Transition Metal-catalysed intramolecular carbenoid C-H insertion for pyrrolidine formation by decomposition of α-diazoesters

The use of Pd‐, Rh(II)‐ and Ru(II)‐based catalysts has been explored in the transition metal‐catalysed intramolecular carbenoid C−H insertion of α‐diazoesters leading to pyrrolidines. Although the outcome of the reaction was highly substrate‐dependent, in general, it was possible to control the chemoselectivity of the process towards pyrrolidines by adequate catalyst selection. The Pd(0)‐catalysts were as efficient as [Rh(Ph3CCO2)2]2 in promoting the C(sp3)−H insertion of ortho‐substituted anilines. In contrast, for anilines bearing meta‐ and para‐substituents, the Rh(II)‐catalyst provided the best chemoselectivities and reaction yields. On the other hand, [Ru(p‐cymene)Cl2]2 was the most efficient catalyst for the insertion reaction of the N‐benzyl‐N‐phenyl and N,N‐dibenzyl α‐diazoesters, while the C(sp3)−H insertion of the N‐benzylsulfonamide substrate was only promoted by [Rh(Ph3CCO2)2]2. According to density functional theory (DFT) calculations, the mechanism involved in the Pd(0)‐ and Ru(II)‐catalysed C(sp3)−H insertions differs considerably from that typically proposed for the Rh(II)‐catalysed transformation. Whereas the Pd(0)‐catalysed reaction involves a Pd‐mediated 1,5‐H migration from the C(sp3)−H bond to the carbenoid carbon atom leading to the formal oxidation of the transition metal, a Ru(II)‐promoted Mannich type reaction involving a zwitterionic intermediate seems to be operative in the Ru(II)‐catalysed transformation. Keywords: carbenoid insertion; diazo compounds; pyrrolidines; palladium-catalysis; density functional theory calculation

Site Selectivity in Pd-Catalyzed Reactions of α-Diazo-α-(methoxycarbonyl)acetamides: Effects of Catalysts and Substrate Substitution in the Synthesis of Oxindoles and β-Lactams

The Pd-catalyzed intramolecular carbene C–H insertion of α-diazo-α-(methoxycarbonyl)acetamides to prepare oxindoles as well as β-lactams was studied. In order to identify what factors influence the selectivity of the processes, we explored how the reactions are affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found that, in the synthesis of oxindoles, ((IMes)Pd(NQ))2 can be used as an alternative to Pd2(dba)3 to catalyze the carbene CArsp2–H insertion, although it was less versatile. On the other hand, it was demonstrated that the Csp3–H insertion leading to β-lactams can be effectively promoted by both Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms involved in these transformations was provided by DFT calculations

Palladium, ruthenium and iron in intramolecular transition metal-catalyzed carbene functionalization reactions of amino-tethered α-diazoesters

