Conjugated organic materials comprise a field of materials chemistry focused on the development of semiconducting organic plastics, popular applications of which are plastic solar cells and display technologies. One of the reasons these materials have gained so much attention is that their optical and electronic properties can be tuned through engineering at the molecular level. Thiophene, an aromatic heterocycle, is a popular building block in the synthesis of many conjugated materials, prized for both the ease in which it can be synthetically functionalized and its ability to form highly conductive and low band gap materials. The Rasmussen group has previously reported on the generation of two classes of materials, the inorganic metal thiophenedithiolenes and the fused-ring heterocycle unit thieno[3,4-b]pyrazine (TP), both of which have applications in conducting materials. In an effort to expand upon the applicability and versatility of these materials, a series of interconnected projects were performed to further tune their optical, electronic, and physical (e.g. solubility) properties. This involved synthetic molecular design, including judicious consideration of structure-function relationships, and characterization of the resulting materials. Highlights include a sterics vs. electronics consideration of the catalyzed hydrodebromination of the molecular building-block 2,3,5-tribromothiophene, variation of the coordinating metal in thiophenedithiolenes to tune the optics and electronics, and characterization of the effects of ring-fusion on TP-based terthienyl homopolymers. Additionally, a new application of the TP monomer was found, whereby it was successfully incorporated as a bridging ligand into a multi-metallic Ru(II) supramolecular assembly, which demonstrated good metal-metal communication.

Thesis advisor: James P. Morken / This dissertation describes the development of a method for the stereoselective synthesis of organoboronates and the applications of these products to target-oriented synthesis. The first chapter discusses an investigation of the palladium-catalyzed conjunctive cross-coupling reaction by kinetic analysis. This reaction enables the asymmetric synthesis of organoboronates by utilizing the 1,2-metallate rearrangement of borates as a mechanistic step in a cross-coupling reaction. The second chapter describes the application of the conjunctive cross-coupling reaction to the asymmetric synthesis of tertiary boronic esters. In chapter three, the conjunctive cross-coupling reaction of 1,2-disubstituted alkenyl boronates is presented. Such a substrate class is susceptible to the undesired Suzuki-Miyaura cross-coupling reaction, and this challenge led to the development of a novel diol ligand for boron as an effective solution. The final chapter details the progress toward the total synthesis of the sarcodictyin natural products, which display promising anti-cancer activity. The synthetic route utilizes reactions of organoboronates for powerful C–C bond formations; the construction of a fully-cyclyzed advanced intermediate is achieved in eight steps. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Cross coupling reactions are a well-established tool in modern organic synthesis and play a crucial role in the synthesis of a high number of organic compounds. Their importance is highlighted by the Nobel Prize in chemistry to Suzuki, Heck and Negishi in 2010. The increasing importance of sustainability requirements in chemical production has furthermore promoted the development of cross-coupling protocols that comply with the principles of “Green Chemistry”1. The Sonogashira reaction is today the most versatile and powerful way to generate aryl alkynes, a moiety recurring in many pharmaceutical and natural products. Despite many improvements to the original reaction, reports on generally applicable protocols that work under sustainable conditions are scarce. Our group recently reported an efficient protocol for a copperfree Sonogashira cross-coupling at low temperature, in aqueous medium and with no addition of organic solvents or additives2. The goal of this work was to further investigate the effects of different reaction parameters on the catalytic activity in order to optimize the protocol. Limitations of the protocol were tested in respect to reaction temperature, heating method, atmosphere, base type and amount, catalyst loading, reaction time and work up procedure. The reaction worked successfully under air and results were not affected by the presence of oxygen in the water phase. Among a variety of bases tested, triethylamine was confirmed to give the best results and its required excess could be reduced from nine to four equivalents. Catalyst loading could also be reduced by up to 90%: Good to near quantitative yields for a broad range of substrates were achieved using a catalyst concentration of 0.25mol% and 5 eq of Et3N at 50°C while more reactive substrates could be coupled with a catalyst concentration as low as 0.025mol%. Filtration experiments showed the possibility of a simplified work up procedure and a protocol completely free of organic solvents. This optimized protocol can be applied to a broad range of substrates, delivers high yields, avoids formation of toxic byproducts, works under air and aqueous conditions, allows for simple product isolation and thus meets not only the criteria of “Green Chemistry” but also those of “Click-Chemistry”

