Given the occurrence and diversity of nitrogen-containing molecules, the development of new amination methods is of significant importance. Indeed, a recent study shows that 60% of the FDA approved drugs contain a nitrogen heterocycle. Undoubtedly, novel methodologies arising for uncommon intermediates for the incorporation of nitrogen atoms are needed to access more complex molecules. The present document focus on the development of new methods for the formation of C-N and N-N bonds for the synthesis of acyclic and heterocyclic products. Isocyanates are useful synthons and reactive intermediates. To overcome their toxicity and instability, blocked (or masked) isocyanates have been developed: an equilibrium generates the isocyanate in-situ, allowing for safer precursors and better control over the concentration of the reactive isocyanate. This strategy enables the development of new reactivity, particularly for heteroatom-substituted isocyanates. However, reactions of oxygen-substituted isocyanates (O-isocyanates) remained severely underdeveloped. In Chapter 2, bench-stable N-oxy-carbamates and N-oxyureas are reacted under basecatalysis or thermal conditions to form the corresponding O-isocyanate intermediate in situ. In the first part of this chapter, a survey was performed and optimum experimental conditions for the controlled formation of O-isocyanate intermediates from the block precursors were found. Gratifyingly, the known side-reactions of O-isocyanates (trimerization and 1,2-shift) were avoided and different nucleophiles and substituents were studied for the controlled formation of N-oxyureas via substitution reaction of blocked O-isocyanates. Cascade reactions provided the opportunity to further develop this controlled reactivity of O-isocyanates. Herein, the first cascade-reaction of O-isocyanates is portrayed using - and -aminoester as the partners for the synthesis of hydantoin and dihydrouracil derivatives (>30 examples). Moreover, the conditions were modified to perform the reaction with -alcohol and - thioesters. Finally, evidence for the O-isocyanate intermediate is provided.

Metalloporphyrins have been shown to catalyze many fundamental and practically important chemical transformations, some of which represent the first demonstrations of these catalytic processes. The most notable examples include an assortment of atom/group transfer reactions, such as oxene, nitrene, and carbene transfers. Atom/group transfer reactions allow for the direct conversion of abundant and inexpensive alkenes and alkanes into value-added functional molecules. Previous reports from our group have shown that cobalt-porphyrin based carbene and nitrene transfer reactions are some of the most selective and practical catalytic systems developed for cyclopropanation and aziridination. Backed by a family of D2-symmetric chiral cobalt porphyrins our group continues the development of stereoselective carbene and nitrene transfer reactions. Metal-catalyzed cyclopropanation of olefins with diazo reagents has attracted great research interest because of its fundamental and practical importance. The resulting cyclopropyl units are recurrent motifs in biologically important molecules and can serve as versatile precursors in organic synthesis. Supported by a family of D2-symmetric chiral cobalt porphyrins, we have demonstrated the use of succimidyl diazoacetate as carbene source for a highly diastereo- and enantioselective cyclopropanation process. The resulting cyclopropyl succinimdyl esters are highly reactive and serve as valuable synthons for generating cyclopropylcarboxamides. We have also developed the first cobalt-porphyrin based intramolecular cyclopropanation, which is able to produce the resulting bicyclic lactones in high yields and enantioselectivity. Nitrene transfer reactions are also an attractive route to produce biologically and synthetically important molecules such as amines and aziridines. Although much progress has been made in nitrene transfer reactions utilizing [N-(p-toluenesulfonyl) imino]phenyliodinane (PhI=NTs) the nitrene source suffers from several drawbacks. Consequently, there has been growing interest in developing catalytic nitrene transfer reactions using alternate nitrene sources. To this end, we have utilized arylsulfonyl azides as nitrene source to explore their use in the development of a cobalt-porphyrin catalyzed enantioselective aziridination system. The cobalt catalyzed process can proceed under mild and neutral conditions in low catalyst loading without the need of other reagents, while generating nitrogen gas as the only byproduct. We have also explored the use of arylsulfonyl azides as nitrene source in a cobalt-catalyzed intramolecular C-H amination process.

