The palladium-mediated cross-coupling of aryl electrophiles and amines (Buchwald-Hartwig amination) has become a widely used method of constructing arylamine frameworks. A crucial aspect of the advancement of this chemistry has been the design of ancillary ligands that are able to promote enhanced reactivity in challenging amination reactions. Despite significant ligand development within the field, challenges in this chemistry remain. Chemoselective aminations, wherein one amine substrate undergoes preferential arylation in the presence of multiple reactive amines has remained an underexplored area of Buchwald-Hartwig amination chemistry. This thesis describes the use of [Pd(cinnamyl)Cl]2 and N-[2-di(1-adamantylphosphino)phenyl]morpholine (Mor- DalPhos) in an extensive study of chemoselective Buchwald-Hartwig aminations, with 62 examples of structurally diverse di-, tri-, and tetraamines obtained in synthetically useful yields at reasonable catalyst loadings (1-5 mol % Pd). The coordination chemistry of [(Mor-DalPhos)Pd] species was also explored, as were complementary chemoselective aminations with the isomeric p-Mor-DalPhos ligand, leading to divergent product formation in some instances. The same [Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system used in the chemoselectivity study was also employed in a series of Buchwald-Hartwig aminations conducted under aqueous and solvent-free conditions, another underexplored area of this chemistry. A total of 52 amine products were isolated using these methodologies, moderate catalyst loadings (3 mol % Pd), and without the use of any additional additives, co-solvents, or rigorous exclusion of air. The synthesis of low-coordinate palladium complexes featuring both NHC and dialkylchlorophosphine ligands is also discussed herein. These complexes are prepared via a previously unreported and straightforward methodology involving an unusual net PCl bond reductive elimination, and represent a potential new class of pre-catalysts forpalladium-mediated reactions.

The field of metal-catalyzed C–H bond functionalizations is an incredibly vibrant and spans beyond the formations of biaryl motifs. The introduction chapter will cover the mechanistic aspects of the C–H bond functionalization with metal-carboxylate complexes. The mechanistic facets of this reaction will be the main conducting line between the different sections and chapters of the first part of this thesis. In the second chapter, will be described additives that can readily promoted C–H bond arylation of poorly reactive substrates. More specifically, we will revisit the intramolecular direct arylation reaction we will demonstrate the effect of pivalic acid as a co-catalyst by developing milder reaction conditions. In the third chapter we be described experimental and computational studies which suggested that the a single pathway might be involved in the palladium-catalyzed C–H bond functionalization of a wide range of (hetero)arene. Following this we will describe a general set of conditions for the direct arylation of wide range of heteroarenes. Also, we will present two different strategies to selectively and predictably arylate substrates containing multiple functionalizable C–H bonds. In the fourth chapter will be presented our efforts toward the development of new C–H bond functionalization methods in which we could apply our knowledge on the C–H bond cleavage and apply it to the formation of new scaffolds. The development of two new palladium-catalyzed methods were also described. In the fifth chapter, our effort toward the development of ligands to specifically promoted C–H bond cleavage will be presented. In the sixth chapter will be presented the latest results on the study of the mechanism of the C–H bond cleavage combining experimental and computational studies. In part B of this thesis will be presented our strategy toward the total synthesis of ginkgolide C that included two gold(I)-catalyzed reactions as key steps in the preparation of the spiro[4.4]nonane core of this natural product. The first studies on the feasibility of the key steps of the synthesis will be described.