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19181号 / 工博第4058号 / 新制||工||1626(附属図書館) / 32173 / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 中村 正治, 教授 辻 康之, 教授 小澤 文幸 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

A method for the preparation of air stable difluoroboryl acrylamides is reported. In contrast to the ubiquitous organotrifluoroborate salts, difluoroboryl acrylamides are relatively nonpolar and are readily purified by silica gel chromatography. Difluoroboryl acrylamides serve as efficient substrates in cross-coupling reactions to afford the corresponding trisubstituted acrylamides in good to excellent yields. The utility of the difluoroboryl group in various chemical transformations is presented. / A new method for the formation of a unique difluorinated boron-based functional group is reported. In contrast to the commonly observed trifluoronated boron species, the difluoroboryl species is relatively nonpolar, which allows for these compounds to be purified by silica gel chromatography, a convenient method for purification of compounds. Similarly to trifluoroborate salts, difluoroboryl species are capable of undergoing cross-coupling reactions, which form carbon-carbon bonds, in good to excellent yields. Additional examples of chemical reactions using difluoroboryl acrylamides are also presented.

A total synthesis of the complex C-aryl glycoside isokidamycin was achieved during an effort to construct the natural product kidamycin, a member of the pluramycin family of antitumor antibiotics. The angolosamine carbohydrate was appended, along with annelation of a benzene ring by the implementation of the Martin group's silicon tether-directed, intramolecular aryne-furan cycloaddition strategy. The vancosamine-derived carbohydrate was then installed by an O -> C-glycoside rearrangement. A novel protocol for the carbonylative cross-coupling of ortho-disubstituted aryl iodides with aryl boronic acids and alkynyl zinc reagents was also discovered during efforts to introduce the pyranone ring of kidamycin. The reaction proved general, as a variety of electron-rich and electron-poor aryl iodides, boronic acids, and alkynyl-zinc reagents participated in the cross-coupling. / text

This work describes the synthesis and functionalization of azoles employing different methodologies, based on organometallic catalysis or not. Firstly, we disclose the synthesis tetra-substituted 5-trifluoromethyl pyrazoles via sequential halogenation of 5-trifluoromethyl pyrazoles and palladium-catalyzed carbon–carbon and carbon–nitrogen cross-coupling reactions employing organozinc reagents and amines as coupling partners, respectively. This work allowed to achieve new pyrazolic systems in moderated to good yields. Posteriorly, we show the synthesis of 1,3-di(hetero)aryl indazoles exploring the complementary catalytic activity of nickel and copper complexes. We commenced this study evaluating different nickel pre-catalysts to perform the intramolecular amination of unprotected 2-chlorophenyl hydrazones. In a second moment, we described the N-(hetero)arylation of the in situ generated NH indazoles, using a simple catalytic system based on copper/DMEDA. This sequential one-pot fashion procedure allowed the achievement of several 1,3-di(hetero)aryl indazoles in moderate to good yields. Lastly, we disclose the formation of pyrazolo[1,5-a]quinoxalin-4(5H)-ones by the reaction between ethyl 1-(2-chlorophenyl)-1H-pyrazole-5-carboxylate and primary amines. The one-pot methodology undergoes by two sequential reactional pathways: i) amidation of the ester moiety attached to the pyrazole ring, and ii) intramolecular cyclization via nucleophilic aromatic substitution. This synthetic approach proved to be efficient only for primary aliphatic amines, allowing to achieve molecules with different substitution patterns in moderate to good yields. Key-words: Azoles, quinoxalinones, Negishi cross-coupling, Buchwald-Hartwig cross-coupling. / Este trabalho descreve a síntese e a funcionalização de azóis através de diferentes metodologias, ancoradas ou não na catálise organometálica. Primeiramente, descrevemos a síntese de 5-trifluormetil pirazóis tetrassubtituídos através de reações de acoplamento cruzado catalisadas por complexos de paládio entre 5-trifluormetil-4-halo pirazóis, reagentes organozinco e aminas. Este trabalho permitiu a obtenção de novos sistemas pirazólicos com rendimentos moderados a bons. Posteriormente realizamos a síntese de 1,3-di(hetero)aril indazóis explorando as atividades catalíticas complementares de complexos de níquel e cobre. Primeiramente avaliamos diferentes pré-catalisadores de níquel para realizar a aminação intramolecular de diferentes 2-clorofenil hidrazonas não protegidas. Em um segundo momento, realizamos a N-(hetero)arilação dos NH indazóis gerados in situ, através do emprego de um sistema catalítico baseado em cobre/DMEDA. A metodologia permitiu a obtenção de diferentes indazóis 1,3-di(hetero)aril substituídos, com rendimentos moderados a bons. Por fim, demonstramos a síntese de pirazolo[1,5-a]quinoxalin-4(5H)-onas a partir da reação entre 1-(2-clorofenil)-1H-pirazolo-5-carboxilatos de etila e aminas primárias. A metodologia one-pot envolve duas etapas sequenciais; i) amidação da função éster do pirazol e ii) ciclização intramolecular via substituição nucleofílica aromática. Esta abordagem sintética provou ser eficiente ao se empregar aminas alquílicas primárias, permitindo a obtenção de diferentes padrões de substituição com rendimentos moderados a bons.

