Pd0-Catalyzed Intramoleculara-Arylation of Sulfones: Domino Reactions in the Synthesis of Functionalized Tetrahydroisoquinolines

A new strategy for the synthesis of tetrahydroisoquinolines based on the Pd(0)-catalyzed intramolecular α-arylation of sulfones is reported. The combination of this Pd-catalyzed reaction with intermolecular Michael and aza-Michael reactions allows the development of two- and three-step domino processes to synthesize diversely functionalized scaffolds from readily available starting materials. KEYWORDS: arylation; domino reactions; nitrogen heterocycles; palladium; sulfone

Palladium-catalysed intramolecular carbenoid insertion of α-diazo α-(methoxycarbonyl)acetanilides for oxindole synthesis

A novel, selective palladium-catalysed carbenoid C(aryl)-H insertion of α-diazo-α-(methoxycarbonyl)acetanilides leading to oxindoles is described

Palladium catalysis in intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to form β-lactams

The intramolecular carbene C-H insertion of α‐diazo‐α‐(methoxycarbonyl)acetamides leading to β‐lactams is effectively catalyzed by palladium complexes. It is found that although Pd0 catalysts typically produce mixtures of β‐lactams together with Buchner‐type reaction products, the use of PdII catalysts results in highly chemoselective transformations. According to DFT calculations, this insertion reaction occurs stepwise and involves an unprecedented PdII‐promoted Mannich‐type reaction through a metallacarbene‐induced zwitterionic intermediate

Exploring Partners for the Domino α‐Arylation/Michael Addition Reaction Leading to Tetrahydroisoquinolines

Sulfonates, sulfonamides, and phosphonates have proven useful nucleophiles for palladium‐catalyzed intramolecular α‐arylation reactions leading to tetrahydroisoquinolines. Although the sulfonate α‐arylation reaction can be successfully combined in a domino process with a broad range of Michael acceptors, only vinyl sulfones can be used in Michael additions when starting from sulfonamides. No domino process was developed with the phosphonate derivative. DFT calculations were carried out to gain more insights into the experimental differences observed in the reactions involving these substrates

Pd-Catalyzed α-Arylation of Sulfones in a Three-Component Synthesis of 3-[2-(Phenyl/methylsulfonyl)ethyl]indoles

A novel four-step domino process for the synthesis of 3-[2-(aryl/alkylsulfonyl)ethyl]indoles starting from readily available 2-iodoanilines is reported. The domino reaction is based on the intramolecular palladium-catalyzed α-arylation of sulfones, which was combined with both intermolecular aza-Michael and Michael addition reactions using vinyl sulfones as the electrophile. The domino process produced good yields and tolerated the presence of substituents with different electronic properties on the aniline ring. In addition, density functional theory (DFT) calculations were carried out to gain more insight into the formation of the observed indole derivatives. Keywords: arylation; density functional calculations; domino reactions; indoles; palladium-catalyze

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

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort

Background Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster.Methods Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3.Results Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3.Conclusions During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis

Palladium in azaheterocyclic synthesis: α-arylation of sulfones, domino processes and C-H carbene insertion reactions

