate. This is thought to be a consequence of the formation of a biphasic mixture, rendering phase transfer the turnover-limiting step. The conditions were thus adapted to maintain a monophasic system using an organic soluble base, 2-tert-butyl-1,1,3,3-tetramethylguanidine, enabling the focus to be transmetalation as the turnover-limiting step. These new conditions show a significant difference in both reaction rate and induction period when using a boronic ester compared to the corresponding boronic acid. The use of guanidine was also shown to have an interesting effect on the boronic acid/ester species by 19F and 11B NMR. Further studies found the use of guanidine to create a boronate species, with this species being an aryl trihydroxyboronate or the hydroxyl"ate"-complex of the boronic ester, depending on the presence of diol in the system. Formation of a boronate species was found to be crucial for efficient cross-coupling. When testing weaker bases, unable to form a boronate species, poor SM cross-coupling conversion was found using the newly developed phosphine-free guanidine conditions, showing the importance of the boronate species under these conditions. The results suggest that depending on the strength of base used, the pathway of transmetalation pathway can be switched, between the boronate pathway and the oxo-palladium pathway, under the specific conditions developed.

Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections. Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent. The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.

The Suzuki-Miyaura Cross-Coupling of aryl halides and aryl boronic esters has become one of the most important and oft used C-C bond forming reactions in industry and academia alike. Recently, substantial effort has been invested in expanding this reaction to include alkyl boronic esters as coupling partners, though until recently, success has been limited to primary alkyl boronic esters. Secondary alkyl boronic esters, with the inherent possibility of being chiral, have proven to be more difficult to couple. As a means of expanding our program on the enantio- and regioselective hydroboration of styrene derivatives, we sought to develop conditions that could couple benzylic (secondary) boronic esters. Not only was the coupling to aryl iodides achieved in moderate to good yield with a commercially available (and relatively cheap) catalyst system and phosphine, but the coupling reaction proceeds with almost complete retention of the stereochemistry installed during the hydroboration reaction. Interestingly, these conditions leave primary (linear) alkyl boronic esters completely untouched. Further examination of the chemoselectivity of the reaction revealed that, despite being unable to cross-couple strictly aliphatic secondary boronic esters, our silver-mediated protocol was able to effectively cross-couple chiral allylic boronic esters in high yield and good regioselectivity. The asymmetric syntheses of novel secondary boronic esters have also been developed to overcome the substrate limitations of the hydroboration reaction. Together with our effective cross coupling strategy, these novel chiral boronic esters have led to the synthesis of exciting new classes of molecules, most notably, the asymmetric triarylmethanes. Finally, the stability of mesoporous silica supports used in Pd catalysis was assessed. Though silica supports effectively reduce Pd-contamination in reaction mixtures to sub-ppm levels, their long-term reusability is hindered by material degradation caused by harsh reaction conditions. It was found that aqueous base, required for the Suzuki-Miyaura reaction, is responsible for silica degradation and the collapse of mesostructure. Interestingly, it was determined that the reaction itself had a protective effect on the material, with the boric acid side-product mitigating the deleterious effect of the base. / Thesis (Ph.D, Chemistry) -- Queen's University, 2011-09-19 14:53:49.444

Trichloroethylene, a simple and very inexpensive material, has been identified as a tri- and tetrafunctionalizable building block. A combination of selective palladium-catalyzed cross-coupling reactions with standard lithiation and electrophilic quenching yields a wide variety of unsaturated linear or cyclic compounds in excellent yields in few synthetic steps. Dichlorovinyl ethers, obtained from a nucleophilic displacement reaction with trichloroethylene, are the basic starting materials. Two sets of conditions have been developed to achieve the reaction of either electron-rich or –deficient phenols with trichloroethylene to give the resultant dichlorovinyl ethers in high yields. Site selective palladium-catalyzed cross-coupling for the specific functionalization of a single C-Cl bond was developed, and could install alkyl, alkenyl, alkynyl and (hetero)aryl moieties. The resulting electrophiles could be reacted with a second organometallic nucleophile forming trisubstituted, electron-rich alkenes, dienes, trienes or enynes in only two or three steps. Alternatively, the product from the first cross-coupling reaction could be isolated, deprotonated and quenched with an electrophile, then cross-coupled with a second organometallic nucleophile to give tetrasubstituted, electron-rich alkenes and dienes. In the course of studying the site selective cross-coupling, it was found that prolonged exposure of the C1-functionalized materials to palladium promoted an intramolecular C-H activation, forming 2-substituted benzofurans. This reaction proved to be very general, and a wide variety of benzofurans were synthesized, containing both electron-withdrawing and electron-donating group groups in the donor arenes, as well as alkyl, alkenyl, alkynyl and aryl functionalities at the 2-position. This method was also extended to the synthesis of 2-substituted indoles from anilines, trichloroethylene and boronic acids.