Cette thèse développe l'étude des complexes de nickel(II) porteurs de ligands carbènes N hétérocycliques (NHC) selon deux axes: la synthèse et la caractérisation de complexes nickelacycliques avec un ligand chélatant carbone-carbone (CNHC, Calkyl); et leur activité catalytique dans la construction des liaisons carbone-carbone (Csp2–Csp2/Csp3) des 1-chalcogènes-azoles par fonctionnalisation des liaisons carbone-hydrogène (C–H). Une série de produits d'addition d'acétonitrile métallacycliques CNHC,Calkyl-Ni(II) cationiques a été synthétisée par élimination d'un ligand cyclopentadiényle des nickelacycles demi-sandwich a 18 électrons de valence parents. Il a été déterminé que les complexes cationiques existaient en tant qu'espèce Ni(II) à 14 électrons de valence en forme de T, insaturée de manière coordonnée et électronique, à l'état solide. L'application de ces nouveaux complexes au couplage croisé du benzothiazole avec les iodoarènes s'est avérée une stratégie efficace dans la formation des liaisons Csp2–Csp2, par la combinaison d'un échafaudage métallacyclique stabilisant avec des ligands labiles. La découverte d'une espèce demi sandwich Ni(II)-(NHC)-(benzothiazolyle) inactif dans l'arylation du benzothiazole, mais actif dans le couplage du benzothiazole avec les iodoalcanes, constitue le premier exemple de construction des liaisons Csp2–Csp3 du benzothiazole avec un catalyseur Ni(II)-NHC. / This thesis develops the study of nickel(II) complexes bearing N-heterocyclic carbene ligands (NHC) in two axes: the synthesis and characterization of nickelacyclic complexes with a carbon-carbon chelating ligand (CNHC,Calkyl); and their catalytic activity in the construction of carbon-carbon bonds (Csp2–Csp2/Csp3) of 1-chalcogene-azoles by carbon-hydrogen (C–H) bond functionalization. A series of cationic CNHC,Calkyl-Ni(II) metallacyclic acetonitrile adducts was synthetized by the removal of a cyclopentadienyl ligand from parent 18 valence electron half-sandwich nickelacycles. The cationic complexes were determined to exist as rare coordinatively and electronically unsaturated T-shaped 14 valence electron Ni(II) species, in the solid state. Application of these new complexes to the cross-coupling of benzothiazole with iodoarenes proved to be a successful strategy in Csp2–Csp2 bond formation, by the combination of a stabilizing metallacyclic scaffold with labile ligands. The discovery of a half-sandwich Ni(II)-(NHC)-(benzothiazolyl) species, inactive in the arylation of benzothiazole, but active for the cross-coupling of benzothiazole with iodoalkanes shows the first example of benzothiazole Csp2–Csp3 bond construction with a Ni(II)-NHC catalyst.

