Carbon-carbon (C-C) bond formation is among the most important processes in organic chemistry. Transition metal catalyzed C-C bond formation is an active research area that shows great potential due to high selectivity and relatively mild conditions. In Chapter 1, a new reaction for direct acylation of aryl halides is discussed. Specifically, the catalytic reaction between aryl halides/pseudohalides and aldehydes is explored. The choice of ligand, base, solvent, temperature, catalyst and substrates are important factors for optimizing this catalytic reaction. The various combinations of all these factors have, therefore, been examined by high-throughput screening (HTS) in order to develop the new C-C coupling reaction. In Chapter 2, a new methodology is reported in order to expand the scope of the Kumada-Corriu cross-coupling reaction. The strategy to achieve this goal is mechanistically based, matching oxidative addition rates with the rate of syringe pump addition of the Grignard to minimize the exposure of sensitive groups to the aggressive nucleophile. Aryl chlorides containing esters, amides, nitriles, pyrazines, carbamates, ketones, and other sensitive functionalities are all demonstrated to undergo chemoselective cross-coupling with this technique. The mechanistic reason for the effectiveness of this strategy is uncovered by continuous-infusion ESI-MS studies.

Our group has developed a strategy for the synthesis of benzofused carbocycles and heterocycles through tandem palladium-catalyzed reactions of gem-dibromoolefins. In these syntheses, one bromide undergoes a Pd-catalyzed cyclization reaction, and the other participates in an orthogonal inter- or intramolecular Pd-catalyzed reaction to functionalize or annulate that ring, respectively. Chapter 1 describes the pairing of an intramolecular C–N bond forming reaction (the Buchwald-Hartwig coupling) with an intramolecular direct arylation for the synthesis of fused indole derivatives. A range of previously unknown heterocycles were synthesized through this method. Chapter 2 describes the synthesis of benzothiophenes through the combination of a Pd-catalyzed C–S coupling with an orthogonal Suzuki, Heck, or Sonogashira reaction. This represents the first example of the incorporation of Pd-catalyzed C–S coupling into a tandem reaction. In Chapter 3, a tandem intramolecular Heck / intermolecular Suzuki reaction is described for the synthesis of methyleneindenes. Studies on this reaction have provided advanced understanding of the mechanism, including how variation of the ligand controls the regioselectivity of the reaction.

Our group has developed a strategy for the synthesis of benzofused carbocycles and heterocycles through tandem palladium-catalyzed reactions of gem-dibromoolefins. In these syntheses, one bromide undergoes a Pd-catalyzed cyclization reaction, and the other participates in an orthogonal inter- or intramolecular Pd-catalyzed reaction to functionalize or annulate that ring, respectively. Chapter 1 describes the pairing of an intramolecular C–N bond forming reaction (the Buchwald-Hartwig coupling) with an intramolecular direct arylation for the synthesis of fused indole derivatives. A range of previously unknown heterocycles were synthesized through this method. Chapter 2 describes the synthesis of benzothiophenes through the combination of a Pd-catalyzed C–S coupling with an orthogonal Suzuki, Heck, or Sonogashira reaction. This represents the first example of the incorporation of Pd-catalyzed C–S coupling into a tandem reaction. In Chapter 3, a tandem intramolecular Heck / intermolecular Suzuki reaction is described for the synthesis of methyleneindenes. Studies on this reaction have provided advanced understanding of the mechanism, including how variation of the ligand controls the regioselectivity of the reaction.

Carbon-carbon bond formation is one of the most important reactions in organic chemistry, and the Suzuki-Miyaura cross-coupling reaction has become a forerunner in this area. Considerable research has been directed at the mechanistic aspects and synthetic utility of the reaction; however, little attention has been given to the formation of the putative PdL2 catalysts. Due to their high reactivities, these catalysts are typically difficult to store and therefore are often generated in situ in unknown yields and at unknown rates via any number of available palladium precursors. This thesis describes research directed towards determining the optimum conditions to quantitatively generate compounds of the type Pd(0)Ln (L = PMePh2, PPh3, PCy3, PMeBut2, PBut3, dppe, dppp, dppf) from Pd(h5-C5H5)(h3-1-Ph-C3H4). Pd(h5-C5H5)(h3-1-Ph-C3H4) has been found to be a superior precursor for synthesizing catalytically active PdL2 compounds due to its ease in handling and reactivity with tertiary phosphines. Furthermore, investigations into the role of water in the transmetallation step of the Suzuki-Miyaura reaction are presented. The research indicates that water is necessary to effect the transmetallation step when coupling [NBu4][PhBF3] with 4-bromotoluene in toluene; however, the amount of water above one equivalent has no significant effect on the rate or yield of the reaction. / Thesis (Master, Chemistry) -- Queen's University, 2009-07-23 12:57:10.248

