Transfer hydrogenation has been recognized to be an important synthetic method in both academic and industrial research to obtain valuable products including alcohols. Transition metal catalysts based on precious metals, such as Ru, Rh and Ir, are typically employed for this process. This thesis starts with a study on the potential of an Fe based complex carrying a PNP ligand (2,6-{Ph2PNH}2(NC5H3)) to function as an active transfer hydrogenation catalyst for the conversion of ketones to alcohols. During the analysis of the performance parameters of this potential catalyst, it was discovered that the added base, KOtBu, was the actual catalyst. Other bases were explored as catalysts for this transformation as well as the general performance features of this simple alkali metal base. In a separate project described in Chapter 3, the search for catalysts shifted focus to a study of the potential of a series of first row transition metal-based complexes supported by a bis(thioether)pyridine “SNS” ligand for photocatalytic hydrogen production. This initial study led to the observation that the Fe complex [Fe(k3-2,6-(CH3SCH2)2C5H3N)Br2]2 was a capable photocatalyst for H2 production in combination with a photosensitizer (Ru(bpy)3)2+) and an electron donor (triethanolamine). Although water was initially believed to be the source of protons that were reduced to H2, analysis of control experiments pointed to the hydrogen source being the electron donor.

The ligand tBu2PC2H4NHCH2Py (PNHN) was synthesized starting from 2-pyridinecarboxaldehyde and 2-chloroethanamine. Initial attempts for coordination of the PNHN ligand to a metal center was performed using [IrCl(COE)2]2, IrCl3·3H2O, [RuCl2(p-cymene)]2 and RuCl2(PPh3)3. The reaction between the PNHN ligand and [IrCl(COE)2]2 under H2 resulted in the chloride IrCl(H)2(PNHN). Synthesis of the active hydride species is currently under investigation. A reaction of the PNHN ligand with RuCl2(PPh3)3 under nitrogen afforded the dichloride RuCl2(PPh3)(PNHN). Treatment of the dichloride with KOBut in 2-pentanol led to the formation of the dihydride RuH2(PPh3)(PNHN). Formation of the 16-electron amido complex RuH(PPh3)3(PNN) was achieved through the evolution of H2. The dihydride demonstrated good potential catalytic activity for transfer hydrogenation of acetophenone and cyclohexanone. Current work involves the synthesis of a chiral analogue of the PNHN ligand.

The ligand tBu2PC2H4NHCH2Py (PNHN) was synthesized starting from 2-pyridinecarboxaldehyde and 2-chloroethanamine. Initial attempts for coordination of the PNHN ligand to a metal center was performed using [IrCl(COE)2]2, IrCl3·3H2O, [RuCl2(p-cymene)]2 and RuCl2(PPh3)3. The reaction between the PNHN ligand and [IrCl(COE)2]2 under H2 resulted in the chloride IrCl(H)2(PNHN). Synthesis of the active hydride species is currently under investigation. A reaction of the PNHN ligand with RuCl2(PPh3)3 under nitrogen afforded the dichloride RuCl2(PPh3)(PNHN). Treatment of the dichloride with KOBut in 2-pentanol led to the formation of the dihydride RuH2(PPh3)(PNHN). Formation of the 16-electron amido complex RuH(PPh3)3(PNN) was achieved through the evolution of H2. The dihydride demonstrated good potential catalytic activity for transfer hydrogenation of acetophenone and cyclohexanone. Current work involves the synthesis of a chiral analogue of the PNHN ligand.

Transfer hydrogenation has been recognized to be an important synthetic method in both academic and industrial research to obtain valuable products including alcohols. Transition metal catalysts based on precious metals, such as Ru, Rh and Ir, are typically employed for this process. In recent years, iron-based catalysts have attracted considerable attention as a greener and more sustainable alternative since iron is earth abundant, inexpensive and non-toxic. In this work, a combination of iron disulfide with chelating bipyridine ligand was found to be effective for the transfer hydrogenation of a variety of ketones to the corresponding alcohols in the presence of a simple base. It provided a convenient and economical way to conduct transfer hydrogenation. A plausible role of sulfide next to the metal center in facilitating the catalytic reaction is demonstrated.