[eng] Transition metal-catalyzed intramolecular C–H insertions of diazo compounds represent one of the most elegant and versatile methods in organic synthesis for the construction of carbocyclic and heterocyclic frameworks. In these reactions a C–C bond is formed with high atom economy, with N2 gas being the only subproduct. In the last years, in the context of a research program aimed at developing efficient methodologies for the synthesis of nitrogen heterocycles, our research group has been studying the transition metal-catalyzed decomposition of amino-tethered α - diazo carbonyl compounds. Specifically, we have reported that palladium catalysts are able to promote the intramolecular carbene C–H insertions to produce pyrrolidines from α-diazoesters, and oxindoles as well as β-lactams from α -diazo- α - (methoxycarbonyl)acetamides. As a continuation of these studies, in this Thesis we first explored the use of Pd, Rh(II) and Ru(II)-based catalysts for the intramolecular carbene C(sp3)–H insertion of γ - amino-α-diazoesters leading to pyrrolidines. Our comparative study allowed us to identify differences in the reactivities and selectivities between the different transition metals. The results obtained in these annulation reactions show that, although the chemoselectivity of the process is highly substrate-dependent, it can be controlled by adequate catalyst selection. Taking this work as a reference, we then investigated the use of some structurally diverse Ru(II)-complexes to promote the C(sp3)–H insertion of γ-amino-α-diazoesters to form pyrrolidines. In this context, we have described the first examples of an unprecedented non-metathetic chemistry of Grubbs complexes, which were applied to achieve this target. Moreover, in our preliminary attempts to develop an enantioselective version of this carbene C(sp3)–H insertion reaction, we focused our attention on the use of different chiral Ru(II)-catalysts. We also investigated the synthesis of tetrahydroquinolines by transition metal- catalyzed intramolecular aromatic CAr(sp2)-H functionalization of γ -anilino α-diazoesters. Both palladium(0)- and Grubbs catalysts were explored for this purpose. Finally, we broadened our investigation on the transition metal-catalyzed decomposition of amino-tethered diazoesters by exploring the reactions of δ−amino and β-amino α-diazoesters. Some diverse palladium and ruthenium complexes as well as different iron salts were studied.[spa] Las reacciones de inserción intramolecular de diazocompuestos en enlaces C–H catalizadas por metales de transición se han convertido en una metodología extraordinariamente versátil para la construcción de sistemas carbocíclicos y heterocíclicos. En estas reacciones, la formación del enlace C–C tiene lugar con una economía atómica considerable ya que se genera N2 gas como único subproducto. Durante los últimos años, como parte de un ambicioso proyecto de investigación enfocado al desarrollo de metodologías más eficientes para la síntesis de heterociclos nitrogenados, en nuestro grupo de investigación se ha estudiado la inserción de carbenos metálicos derivados de compuestos α-diazocarbonilicos en enlaces C–H. En este contexto, se ha demostrado que los catalizadores de paladio pueden promover la inserción intramolecular de carbenos generados a partir de diferentes compuestos α- diazocarbonilicos. En concreto, se ha descrito su utilización en la síntesis de pirrolidinas a partir de α-diazoésteres, y de oxindoles y β-lactamas a partir de α-diazo-α- (metoxycarbonil)acetamidas. Como continuación de estos estudios y con el objetivo de desarrollar una metodología más eficiente para la síntesis de pirrolidinas, en la primera parte de la presente tesis doctoral nos propusimos explorar la viabilidad de diversos complejos de Pd, Rh(II) y Ru(II)como catalizadores en la reacción de inserción en enlaces C(sp3)–H a partir de γ - amino-α-diazoésteres. Este estudio comparativo ha permitido identificar las diferencias de reactividad y selectividad entre los distintos metales de transición. Los resultados obtenidos han puesto de manifiesto que la quimioselectividad de la reacción, aunque es altamente dependiente de la estructura del substrato, puede controlarse mediante una adecuada selección del catalizador. Seguidamente, decidimos explorar la utilización de otros complejos de Ru(II), escogidos en base a su considerable diversidad estructural, como catalizadores de la inserción en enlaces C(sp3)–H a partir de γ -amino-α-diazoésteres. En este contexto, hemos demostrado que los complejos de Grubbs también pueden emplearse para promover la inserción de carbenos en enlaces C(sp3)–H para preparar pirrolidinas. Este trabajo constituye el primer ejemplo de la utilización de este tipo de catalizadores en reacciones de inserción, una transformación química muy distinta de su aplicación clásica en las reacciones de metátesis. En este mismo contexto, hemos realizado también un estudio preliminar encaminado al desarrollo de una versión enantioselectiva de la reacción de inserción, utilizando distintos catalizadores de Ru(II) quirales. Por otro lado, hemos desarrollado un procedimiento para la síntesis de tetrahidroquinolinas mediante la inserción intramolecular de carbenos generados a partir de γ -anilino-α-diazoésteres en enlaces C(sp2)–H aromáticos. Para esta reacción se han explorado tanto los catalizadores de Pd(0) como los complejos de Grubbs. Finalmente, hemos ampliado nuestra investigación acerca de la utilización de distintos metales de transición para promover la descomposición de compuestos α- diazocarbonilicos con el estudio de la reacción a partir de δ-amino- y β-amino-α- diazoésteres. Para ello hemos explorado la utilización de distintos complejos de paladio y rutenio, así como de sales de hierro

Cyrene: A Green Solvent for the Synthesis of Bioactive Molecules and Functional Biomaterials

In the panorama of sustainable chemistry, the use of green solvents is increasingly emerging for the optimization of more eco-friendly processes which look to a future of biocompatibility and recycling. The green solvent Cyrene, obtained from biomass via a two-step synthesis, is increasingly being introduced as the solvent of choice for the development of green synthetic transformations and for the production of biomaterials, thanks to its interesting biocompatibility, non-toxic and non-mutagenic properties. Our review offers an overview of the most important organic reactions that have been investigated to date in Cyrene as a medium, in particular focusing on those that could potentially lead to the formation of relevant chemical bonds in bioactive molecules. On the other hand, a description of the employment of Cyrene in the production of biomaterials has also been taken into consideration, providing a point-by-point overview of the use of Cyrene to date in the aforementioned fields

Palladium‐ and Ruthenium‐Catalyzed Intramolecular Carbene CAr−H Functionalization of γ‐Amino‐α‐diazoesters for the Synthesis of Tetrahydroquinolines

