Rapid synthesis of an electron-deficient t-BuPHOX ligand: cross-coupling of aryl bromides with secondary phosphine oxides

Herein an efficient and direct copper-catalyzed coupling of oxazoline-containing aryl bromides with electron-deficient secondary phosphine oxides is reported. The resulting tertiary phosphine oxides can be reduced to prepare a range of PHOX ligands. The presented strategy is a useful alternative to known methods for constructing PHOX derivatives

Activation biofonctionnelle de liaisons N-H et diamination d'alcènes catalysée par métaux de transition

Cette thèse traite de l'activation de liaisons N-H ainsi que du transfert catalytique d'atome d azote vers des alcènes non-activés. Dans une première partie, l'activation des liaisons N-H par des métaux de transition du groupe VIII a été étudiée. Il a été démontré que les complexes de Ru, Rh et Ir basés sur les catalyseurs d'hydrogénation de transfert de Noyori activent la liaison N-H des amides avec une grande bande passante en acidité (Schéma 1). Ainsi, des complexes énantiomériquement purs d'acrylamide, benzamide et de divers sulfonamides ont pu être isolés. Ils présentent une grande stabilité et deux parmi douze ont été caractérisés à l'aide d'une structure aux rayons X. Pendant la formation extrêmement rapide du complexe (seulement quelques secondes à - 60C dans THF-d8), un rapide échange des hydrogènes des atomes d'azote du ligand a eu lieu comme observé pour les amides deutérés.La seconde partie de la thèse traite de la transformation d'alcènes désactivés en une fonction azotée. La première diamination catalysée d'oléfines a ainsi été développée (Schéma 2). Les N-tosylurées, liées à un alcène, permettent une réaction de diamination hautement sélective lors de l ajout, en quantités catalytiques, d'acétate de palladium, d 1 éq. NaOAc/Me4NCl (1:1, n/n) et de (diacetoxyiodo)benzène en tant qu oxydant.Cette réaction permet d'obtenir de très bon rendement dans le cas d'une diamination. Elle est réalisable á température ambiante et ne nécessite pas de conditions strictes. Il n'y a pas de dépendance significative à la polarité du solvant ou à la source de Pd(II) utilisée. La réaction est entièrement diastéreoselective et se produit via un mécanisme Pd(II)/(IV) qui consiste en une syn-aminopalladation, une oxydation du Pd(II) en Pd(IV) et enfin une élimination anti réductrice de Pd(II) (Schéma 3).L'inconvénient majeur d'une telle méthode de développement réside en la déprotection difficile des imidazolidinones résultantes, en diamines libres. Ainsi la diamination des sulfamides correspondants, portant des groupes protecteurs différents, a été envisagée. Lorsque les conditions de la précédente catalyse au palladium ont été appliquées à ces substrats, une aminoacétoxylation selective a été observée. Etonnamment, une expérimentation plus poussée a révélé que, non seulement les urées, mais également les sulfamides et les guanidines cyclisent de façon sélective pour donner le produit de diamination. Les rendements sont élevés lorsque des sels de nickel(II) sont employés en tant que catalyseurs (Schéma 4). Des expériences sur des urées deutérées ont montré que l'une des deux étapes du mécanisme (aminométallation ou élimination réductrice) doit être inversée en comparaison avec la catalyse au palladium(II); étant donné que la configuration relative du produit est changée.Ainsi, cette diamination catalysée par du nickel est plus économique, les produits de départ sont facilement accessibles. Des expériences approfondies démontrent une déprotection facile, partielle ou totale, des sulfamides cyclisés. Ceci permet une application plus simple et plus diversifiée que le protocole palladium-urée.Pour démontrer l'applicabilité de la méthode décrite précédemment, une diamination de guanidines catalysée par du palladium a été établie. Plus précisément, l'oxydant dangereux pourrait être remplacé par du chlorure de cuivre(II) et 1 éq. de K2CO3 en tant que base se trouve être le meilleur choix. A nouveau, la réaction se fait de façon hautement sélective et conduit aux guanidines cycliques avec de très bons rendements. Ce protocole est une nette amélioration des guanidinylations connues dans la littérature qui consistent en de