The results of kinetic isotope determination and computational studies on Noyori-type catalytic systems for the hydrogenation of ketones are presented. The catalysts examined include RuH2(NHCMe2CMe2NH2)(R-binap) and RuH(NHCMe2CMe2NH2)(PPh3)2. These complexes are active catalysts for ketone hydrogenation in benzene without addition of an external base. The kinetic isotope effect (KIE) for catalysis by RuH2(NHCMe2CMe2NH2)(R-binap) was determined to be 2.0 ± (0.1). The calculated KIE for the model system RuH(NHCH2CH2NH2)(PH3)2 was 1.3, which is smaller than the experimentally observed value but does not include tunneling effects. The complex OsH(NHCMe2CMe2NH2)(PPh3)2 is known to display autocatalytic behaviour when it catalyzes the hydrogenation of acetophenone in benzene. Pseudo first-order reaction conditions are obtained via addition of the product alcohol at the beginning of each kinetic experiment. The KIE determined using various combinations of deuterium-labeled gas, alcohol and ketone was found to be 1.1 ± (0.2). DFT calculations were used to explore the effect of the alcohol and the KIE. An induction period is observed at the start of the hydrogenation that is attributed to the formation of an alkoxide complex. A novel, diamine-orchestrated hydrogen-bonding network is proposed based on DFT calculations to explain how the alkoxide is converted back to the active catalyst. The tetradentate complexes trans-RuHCl[PPh2(ortho-C6H4)CH2NHCH2)]2 and RuHCl[PPh2(ortho-C6H4)CH2NHCMe2)]2 are known to be catalysts for the hydrogenation of acetophenone and benzonitrile in toluene when activated by KOtBu/KH. DFT studies were performed and a mechanism is proposed. The calculated rate limiting step for acetone hydrogenation was found to be heterolytic splitting of dihydrogen, which agrees well with experiment. The novel outer-sphere sequential hydrogenation of a CN triple bond and then a C=N double bond is proposed. A mechanism is proposed, which is supported by DFT studies, to explain the selectivity observed in the nucleophilic attack of amines or aziridines on palladium -prenyl phosphines complexes. Calculations on based on a palladium complex with two phosphorus donor ligands indicated that the observed selectivity would not be produced. Using two new model intermediates with either THF or aziridine substituted for a phosphine ligand trans to the unhindered side of the prenyl ligand did predict the experimentally observed selectivity.

The results of kinetic isotope determination and computational studies on Noyori-type catalytic systems for the hydrogenation of ketones are presented. The catalysts examined include RuH2(NHCMe2CMe2NH2)(R-binap) and RuH(NHCMe2CMe2NH2)(PPh3)2. These complexes are active catalysts for ketone hydrogenation in benzene without addition of an external base. The kinetic isotope effect (KIE) for catalysis by RuH2(NHCMe2CMe2NH2)(R-binap) was determined to be 2.0 ± (0.1). The calculated KIE for the model system RuH(NHCH2CH2NH2)(PH3)2 was 1.3, which is smaller than the experimentally observed value but does not include tunneling effects. The complex OsH(NHCMe2CMe2NH2)(PPh3)2 is known to display autocatalytic behaviour when it catalyzes the hydrogenation of acetophenone in benzene. Pseudo first-order reaction conditions are obtained via addition of the product alcohol at the beginning of each kinetic experiment. The KIE determined using various combinations of deuterium-labeled gas, alcohol and ketone was found to be 1.1 ± (0.2). DFT calculations were used to explore the effect of the alcohol and the KIE. An induction period is observed at the start of the hydrogenation that is attributed to the formation of an alkoxide complex. A novel, diamine-orchestrated hydrogen-bonding network is proposed based on DFT calculations to explain how the alkoxide is converted back to the active catalyst. The tetradentate complexes trans-RuHCl[PPh2(ortho-C6H4)CH2NHCH2)]2 and RuHCl[PPh2(ortho-C6H4)CH2NHCMe2)]2 are known to be catalysts for the hydrogenation of acetophenone and benzonitrile in toluene when activated by KOtBu/KH. DFT studies were performed and a mechanism is proposed. The calculated rate limiting step for acetone hydrogenation was found to be heterolytic splitting of dihydrogen, which agrees well with experiment. The novel outer-sphere sequential hydrogenation of a CN triple bond and then a C=N double bond is proposed. A mechanism is proposed, which is supported by DFT studies, to explain the selectivity observed in the nucleophilic attack of amines or aziridines on palladium -prenyl phosphines complexes. Calculations on based on a palladium complex with two phosphorus donor ligands indicated that the observed selectivity would not be produced. Using two new model intermediates with either THF or aziridine substituted for a phosphine ligand trans to the unhindered side of the prenyl ligand did predict the experimentally observed selectivity.

Thèse de doctorat : Chimie organique : Strasbourg 1 : 2008. / Titre provenant de l'écran-titre. Bibliogr. p. 105-110.