A synthetic method to prepare tetrahydroquinoline‐4‐carboxylic acid esters has been developed through the transition‐metal‐catalyzed intramolecular aromatic C−H functionalization of α‐diazoesters. Both [{Pd(IMes)(NQ)}2] (IMes=1,3‐dimesitylimidazol‐2‐ylidene, NQ=1,4‐naphthoquinone) and the first‐generation Grubbs catalyst proved effective for this purpose. The ruthenium catalyst was found to be the most versatile, although in a few cases the palladium complex afforded better yields or selectivities. According to DFT calculations, Pd0‐ and RuII‐catalyzed sp2‐CAr−H functionalization proceeds through different reaction mechanisms. Thus, the Pd0‐catalyzed reaction involves a Pd‐mediated 1,6‐H migration from the sp2‐CAr−H bond to the carbene carbon atom, followed by a reductive elimination process. In contrast, electrophilic addition of the ruthenacarbene intermediate to the aromatic ring and subsequent 1,2‐proton migration are operative in the Grubbs catalyst promoted reaction

Site selectivity in Pd-catalyzed reactions of α-diazo-α-(methoxycarbonyl)acetamides: effects of catalysts and substrate substitution in the synthesis of oxindoles and ß-lactams

The Pd-catalyzed intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to prepare oxindoles as well as β-lactams was studied. In order to identify what factors influence the selectivity of the processes, we explored how the reactions are affected by the catalyst type, using two oxidation states of Pd and a variety of ligands. It was found that, in the synthesis of oxindoles, ((IMes)Pd(NQ))2 can be used as an alternative to Pd2(dba)3 to catalyze the carbene CArsp2-H insertion, although it was less versatile. On the other hand, it was demonstrated that the Csp3-H insertion leading to β-lactams can be effectively promoted by both Pd(0) and Pd(II) catalysts, the latter being most efficient. Insight into the reaction mechanisms involved in these transformations was provided by DFT calculations

Transition Metal-catalysed intramolecular carbenoid C-H insertion for pyrrolidine formation by decomposition of α-diazoesters

The use of Pd‐, Rh(II)‐ and Ru(II)‐based catalysts has been explored in the transition metal‐catalysed intramolecular carbenoid C−H insertion of α‐diazoesters leading to pyrrolidines. Although the outcome of the reaction was highly substrate‐dependent, in general, it was possible to control the chemoselectivity of the process towards pyrrolidines by adequate catalyst selection. The Pd(0)‐catalysts were as efficient as [Rh(Ph3CCO2)2]2 in promoting the C(sp3)−H insertion of ortho‐substituted anilines. In contrast, for anilines bearing meta‐ and para‐substituents, the Rh(II)‐catalyst provided the best chemoselectivities and reaction yields. On the other hand, [Ru(p‐cymene)Cl2]2 was the most efficient catalyst for the insertion reaction of the N‐benzyl‐N‐phenyl and N,N‐dibenzyl α‐diazoesters, while the C(sp3)−H insertion of the N‐benzylsulfonamide substrate was only promoted by [Rh(Ph3CCO2)2]2. According to density functional theory (DFT) calculations, the mechanism involved in the Pd(0)‐ and Ru(II)‐catalysed C(sp3)−H insertions differs considerably from that typically proposed for the Rh(II)‐catalysed transformation. Whereas the Pd(0)‐catalysed reaction involves a Pd‐mediated 1,5‐H migration from the C(sp3)−H bond to the carbenoid carbon atom leading to the formal oxidation of the transition metal, a Ru(II)‐promoted Mannich type reaction involving a zwitterionic intermediate seems to be operative in the Ru(II)‐catalysed transformation. Keywords: carbenoid insertion; diazo compounds; pyrrolidines; palladium-catalysis; density functional theory calculation

Dual Functionalized Liposomes for Selective Delivery of Poorly Soluble Drugs to Inflamed Brain Regions

Dual functionalized liposomes were developed to cross the blood–brain barrier (BBB) and to release their cargo in a pathological matrix metalloproteinase (MMP)-rich microenvironment. Liposomes were surface-functionalized with a modified peptide deriving from the receptor-binding domain of apolipoprotein E (mApoE), known to promote cargo delivery to the brain across the BBB in vitro and in vivo; and with an MMP-sensitive moiety for an MMP-triggered drug release. Different MMP-sensitive peptides were functionalized at both ends with hydrophobic stearate tails to yield MMP-sensitive lipopeptides (MSLPs), which were assembled into mApoE liposomes. The resulting bi-functional liposomes (i) displayed a −5 cm/min; (iii) when exposed to functional MMP2 or 9, efficiently released an encapsulated fluorescein dye; (iv) showed high biocompatibility when tested in neuronal cultures; and (v) when loaded with glibenclamide, a drug candidate with poor aqueous solubility, reduced the release of proinflammatory cytokines from activated microglial cells