This thesis describes the chemistry developed during a study of novel transition metalcatalysed reactions for the synthesis of carboxylic acid derivatives. Chapter 2 describes a novel protocol for the synthesis of primary amides from alcohols in one-pot where a metal complex mediates two fundamentally different catalytic processes. An iridium catalyst has been shown to be effective for the selective rearrangement of aldoximes into primary amides. In addition, an iridium-catalysed oxidation of activated alcohols via hydrogen transfer has been developed using an alkene as formal oxidant. These reactions have been combined in a sequential process affording good yields for a range of benzylic alcohols. An improved system for the rearrangement of aldoximes into amides using a new ruthenium catalyst is described in Chapter 3. Through a systematic program of optimisation excellent selectivity was achieved for a wide range of substrates at markedly reduced catalyst loading. Chapter 4 describes the development of a ruthenium-catalysed elimination reaction for the conversion of oxime ethers into nitriles. The application of this reaction to tandem and sequential reactions has been explored, albeit with limited success. Also, a method for the ruthenium-catalysed oxidation of alcohols using an electron-deficient alkene as hydrogen acceptor is described, and its application to a tandem oxidation process with a nitrogen nucleophile demonstrated. As an extension of the concept presented in Chapter 4, tandem oxidation processes with oxygen nucleophiles are the subject of Chapter 5. This strategy has been used for the oxidation of primary alcohols to their corresponding methyl esters in one-pot, with good yields obtained for a range of substrates. The use of water as a nucleophile in such a process has also been examined.

A central tenant of organic synthesis is the construction of carbon-carbon bonds. One of the traditional methods for carrying out such transformations is that of carbonyl addition. Unfortunately, traditional carbonyl addition chemistry suffers various drawbacks: preactivation, moisture sensitivity, and the generation of stoichiometric organometallic waste. The research presented in this dissertation focuses on the development of methods that make use of nucleophile-electrophile pairs generated in situ via transfer hydrogenation, which allow the formation of carbonyl or imine addition products from the alcohol or amine oxidation level; streamlining the construction of complex molecules from simple, readily available starting materials. Additionally, studies toward the total synthesis of the fibrinogen receptor inhibitor tetrafibricin, utilizing the methods developed in catalytic carbon-carbon bond formation through the addition, transfer or removal of hydrogen, are presented. / text

Environmental concerns have birthed an awareness of how we conduct ourselves as citizens of this planet. To reduce environmental impact, we have learned that we must be responsible stewards in all ranges of life: from buying locally grown food to how scientific research and industrial processes are executed. In the realm of chemical research, "green chemistry" has initiated the development of new, sustainable methods that make use of atom economy, step economy, and utilize renewable materials to minimize waste and production of toxic by-products. The formation of carbon-carbon bonds lies at the very heart of organic synthesis, and traditional methods for forming such bonds generally require the use of at least one stoichiometrically preformed organometallic reagent. This corresponds to at least one equivalent of metallic waste byproduct. The in situ formation of alkyl metal nucleophiles for carbonyl additions via hydrogenation of [pi]-unsaturates represents an alternative to use of preformed organometallic reagents. Comprising nearly 90% of the atoms in the universe, hydrogen is vastly abundant and very cheap. The Krische group seeks to contribute new technologies which make use of catalytic hydrogenation and transfer hydrogenation in the reductive coupling of basic chemical feedstocks. / text

By simply hydrogenating enones in the presence of aldehydes at ambient temperature and pressure, aldol adducts are generated under neutral conditions in the absence of any stoichiometric byproducts. Using cationic rhodium complexes modified by tri(2-furyl)phosphine, highly syn-diastereoselective reductive aldol additions of vinyl ketones are achieved. Finally, using novel monodentate TADDOL-like phosphonite ligands, the first highly diastereo- and enantioselective reductive aldol couplings of vinyl ketones were devised. These studies, along with other works from our laboratory, demonstrate that organometallics arising transiently in the course of catalytic hydrogenation offer byproduct-free alternatives to preformed organometallic reagents employed in classical carbonyl addition processes. Existing methods for enantioselective carbonyl allylation, crotylation and tert-prenylation require stoichiometric generation of pre-metallated nucleophiles, and often employ stoichiometric chiral modifiers. Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium C,O-benzoate catalyst, enantioselective carbonyl allylations, crotylations and tert-prenylations are achieved in the absence of stoichiometric metallic reagents or stoichiometric chiral modifiers. Moreover, under transfer hydrogenation conditions, primary alcohols function dually as hydrogen donors and aldehyde precursors, enabling enantioselective carbonyl addition directly from the alcohol oxidation level. / text