This doctoral dissertation described herein will be comprised of two parts. The first portion will address our efforts towards the synthesis of [alpha]-amino carbonyls from silyl enol ethers and the second portion will describe our unrelated efforts towards the synthesis of proaporphine alkaloids. A full discussion of the relevant literature, experiments and development of the methodologies will be provided along with all relevant experimental data. Part I: The [alpha]-amino carbonyl moiety has great potential for being a very useful synthetic intermediate for the incorporation of nitrogen owing to the synthetic utility and versatility of the carbonyl functional group. Despite this potential the synthesis has long been problematic owing to their tendency to undergo condensation reactions. We aimed to synthesize them utilizing a protected carbonyl in the form of a triisopropylsilyl enol ether and an electrophilic nitrogen source that could incorporate the nitrogen via an ene-[2,3] sigmatropic reaction sequence. To this end we used an N-sulfinyl carbamate as an electrophilic source of nitrogen that could be utilized for a regiospecific allylic amination of alkenes or could be used to form a highly reactive sulfur diimide that could be used for the allylic amination of alkenes or silyl enol ethers. Part II: Many pharmacologically important and synthetically interesting alkaloids have been formed in nature by the o,p oxidative phenolic coupling of various benzyl-tetrahydroisoquinoline alkaloids. One major class of alkaloids derived from this generalized oxidation is the proaporphine alkaloids and they possess an acid labile spirocyclic-dienone system obtained from this coupling. These compounds have great potential for being used for their anesthetic properties. Despite the relative ease of synthesizing the benzylisoquinoline alkaloids the application of the biomimetic oxidative coupling to make the quaternary center of these compounds gives very poor yields. We opted to form this spiro-dienone system by using a two step Suzuki coupling-para phenolate alkylation methodology that had been used to synthesize the related alkaloids codeine and narwedeine. In doing this we opted to extend the practical application of this methodology by the displacement of an alcohol derived leaving group. / text

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.

The synthesis, structure, and reactivity of some organometallic-fusedheterocycles were studied. This work was divided into three parts: first,thiapentalenyl tricarbonyl manganese complexes [Mn(CO)3{??5-SC7H3-1,3-(R)2}]were synthesized employing thiation on diacyl precursors; second, attempts toform the 5,5-fused ring pyrrole analogs to the thiapentalenyl complexes led to theformation of various amine and imine ligands and manganese complexes, but notthe desired ring-closed pyrroles; third, reductive amination on a ferrocenylmonoaldehyde substrate led to the formation of di(N-(ferrocenylmethyl))-Nmethylamineand its cyanoborane and cyanoborohydride analogs.Isolation of the desired thiapentalenyl manganese complexes wasaccomplished by first forming 1,2-diacylcyclopentadienes (fulvenes), convertingto the corresponding thallium salts [Tl{1,2-C5H3(COR)2}] employing thalliumethoxide, transmetallating with [Mn(CO)5Br], and ring closing using either P4S10or Lawesson's Reagent. Ring closure from the diacylmanganese complexes[Mn(CO)3{??5-1,2-C5H3(COR)2}] gave air stable thiapentalenyl complexes inmoderate to good yield and was tolerable to a variety of functional groups (aryl,arylacetyl, t-butyl). In the cases where 1,2-diarylacetyl complexes wereemployed, the isolated products were "quinoidal". While ring closure on thecorresponding diacylrhenium tricarbonyl complexes was not feasible, it wasobserved that these quinoidal thiapentalenyl structures could be formed on aruthenium Cp* moiety using the arylacetyl fulvenes.Various keto-amines or enol-imines could be formed from the 1,2-dibenzoyl fulvene employing primary amines (R = H, Me, OH, OMe). In thepresence of a reducing agent, neither reduction nor ring closure was observedfor any of the cases investigated. Formation of the corresponding manganesetricarbonyl complex for the methyoxyimine case was accomplished by reaction ofthe enol-methoxyimine with thallium ethoxide and then transmetallating with[Mn(CO)5Br]. Reaction of this keto-imine complex with various reducing agentsdid not lead to the desired 5,5-fused ring pyrrole complex but to reduction to thecorresponding alcohol.Diferrocenylmethyl methylamine complexes were obtained by reaction offerrocene monoaldehyde with ferrocenylmethyl methylamine in the presence of amild reducing agent (NaCNBH3). Isolation under anhydrous conditions gave theunexpected cyanoborohydride salt, di(N-(ferrocenylmethyl))-N-methylammoniumcyanoborohydride. Aqueous work-up gave the corresponding free amine.Conversion of the cyanoborohydride salt to the corresponding cyanoborane,di(N-(ferrocenylmethyl))-N-methylammonium–cyanoborane, was accomplishedby refluxing the cyanoborohydride salt in THF.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references. Also available in print.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 186-194).