Orientadores: Elizabete Jordão, Wagner Alves Carvalho / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica / Made available in DSpace on 2018-08-04T22:19:56Z (GMT). No. of bitstreams: 1 Figueiredo_FlaviaCamargoAlves_M.pdf: 2792481 bytes, checksum: 30096a0a78d59802544c5d197d9aa7ea (MD5) Previous issue date: 2005 / Resumo: A hidrogenação do adipato de dimetila catalisada por Pt e por Pd foi avaliada. Os catalisadores foram suportados em alumina, titânia e carvão. Os parâmetros investigados foram: a influência do suporte, a influência do metal ativo Pd quando comparado com Pt e a influência dos promotores Sn e K em alguns catalisadores. A caracterização físico-química dos sistemas catalíticos foi feita por Fisissorção de 'N IND. 2¿ ¿ BET, Quimissorção de 'H IND. 2¿, Microscopia Eletrônica de Varredura ¿ MEV, Redução a Temperatura Programada ¿ TPR e Espectrometria de Emissão Ótica em Plasma Indutivamente Acoplado ¿ ICP OES. A dispersão dos metais nos catalisadores mostrou-se diretamente relacionada à área superficial dos suportes, sendo que partículas bimetálicas ou parcialmente cobertas (no caso da titânia) podem estar presentes. O suporte altera o comportamento dos metais presentes na sua superfície por diferentes maneiras: efeito SMSI (titânia), acidez (aluminia) e presença de grupos funcionais oxidados (carvão). A conversão de adipato de dimetila á reduzida na presença do suporte titânia e aumenta quando o suporte é alumina, o que está relacionado à acidez deste, com a formação de uma elevada quantidade de produtos indesejáveis. Maiores valores de seletividade para a produção de 1,6 ¿ hexanodiol são observados com o uso de titânia, uma vez que espécies parcialmente reduzidas do suporte favorecem a ativação da carbonila do substrato ...Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital / Abstract: The hidrogenation of dimethyl adipate catalyzed by Pt and Pd was evaluated. The catalysts were supported in 'Al IND. 2¿¿O IND. 3¿, 'TiO IND. 2¿ and coal. The investigated parameters were: the influence of the support, the influence of the active metal Pd when compared to Pt and the influence of Sn and K as promoters in some catalysts. The physical-chemistry characterization of the catalytic system was made by 'N IND. 2¿ sorption ¿ BET, 'H IND. 2¿ soption, Scanning Electron Microscopy ¿ SEM, Temperature Programmed Reduction ¿ TPR and Inductively coupled Plasma Optics Emission superficial area of the supports, and bimetallic particles or partially covered (in the case of the 'TiO IND. 2¿) can be present. Support modifies the behavior of metals in the surface for different ways: SMSI effect ('TiO IND. 2¿), acidity ('Al IND. 2¿¿O IND. 3¿) and presence of oxidized functional groups (coal). The conversion of dimethyl adipate is reduced in the presence of 'TiO IND. 2¿ and increases when the support is 'Al IND. 2¿¿O IND. 3¿. This is related to the 'Al IND. 2¿¿O IND. 3¿ acidity, with the formation of many undersirable products. Higher selectivity values for the production of 1,6-hexaodiol are observed with 'TiO IND. 2¿, due to the partially reduced species of the support that favor the activation of the carbonyl...Note: The complete abstract is available with the full electronic digital thesis or dissertations / Mestrado / Sistemas de Processos Quimicos e Informatica / Mestre em Engenharia Química

The field of metal-catalyzed C–H bond functionalizations is an incredibly vibrant and spans beyond the formations of biaryl motifs. The introduction chapter will cover the mechanistic aspects of the C–H bond functionalization with metal-carboxylate complexes. The mechanistic facets of this reaction will be the main conducting line between the different sections and chapters of the first part of this thesis. In the second chapter, will be described additives that can readily promoted C–H bond arylation of poorly reactive substrates. More specifically, we will revisit the intramolecular direct arylation reaction we will demonstrate the effect of pivalic acid as a co-catalyst by developing milder reaction conditions. In the third chapter we be described experimental and computational studies which suggested that the a single pathway might be involved in the palladium-catalyzed C–H bond functionalization of a wide range of (hetero)arene. Following this we will describe a general set of conditions for the direct arylation of wide range of heteroarenes. Also, we will present two different strategies to selectively and predictably arylate substrates containing multiple functionalizable C–H bonds. In the fourth chapter will be presented our efforts toward the development of new C–H bond functionalization methods in which we could apply our knowledge on the C–H bond cleavage and apply it to the formation of new scaffolds. The development of two new palladium-catalyzed methods were also described. In the fifth chapter, our effort toward the development of ligands to specifically promoted C–H bond cleavage will be presented. In the sixth chapter will be presented the latest results on the study of the mechanism of the C–H bond cleavage combining experimental and computational studies. In part B of this thesis will be presented our strategy toward the total synthesis of ginkgolide C that included two gold(I)-catalyzed reactions as key steps in the preparation of the spiro[4.4]nonane core of this natural product. The first studies on the feasibility of the key steps of the synthesis will be described.

No description available.

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.

Chapter 1 is a brief review on some of the recents developments in palladium-catalysed C-H functionalisation chemistry. The synthesis and functionalisation of heterocycles using these methodologies was particularly emphasised. Chapter 2 presents our efforts to identify a new catalytic system to promote the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds for the formation of benzofurans. Dihydrobenzofurans were obtained efficiently under mild conditions in the presence of Pd(OAc)₂, X-Phos and K₂CO₃ in DMA at 80 °C and a subsequent one-pot isomerisation under acidic conditions afforded the desired benzofurans. A new strategy has also provided access to more complex benzofurans by functionalisation of the exocyclic alkene isomer in both a chiral and achiral manner. In Chapter 3, mechanistic studies were performed on the benzofuran formation reaction. The analysis of substituent effects on the aromatic ring is in accordance with an electrophilic aromatic substitution mechanism (SEAr); however, the existence of both intra and intermolecular kinetic isotope effects suggest a SE3 type pathway rather than a pure SEAr. In Chapter 4, the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds was further extended to the synthesis of six-membered heterocycles by direct arylation of alkenyl bromide derivatives in the presence of Pd(OAc)₂, dppf and K₂CO₃ in DMA at 120 °C. The synthetic utility of this methodology was exemplified by the synthesis of substituted isoquinolines in six steps. Moreover, we have applied our methodology to the direct arylation of sulfonamides, leading to an interesting synthesis of widely used sultams. Both these new routes are currently being investigated and should provide access to a variety of differently substituted cyclic sulfonamides and isoquinolines. Finally, Chapter 5 presents a new strategy for the synthesis of benzo[b]furan was briefly investigated. It consists in consecutive Tsuji-Trost and C-H functionalisation reactions. This methodology requires simpler and more versatile substrates, allowing access to various heteroaromatics in a single step. We successfully proved the viability of this reaction through the synthesis of a range of benzofurans in modest yields. To our knowledge, this is the first example of a single palladium catalyst performing these different reactions in tandem in a simple procedure.