This research focused on the synthesis of novel ogranoboron reagents in efforts to perform a variety of synthetic transformations, and additionally, the development of new methodologies to generate drug-like scaffolds. Initially, three novel tripod ligands were synthesized, and two were effectively chelated to boron to provide the desired organoborates. Such organoborates were employed in nucleophilic additions where they were found to be ineffective, whereas some activity was observed in Suzuki-Miyaura cross-coupling reactions. An additional project on organoboron compounds was conducted and focused on the development of organoboron frustrated Lewis pairs (FLPs) to facilitate the storage and transfer of hydrogen, nucleophilic addition reactions, and Claisen rearrangements. A new method for synthesizing a pyrrolidine diol unit was accomplished, and this intermediate was utilized to synthesize two FLPs. The reactivity of the FLPs with small molecules was assessed, and the pyrrolidine diol unit was subsequently evaluated for its ability to undergo a multicomponent reaction (MCR) to yield compounds possessing beneficial biological activity. Further research in this area was conducted, and a 5-aminoimidazole scaffold was synthesized employing a new MCR which is more efficient than previously reported methodologies. 5-Aminoimidazoles are frequently found in compounds which possess desirable biological activity, and this novel method was employed to generate a library of eleven 5-aminoimidazoles. Additionally, two post condensation modification reactions were developed. During initial studies, a side product was observed which was identified as a dihydrotriazine, which is another biologically appealing chemotype. Therefore, an enhanced method of synthesizing this product was developed, and a library of eleven dihydrotriazines was produced. In summary, novel organoboron reagents were synthesized, and their activity was evaluated. The pyrrolidine diol utilized to synthesize FLPs was applied towards an MCR. Furthermore, a novel MCR was developed for the synthesis of 5-aminoimidazoles, and an enhanced protocol for the synthesis of dihydrotriazines was found.

Progress towards a concise total synthesis of subincanadine E is reported. This natural product was first isolated from the Picralima nitida cell suspension culture line in 1982 under the name pericine and later in 2002 from Aspidosperma subincanum as subincanadine E. It is the most potent compound of its class with in vitro cytotoxicity against both murine lymphoma L1210 and human epidermoid carcinoma KB cells (LD50, 0.3 ug/mL and 4.4 ug/mL, respectively) and was found to be six times more potent than codeine as an opiate agonist in a 3H-naloxone binding study (IC50, 0.6 umol/L). The first-generation synthesis produced an undesired internal olefin that, upon attempted isomerization, catalyzed an unusual intermolecular Diels-Alder reaction. A revised second-generation synthesis employed (±)-harmicine and showcased an intramolecular Pd-catalyzed cross-coupling reaction that furnished an unanticipated 5-membered ring instead of the predicted 6-membered ring via methylene linker activation. Further studies utilizing an amide intermediate and organocuprate chemistry produced no desired carbon-carbon bond formation. A third-generation synthesis was carried out from enantiopure (S)-carvone. This route explored regioselective oxime formation and protecting group manipulations for a subsequent Beckmann rearrangement, which provided the first access to 5-amino derivatives of carvone. An intramolecular Pd-catalyzed cross-coupling reaction was performed to construct the aza-bicycle prior to indole installation. Contingent on its success, indole introduction and a double alkylation would provide an akuammicine-like scaffold that can ring-open upon hydride exposure to afford (15S)-subincanadine E in 16 overall steps. This work accomplished 10 steps toward the first total asymmetric synthesis of (15S)-subincanadine E.