laborieuses synthèses multi-etapes (Schéma 5).Un travail sur une application de la diamination des guanidines dans la synthèse d'un produit naturel est toujours en cours et conclura la thèse en tant que dernier chapitre. Des recherches supplémentaires ont été effectuées sur la diamination des butadiènes et sont décrites en détail dans la thèse. Une variante de la diamination utilisant des bromures ainsi que des iodures en tant que catalyseurs a également été étudiée.The thesis deals with the activation of N-H bonds and the catalytic nitrogen transfer to unactivated alkenes. According to this the activation of nitrogenhydrogen bonds by group 8 transition metals was explored in the first part of the thesis. It was shown that ruthenium-, rhodium- and iridiumcomplexes based on the Noyori transferhydrogenation catalyst activate N-H bonds of amides with a great bandwidth in acidity. Thus enantiomerically pure, extremely stable metal complexes of acrylamides, benzamides or diverse sulfonamides could besolated. Two complexes out of twelve have been characterized by crystal structures. During the ultrafast complex formation (a few seconds at -60C in THF-d8) a fast scrambling of the hydrogens on the ligands' nitrogen atoms took place as observed for deuterated amides.The second Part of the thesis is about nitrogen functionalization of unactivated alkenes. The first catalyzed diamination of olefins was developed. N-tosylureas, tethered with an alkene, perform a highly selective diamination reaction when catalytic amounts of palladium acetate, 1eq. NaOAc/Me4NCl (1:1, n/n) and iodosobenzene diacetate as oxidant are added.The reaction gives very high yields of the diamination product, proceeds at room temperature and emerged to be very robust. There is no significant dependence on solvent polarity or the palladium(II) source applied. The completely diastereoselective reaction proceeds via a Pd(II)/(IV) mechanism which consists of a (syn)-Aminopalladation, oxidation to Pd(IV) and subsequent reductive (anti)- elimination of Pd(II).The major drawback of the such developed method is the difficult deprotection of the resulting imidazolidinones to the free diamine. Hence the diamination of corresponding sulfamides bearing different carbamate groups was envisioned. When the conditions of the previous palladium catalysis were applied to these substrates either selective aminoacetoxylation was observed. Surprisingly, further screening experiments revieled that not only ureas but also sulfamides and guanidines selectively cyclise to the diamination products in high yields when nickel(II) salts are employed as catalyst. Deuterium experiments on ureas showed that one of the two mechanistic steps (aminometallation or reductive elimination) must be inverted compared to the Pd(II) catalysis since the relative configuration of the product is changed. The thus developed nickel catalysed diamination is more economic, the starting materials are easily accessable and further experiments proof the facile partial or complete liberation of the free diamine from the cyclised sulfamides. This allows for an easier and more versatile follow-up chemistry compared to the palladiumurea protocol.To show the applicability of the previously described methodology a palladium catalysed diamination of guanidines was established. More precisely the hazardous oxidant could be changed to copper(II) chloride and as base 1 eq. of K2CO3 prove to be the best choice. Again, the reaction proceeds highly selective and furnishes the cyclic guanidines in excellent yields. This protocol is a great improvement to literature known guanidinylations which consist of laborious multiple step syntheses. Work on an application of the diamination of guanidines in natural product synthesis is still in progress and will conclude the thesis as the last chapter. Additional investigations have been carried out on the diamination of butadienes and are described within the thesis in detail. Also a diamination variant employing bromides or iodides as catalysts has been worked out.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Kinetic Analysis Uncovers Hidden Autocatalysis and Inhibition Pathways in Titanium(III)-Catalyzed Ketone-Nitrile Couplings