Until recently, secondary organoboronic esters were not viable substrates in the Suzuki-Miyaura cross-coupling reaction; however under recently reported conditions from the Crudden group1, which includes the addition of silver oxide to a palladium/phosphine catalyst system, this coupling can now be achieved. This thesis centres on optimizing the reaction conditions and expanding the substrate scope of this difficult but important secondary coupling. Optimal coupling conditions, for the example reaction of 4-iodoacetophenone and (R)-pinacol(1-phenylethyl)boronate, were found to be 8 mol% Pd(PPh3)4, 32 mol% PPh3, 1.5 eq. Ag2O and 1.5 eq. K2CO3 in DME at 85 °C for 24 h. This gave the desired coupling product in 64 % yield with 99.5 % retention of stereochemistry. Using this set of conditions, an array of aryl iodides were screened. The reaction conditions could not be extended to triflate or diazonium electrophiles. Amide functionality is important in many natural products and pharmaceuticals. The extension of reaction conditions to amides possessing boronic ester functionality at the β-position was attempted; however, no conditions could be determined to generate the cross-coupling product. An α-substitution pattern would better exemplify the benzylic positioning found to work for the original substrates. Attempts to synthesize the α-substituted amide were made without success. The optimal reaction conditions gave hope for differentiation between an aryl and a secondary aliphatic boronic ester. Using an aryl triflate to couple the aryl position and an aryl iodide to couple the aliphatic position, conditions for selective coupling were determined and applied to a one-pot procedure. / Thesis (Master, Chemistry) -- Queen's University, 2010-09-22 23:33:10.984

First popularized in the 1970s, transition metal-catalyzed cross-couplings now constitute staple reactions for the formation of carbon-carbon and carbon-heteroatom bonds. Recent endeavours in the field have been invested towards expanding the range of compatible coupling partners, with the aim of accessing complex molecules from simple, widely available starting materials. Notably, esters represent an attractive class of alternative coupling partners compared to traditional aryl halides, due to their ubiquity and robustness. Moreover, different cleavage modes can be accessed with esters. Which bond cleavage occurs is highly dependent on which catalyst is used, providing an opportunity to quickly access diverse products from a common precursor. Chapter 1 of this thesis provides a literature overview of cross-couplings with carboxylic acid derivatives to contextualize our contributions described in Chapter 2 and 3. Chapter 2 describes the Pd-catalyzed cross-coupling of phenyl esters with alkyl boranes. Two reaction modes are enabled, namely C(acyl)–O bond activation with carbonyl-retention and C(acyl)–O bond activation with decarbonylation. As such, both alkyl ketones and alkylated arenes are accessed selectively by simple changes in the catalytic system. The disclosed reaction is applied to the diversification of bioactive molecules and discussed in light of recent mechanistic studies of related transformations. In Chapter 3, the first additive-free Ni-catalyzed amidation and transesterification of methyl esters are disclosed. In both transformations, a simple Ni catalyst enables widely available methyl or ethyl esters to be converted into value-added products, producing methanol as the only stoichiometric waste by-product. The Ni-catalyzed amidation protocol strongly contrasts wasteful yet common methods used to convert methyl esters into amides, involving wasteful hydrolysis and coupling with stoichiometric activating agents.