Cette étude présente la préparation et l’évaluation de l’activité d’un nouveau catalyseur monolithique en microréacteur. La réaction d’hydrogénation du p-nitrophénol par transfert d’hydrogène avec l’acide formique a été choisie comme réaction modèle pour comparer les performances du monolithe à celles d’un catalyseur commercial en lit fixe.Cette thèse comporte une partie expérimentale importante. D’un côté, un montage expérimental et des protocoles d’analyse en ligne ont été mis au point pour faire une étude quantitative précise de la réaction modèle. De l’autre côté, les conditions de préparation d’un monolithe de silice fonctionnalisée dans le tube-réacteur en acier chemisé de verre ont été optimisées. Il a été chargé en nanoparticules de Pd par une méthode en écoulement. Le monolithe comporte un réseau de macropores pour l’écoulement et une organisation hexagonale typique de mésopores et micropores, et cela presque sans retrait au séchage. L’activité des 2 types de catalyseurs dans la réaction modèle a été comparée par leur cinétique de réaction et leur comportement dynamique dans la phase de mise en régime du microréacteur. Une partie théorique présente la modélisation du microréacteur en régime stationnaire pour l’établissement des cinétiques et en régime transitoire pour rationaliser les observations expérimentales. Le monolithe Pd@silice et le catalyseur commercial Pd@alumine ont des comportements différents et obéissent à des lois cinétiques différentes. Un modèle réactionnel impliquant un changement de propriétés de la surface catalytique pourrait expliquer le profil de concentration inhabituel observé avec le catalyseur commercial. La comparaison démontre la supériorité du nouveau catalyseur monolithe, et lui ouvre de bonnes perspectives industrielles. / This study presents the preparation and the evaluation of performance of a new monolithic catalyst in microreactor. The transfer hydrogenation of p-nitrophenol by formic acid is chosen as the model reaction for the comparison of the monolith with a traditional packed-bed microreactor containing commercial catalyst.This thesis includes an important experimental part. On the one hand, experimental set-up and protocols involving on-line analysis have been developed in order to study quantitatively the model reaction; On the other hand, the conditions of preparation of functionalized silica monolith in a stainless steel tube with the inner wall pre-coated by glass were optimized, and the palladium nanoparticles were immobilized by a continuous flow method. The monolith possesses the flow-through macropores, typical hexagonal organization of mesopores and micropores, and scarcely any shrinkage. The comparison of the two types of catalysts mainly focuses on the activity of catalysts in the model reaction, their kinetic model and their dynamic behavior in the start-up phase of the flow microreactor. In the theoretical part, the modelisation of reactor has been investigated both under stationary conditions for kinetics determination and under transient conditions for the rationalization of experimental observations. Pd@silica monolith and commercial Pd@alumina powder have different behavior and gives different kinetic laws. A reaction model with change in the catalytic surface properties could explain the unusual profile of concentrations observed with commercial catalyst. The superior performance of monolithic catalyst is demonstrated, which also exhibits particular industrial interests.

Novel 1,4-chiral diamine ligand possessing a trans-9,10-dihydro-9,10-ethanoanthracene backbone was synthesized. The synthetic plan involves first LiAlH4 reduction of the Diels-Alder adduct obtained by reaction of dimenthyl fumarate and anthracene, which is followed by reacting the corresponding alcohol and subsequent attachment of mesylate and triflate units to get good leaving groups which are available substances for introducing nitrogen units via SN2 type reactions. Consequently, by using dimesyl ester and ditriflate esters five catalysts 27, 29, 30, 33 and 38 were synthesized. The first four catalysts 27, 29, 30 and 33 were used in transfer hydrogenation reactions with transition metal whereas catalyst 38 used as an organocatalyst in direct aldol reaction between acetone and p-nitrobenzaldehyde.