In the following thesis, new methodologies towards the synthesis of a range of sulfonyl (-SO₂-) containing functional groups are documented. These methods utilise easy-to-handle sulfur dioxide surrogates, such as DABSO (vide infra), and exploit palladium catalysis as a new mechanistic protocol for the incorporation of the -SO2- unit. <b>Chapter 1</b> is a literature review surveying sulfur dioxide in organic synthesis, the established uses of SO₂ surrogates and the importance of the sulfonyl moiety in chemistry. Palladium-catalysed (carbonylative) cross-couplings are also broadly discussed as they provide inspiration for, and mechanistic similarities with, the proposed chemistry. <b>Chapter 2</b> describes a de novo synthesis of the sulfonamide functional group; a three-component and convergent methodology coupling (hetero)aryl and alkenyl halides with sulfur dioxide (provided by easy-to-handle surrogates such as DABSO) and hydrazine nucleophiles, is documented. This is achieved through the action of a readily available palladium catalytic system and is the first example of a metal-catalysed sulfonylative cross-coupling of halide based electrophiles. <b>Chapter 3</b> presents a new method of generating (hetero)aryl and alkenyl sulfones. The ability of organometallic reagents to add to sulfur dioxide (supplied via DABSO) is applied to deliver the corresponding metal sulfinate salt. This in situ derived sulfinate is coupled with an (hetero)aryl or alkenyl (pseudo)halide using palladium catalysis to form the desired sulfone. An electronically modified XantPhos-type ligand was designed for the reaction in order to suppress unwanted aryl-aryl exchange. <b>Chapter 4</b> documents the generation of (hetero)aryl and alkenyl sulfinates from the corresponding halide and DABSO through a palladium-catalysed sulfination protocol, obviating the need for organometallic reagents. A mild set of conditions using IPA as both a solvent and reductant together with a low loading of palladium catalyst offers an attractive route to sulfonyl compounds thanks to the in situ derived sulfinates being converted into a broad variety of functional groups via established onwards reactivity. <b>Chapter 5</b> discusses the conclusion of the research and the potential for future work. <b>Chapter 6</b> presents the experimental data.

The main focus of this thesis has been directed towards preparation and oxidative carbocyclization of en-, dien- and aza-enallenes. In the first part of this thesis, a stereoselective oxidative carbocyclization of dienallenes was realized. By employing cheap and readily available palladium trifluoroacetate we were able to efficiently cyclize a variety of dienallenes into hydroxylated carbocycles in high yield and high selectivity. This oxidative process was compatible with two different reoxidation protocols: one relying on p-benzoquinone (BQ) as the oxidant and the other employing molecular oxygen as the oxidant. In the second part of the thesis the carbocyclization methodology was extended to include carbocyclization of aza-enallenes. This was achieved in two distinct steps. First, a copper-catalyzed coupling of allylic sulfonamides with bromoallenes was developed, giving access to the corresponding aza-enallenes. Subjecting these substrates to catalytic amounts of palladium acetate, along with BQ as the oxidant, rendered N-heterocycles in good yield. The reactivity of these N-heterocycles towards activated dienophiles was later exploited in a tandem (aerobic) oxidative carbocyclization/Diels-Alder reaction. The third topic involves efficient oxidative arylative/borylative carbocyclization of enallenes. These reactions, catalyzed by palladium acetate, relies on transmetallation of a (σ-alkyl)palladium(II) intermediate with diboranes or arylboronic acids. With this novel methodology we were able to obtain an array of arylated or borylated carbocycles, as single diastereomers, in high yield. Finally, we developed a palladium(II)-catalyzed cyclization of allylic carbamates. This mild, operationally simple, and scalable catalytic reaction opens up access to an array of oxazolidinones in high yield and excellent diastereoselectivity. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 6: Manuscript.</p>

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.