Through kinetic analysis, we demonstrate that the formation of catalyst and substrate reservoirs plays a crucial role in the titanium(III)-catalyzed ketone-nitrile coupling reaction. Together with the insight from previous studies, a kinetic model is assembled that reflects the observed influence of ZnCl2 and Et3N byproducts as well as the hydrochloride additive, which is employed frequently in titanium(III) catalysis. We further propose for the Cp2TiCl2 -catalyzed reaction that the acceleration phase of the reaction originates from a hidden autocatalytic cycle, which leads to a change in the rate-determining step over the course of the reaction

Catalytic Asymmetric β‐Oxygen Elimination

A catalytic enantioselective beta-O-elimination reaction is reported in the form of a zirconium-catalyzed asymmetric opening of meso-ketene acetals. Furthermore, a regiodivergent beta-O-elimination is demonstrated. The reaction proceeds under mild conditions, at low catalyst loadings, and produces chiral monoprotected cis-1,2-diols in good yield and enantiomeric excess. The combination with a Mitsunobu reaction or a one-pot hydroboration/Suzuki reaction sequence then gives access to additional diol and aminoalcohol building blocks. A stereochemical analysis supported by DFT calculations reveals that a high selectivity in the hydrozirconation step is also important for achieving high enantioselectivity, although it does not constitute the asymmetric step. This insight is crucial for the future development of related asymmetric beta-elimination reactions

Catalytic Asymmetric β-Oxygen Elimination

A catalytic enantioselective β-O-elimination reaction is reported in the form of a zirconium-catalyzed asymmetric opening of meso-ketene acetals. Furthermore, a regiodivergent β-O-elimination is demonstrated. The reaction proceeds under mild conditions, at low catalyst loadings, and produces chiral monoprotected 1,2-diol building blocks in good yield and enantiomeric excess. The combination with a Mitsunobu reaction then gives access to all 1,2-diol stereoisomers and trans-1,2-aminoalcohols in high enantiomeric purity. A stereochemical analysis supported by DFT calculations reveals that a high selectivity in the hydrozirconation step is also important for achieving high enantioselectivity, although it does not constitute the asymmetric step. This insight is crucial for the future development of related asymmetric β-elimination reactions

A Guide to Low-Valent Titanocene Complexes as Tunable Single-Electron Transfer Catalysts for Applications in Organic Chemistry

Low-valent titanocene catalysts are a versatile tool for organic synthesis. They promote inter- and intramolecular reactions ranging from homolytic bond cleavages to reductive umpolung reactions to additions and cyclizations in single electron steps. These reactions heavily depend on the redox potential of an in situ formed titanium(III) center, which can be adjusted by the choice of appropriate ligands. We herein review various chiral and achiral ligand-modified titanocene catalysts and their reduction potentials E-p/2 obtained via cyclic voltammetry. The latter are found to correlate with the Hammett parameters sigma(p) of the cyclopentadienyl substituents and to the pK(a) values of the corresponding acids of the Ti-X ligands. For selected examples, we further discuss how the adjustment of the redox properties through modifications of the titanocene ligands can lead to greatly improved reaction outcomes in titanium(III) catalyzed single-electron transfer reactions

Methoxide-Enabled Zirconium-Catalyzed Migratory Alkene Hydrosilylation

A Cp2ZrCl2-catalyzed alkene hydrosilylation is reported that can be applied to non-activated and conjugated terminal and internal alkenes. It involves a catalytic Zr-walk process and leads to a selective conversion to the linear product. Lithium methoxide serves as mild catalyst activating agent, which significantly increases the applicability and operational simplicity in comparison to earlier zirconium(II)-based protocols. Supported by additional experiments, a mechanism via zirconium(IV) intermediates is proposed. Due to the benign nature and ready-availability of the zirconium catalyst, the reaction is an attractive alternative to established alkene hydrosilylation methods

Amidato complexes of ruthenium, rhodium and iridium from concise NeH bond activation: exploration in catalysis

Acceptor-substituted N-H groups as found in carbamides and sulfonamides are readily activated through suitable unsaturated metal complexes applying the concept of metal-ligand bifunctionality. This process constitutes the basis for an enantioselective intramolecular addition of N-H groups onto activated alkenes. The resulting compounds can also be employed as catalyst precursors for transferhydrogenation.</p

Palladium-Catalyzed Intramolecular Diamination of Acrylic Esters Using Sulfamates as Nitrogen Source

An intramolecular diamination of acrylates is reported using sulfamates as nitrogen sources. This reaction proceeds under palladium­(II) catalysis with copper bromide as oxidant and gives rise to <i>anti</i>-configured 2,3-diamino carboxylates as bicyclic sulfamate derivatives. An aminobrominated intermediate within the diamination reaction was isolated that allowed to clarify the reaction mechanism and to rationalize the observed preferential product stereochemistry