Thesis advisor: James P. Morken / The development of boron and palladium ligands for conjunctive cross-coupling provides access to new reactivity. Some of these advances are outlined in this dissertation. Chapter one describes an enantioselective and diastereoselective palladium catalyzed conjunctive cross-coupling of β-substituted alkenyl boron “ate” complexes to afford contiguous benzylic stereocenters. “Mac” diol was discovered as a useful boron ligand in conjunctive cross-coupling by reducing unwanted Suzuki-Miyaura cross-coupling. Chapter two describes the utilization of “mac” diol in the enantioselective conjunctive cross-coupling of α-substituted alkenyl boron “ate” complexes with carbamoyl chlorides. This transformation affords tertiary, β-boryl amides, which provide a complementary approach to Mannich, aldol, and conjugate borylation products. Water was an essential additive to enable high yield and high enantioselectivity, and its reaction role was investigated. The synthetic utility of this cross-coupling was demonstrated with the asymmetric synthesis of (+)-adalinine. Chapter three describes the thought process behind discovering a new palladium ligand for conjunctive cross-coupling. Phosphinooxazolines (PHOX) are useful and inexpensive ligands for enantioselective palladium-catalyzed conjunctive cross-coupling. A stereochemical model of this cross-coupling with this ligand was examined. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Une nouvelle voie d’accès à des structures tri-cycliques originaux les « oxazino-indole di-iodés» a été mise au point à partir des acides 1H-indole-2-carboxyliques commerciaux ou des acides 1H-indole-2-carboxyliques fonctionnalisés obtenus par la réaction d’Hemetsberger-Knittel. La dernière étape de cette séquence est une réaction d’iodocyclisation qui s’est avérée totalement régio- et stéréosélective selon un processus de type 6-exo-dig. Cette méthodologie a ensuite été étendue en série isoindolique permettant un accès à des motifs « oxazino-isoindolique di-iodés » originaux. Afin d'étendre davantage cette méthodologie, de nouveaux « oxazepino-indole di-iodés » ont été préparés en utilisant la même approche synthétique à partir de l'acide 1H-indole-7-carboxylique. La réactivité des structures tri-cycliques di-iodés a été étudiée via des réactions de Cross-Coupling (Stille, Sonogashira, Suzuki) par l’utilisation de sels de palladium permettant une fonctionnalisation régiosélective de l’iode exocyclique. / A new access pathway to the original tricyclic structures "di-iodinated oxazino-indole" was developed from the commercial 1H-indole-2-carboxylic acids or functionalized 1H-indole-2-carboxylic acid obtained by Hemetsberger-Knittel reaction. The last step in this sequence is an iodocyclisation reaction that is proved to be completely regio- and stereoselective via 6-exo-dig process. This methodology was then extended to isoindolic series allowing access to original "di-iodinated oxazino-isoindole" motifs. To further extend this methodology, new"di-iodinated oxazepino-indoles" were prepared using the same synthetic approach from the 1H-indole-7-carboxylic acid. The reactivity of the di-iodinated tri-cyclic structures has been studied via Cross-Coupling reactions (Stille, Sonogashira and Suzuki) by the use of palladium salts allowing a regioselective functionalization of the exocyclic iodine.

Thesis advisor: Jeffrey A. Byers / Chapter 1: There are a limited number of examples of metal-catalyzed Brook rearrangements in the literature, none of which involve ruthenium, rhodium, or iridium which are common ketone hydrogenation catalysts. The content of this chapter introduces the traditional Brook rearrangement and its advantages and disadvantages in chemical synthesis. Furthermore, the few examples of metal-catalyzed Brook rearrangements of acylsilanes and structurally similar moieties are discussed. Chapter 2: Utilizing a Brook rearrangement under hydrogenation or transfer hydrogenation conditions opens up a new area of catalytic reactivity that has not been fully explored. To our knowledge, metal complexes based on ruthenium and rhodium have never been shown to catalyze a Brook rearrangement of acylsilanes. This chapter describes the mechanistic implications of a Brook rearrangement under hydrogenation or transfer hydrogenation conditions as well as the first example of a ruthenium-catalyzed Brook rearrangement of aryl acylsilanes. Chapter 3: Pioneering work performed by Jeffrey Johnson and co-workers in the area of catalytic coupling of acylsilanes and various electrophiles showed that formation of new C-C bonds through a Brook rearrangement can be a powerful synthetic tool. In this chapter, we investigate an intermolecular coupling of aryl acylsilanes and aldehydes through a metal-catalyzed Brook rearrangement under transfer hydrogenation conditions to yield two synthetically useful motifs, specifically oxygenated bicyclic compounds. A reaction screen was performed on the coupling capabilities of these two species with various ruthenium and rhodium catalysts. The result of the screen was synthesis of a silyl ether acetal through employing the starting material as the reducing equivalent. Additionally, mechanistic insight was gained to further develop the proposed methodology. Chapter 4: An intramolecular approach to achieving coupling of acylsilanes and many different types of electrophiles was envisioned as a way of furnishing synthetically useful bicyclic compounds in one step. The focus of this chapter is the synthesis of a novel acylsilane that we proposed could undergo an intramolecular cross coupling reaction under transfer hydrogenation conditions. The conclusion of this chapter outlines the future direction of the project, which entails a new route to an intermolecular cross coupling of acylsilanes and various electrophiles. Published work from Michael Krische's laboratory helped us envision a different type of acylsilane, specifically an α,β-unsaturated acylsilane, in which binding to a metal center would proceed through a π-allyl intermediate. Ongoing efforts in the coupling of α,β-unsaturated acylsilanes with electrophiles are currently underway. / Thesis (MS) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / Detailed within this dissertation are three new reactions involving allylboron reagents. Chapter 1 describes the development of Pd-catalyzed allyl-allyl cross-coupling for the preparation of enantioenriched all-carbon quaternary stereogenic centers. This methodology represents a novel approach to a significant challenge for synthetic chemists. Subsequently, an allyl-allyl cross-coupling is described which generates functionally differentiated 1,5-dienes. Such structures allow for several chemoselective manipulations, which add a significant practical note to this cross-coupling methodology. Chapter 2 details the development of the allylboration of nitrosobenzene with (Z)-crotylboronate derivatives, which results in the formation of branched allylic alcohols. This methodology provides a regioselective complement to standard boron oxidation conditions. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.