The use of homogeneous organometallic catalysis for otherwise challenging chemical transformations is a concept that has gained significant interest in recent decades, providing access to a variety of useful chemical products. The catalytic reactivity of transition metals and non-reactive ancillary ligands that bind to the metal center has played an important role in such methods, with notable breakthroughs being Nobel Prize-winning reactions (palladium-catalyzed C-C cross-coupling, 2010). The research compiled in the thesis further develops the themes of ligand design and catalytic applications currently studied in the Stradiotto group. Key ideas throughout the thesis are to establish an understanding of the palladium/Mor-DalPhos catalyst system in ammonia arylation with respect to mechanism and substrate scope, and to expand the reactivity profile of the DalPhos ligand set to more challenging C-N and related cross-coupling processes. The first section describes an examination of the [Pd(cinnamyl)Cl] dimer/Mor-DalPhos catalyst system in C-N cross-coupling employing ammonia to better understand the catalyst formation process and to provide a guide for the development of precatalysts for otherwise challenging room-temperature ammonia monoarylations. Oxidative addition complex [(Mor-DalPhos)Pd(Ph)Cl] proved to be the optimal catalyst for arylation of ammonia at room temperature using aryl halides and tosylates. In the second section, ammonia cross-coupling was extended by applying it in the construction of indole frameworks, for the first time, which gave access to NH-indoles directly from ortho-alkynylbromoarenes. The Pd/JosiPhos was the superior catalyst system in comparison to Pd/Mor-DalPhos for this reaction and further stoichiometric studies revealed the reasons for this may be that the bulky arylalkyne ligand induces loss of ammonia from (Mor-DalPhos)Pd catalytic intermediates, and that catalyst inhibition by the alkyne substrate through irreversible metal binding is also a possible factor prior to the oxidative addition step. The reactivity profile of the DalPhos ligand set was successfully expanded in the third section of the thesis to palladium-catalyzed aminocarbonylation of aryl bromides using a pyridine-derived DalPhos variant (Pyr-DalPhos). Several different aryl and some heteroaryl bromides were accommodated in the coupling reaction with ammonia and carbon monoxide as reagents, providing aryl amide products in synthetically useful yields. The methodology described in the final thesis section demonstrated the use of Mor-DalPhos and [Pd(cinnamyl)Cl] dimer mixtures for gaining access to the first examples of ketone alpha-arylation employing aryl methanesulfonates (mesylates) and expanding the scope of amination reactions involving these non-halide aryl electrophiles to primary alkyl amines for the first time. These transformations featured acetone and methylamine as coupling partners, both of which can be difficult substrates to monoarylate but were found to be coupled with ease in this chemistry.

Trichloroethylene, a simple and very inexpensive material, has been identified as a tri- and tetrafunctionalizable building block. A combination of selective palladium-catalyzed cross-coupling reactions with standard lithiation and electrophilic quenching yields a wide variety of unsaturated linear or cyclic compounds in excellent yields in few synthetic steps. Dichlorovinyl ethers, obtained from a nucleophilic displacement reaction with trichloroethylene, are the basic starting materials. Two sets of conditions have been developed to achieve the reaction of either electron-rich or –deficient phenols with trichloroethylene to give the resultant dichlorovinyl ethers in high yields. Site selective palladium-catalyzed cross-coupling for the specific functionalization of a single C-Cl bond was developed, and could install alkyl, alkenyl, alkynyl and (hetero)aryl moieties. The resulting electrophiles could be reacted with a second organometallic nucleophile forming trisubstituted, electron-rich alkenes, dienes, trienes or enynes in only two or three steps. Alternatively, the product from the first cross-coupling reaction could be isolated, deprotonated and quenched with an electrophile, then cross-coupled with a second organometallic nucleophile to give tetrasubstituted, electron-rich alkenes and dienes. In the course of studying the site selective cross-coupling, it was found that prolonged exposure of the C1-functionalized materials to palladium promoted an intramolecular C-H activation, forming 2-substituted benzofurans. This reaction proved to be very general, and a wide variety of benzofurans were synthesized, containing both electron-withdrawing and electron-donating group groups in the donor arenes, as well as alkyl, alkenyl, alkynyl and aryl functionalities at the 2-position. This method was also extended to the synthesis of 2-substituted indoles from anilines, trichloroethylene and boronic acids.

The research conducted for this thesis has led to the development of an intramolecular gold-catalysed direct arylation protocol whereby tethered arenes and aryltrimethylsilanes are coupled (Scheme 1). In Chapter 1, the key synthetic and mechanistic studies that have ultimately led to the conception of this project are introduced. In Chapter 2, the substrate scope of intramolecular direct arylation is assessed. The reaction tolerates a wide range of substrates with tether lengths between one and five units (containing C, N and O) generating 5- to 9- membered rings. Substrates that lead to 5-membered rings (1 → 2) can tolerate a broad electronic range of substituents and proceed under the mildest reaction conditions (≤ 1 mol% catalyst, room temperature) and with excellent yields. A smaller collection of examples is demonstrated for the cyclisation to 6- and 7- membered rings (3 → 4, 5 → 6), but no heating is required and good yields are maintained throughout the series. The synthetically challenging synthesis of 8- and 9- membered rings (7 → 8, 9 → 10) is successful, albeit with slightly more forcing conditions (4 mol%, up to 50 °C). The methodology was subsequently applied in the successful 10-step synthesis of natural product allocolchicine 11. In Chapter 3, the operative reaction mechanism is elucidated. Reaction monitoring techniques allowed for the detailed study of linear free energy relationships (LFERs) and kinetic isotope effects (KIEs), which in turn allowed for deduction of the reaction turnover-limiting step (TLS) and thus the first quantitative experimental data on the effects of aryl electron demand and conformational freedom on the rate of reductive elimination from diarylgold(III) species. The mechanistic investigation led to the observation of complex kinetic profiles for specific substrates. The origin of these unusual effects is the focus of Chapter 4. By combining experiment with kinetic simulation, an off-cycle catalyst inhibition pathway was identified and the understanding of this process allowed for a re-optimisation of reaction conditions. In Chapter 5, the general kinetic parameters that could govern any domino reaction combining inter- and intramolecular direct arylation are deduced through kinetic analysis and simulation of hypothetical systems. The results of the kinetic analysis were proved experimentally through the successful combination of intra- and intermolecular gold-catalysed direct arylation. The products of intramolecular cyclisation 2, generated in-situ, are demonstrated to couple with intermolecular aryltrimethylsilanes 12, resulting in a rapid increase in molecular complexity from simple substrates in one pot.