[eng] Next, the intramolecular palladium catalysed α-arylation reaction was explored using nucleophiles derived from sulfonates, sulfonamides and phosphonates. Although feasible, these nucleophiles are less efficient in the intramolecular cyclization leading to the tetrahydroisoquinoline ring. Domino processes based on α-arylation/Michael addition reactions starting from sulfonates and sulfonamides using diverse Michael acceptors were also reported. Attempts to pursue domino process starting from phosphonates were unsuccessful. In the second part of the thesis, a synthetic methodology for the synthesis of nitrogen heterocycles based on palladium catalysed decomposition of α- diazoacetamidas was studied. Decomposition of α-diazo-α-(methoxycarbonyl) acetanilides catalyzed by palladium leads to the chemoselective Csp2-H insertion and the synthesis of oxindole type products. Although Pd(0) and Pd(II) catalysts are able to promote this transformation, Pd(0) catalysts such as Pd2(dba)3 or [IMes)Pd(NQ)]2 yield the best results. DFT calculations suggest that the insertion reaction involves a novel stepwise mechanism that implies a palladium mediated 1,5-hidrogen migration followed by reductive elimination that yields two products: the insertion product and the Pd(0) catalyst. Finally, we studied the palladium catalysed decomposition of α-diazo-α- (methoxycarbonyl) acetamides to promote intramolecular Csp3-H insertion to form β-lactams. In these transformations, though both Pd (0) and Pd(II) catalysts can be used, Pd(II) complexes were found to be the most versatile and efficient.[spa] De entre todos los metales de transición utilizados en síntesis orgánica, el paladio ha ocupado un lugar central durante décadas y ha sido uno de los metales que más ha contribuido al desarrollo de este campo. En la presente Tesis Doctoral se han desarrollado diversas metodologías para la síntesis de heterociclos nitrogenados basados en procesos dominó catalizados por paladio. Por otro lado, los estudios experimentales se han combinado con estudios computacionales DFT para desentrañar el mecanismo implicado en estas transformaciones. En la primera parte de la Tesis Doctoral se ha llevado a cabo un extenso estudio de la reacción de α-arilación intramolecular de sulfonas catalizado por paladio. La combinación de la reacción de α-arilación con la subsiguiente adición conjugada a diversos aceptores de Michael, ha permitido el desarrollo de procesos dominó en 2, 3 y 4 etapas para la síntesis de tetrahidroisoquinolinas e indoles diversamente funcionalizados. Los estudios computacionales DFT de este proceso para la formación de indoles sugieren que la reacción de α-arilación transcurre mediante un proceso de desprotonación-metalación concertado (CMD) seguido de una eliminación reductora. H SO2R' SO2R' Pd(0) I base SO2R' SO2R' PhO2S SO2R' n= 0,1 N n Aza-Michael N -arilación N n n adición N R conjugada n=1 SO2R' SO2R' adición conjugada n=0 R'O2S SO2R' N -eliminación N R R A continuación, la reacción de α-arilación intramolecular catalizada por paladio se ha extendido a la utilización de sulfonatos, sulfonamidas y fosfonatos. Aunque los tres tipos de nucleófilos pueden utilizarse en la reacción de α-arilación para la preparación de tetrahidroisoquinolinas, la reacción transcurre de manera menos eficiente en relación a las sulfonas estudiadas. Asimismo, la versatilidad de los procesos dominó desarrollados a partir de ésteres sulfónicos y sulfonamidas fue menor. Por otro lado, los fosfonatos han resultado ser completamente inactivos en los diferentes procesos domino estudiados. La reacción de α-arilación de sulfonatos, sulfonamidas y ésteres sulfónicos también se ha estudiado computacionalmente. Estos estudios han puesto de manifiesto que la reacción transcurre por mecanismos distintos en función del nucleófilo y de la base utilizada. En la segunda parte de la Tesis, se ha estudiado la viabilidad de los complejos de paladio en reacciones de inserción de carbenos en enlaces C-H generados a partir de α-diazoacetamidas. La descomposición de las α-diazo-α-(metoxicarbonil) acetanilidas catalizadas por complejos de paladio ha dado lugar a la formación de oxindoles como resultado de una inserción quimioselectiva en el enlace Csp2-H. Aunque tanto los catalizadores de Pd(0) como los de Pd(II) pueden promover esta reacción de inserción, los mejores resultados se han obtenido al utilizar complejos de Pd(0), en especial Pd2(dba)3 o [(IMes)Pd(NQ)]2. Los cálculos computacionales DFT de este proceso sugieren que la inserción tiene lugar mediante un mecanismo por etapas inédito que implica una migración 1,5 de hidrógeno promovida por el paladio seguido de un proceso de eliminación reductora. Finalmente, también se ha estudiado la descomposición de α-diazo-α- (metoxicarbonil) acetamidas catalizada por paladio para promover inserciones Csp3-H y la formación de β-lactamas. Aunque tanto los catalizadores de Pd(0) como de Pd(II) son capaces de promover esta reacción, los catalizadores de Pd(II) son más eficientes y versátiles

Pd0-Catalyzed Intramoleculara-Arylation of Sulfones: Domino Reactions in the Synthesis of Functionalized Tetrahydroisoquinolines

A new strategy for the synthesis of tetrahydroisoquinolines based on the Pd(0)-catalyzed intramolecular α-arylation of sulfones is reported. The combination of this Pd-catalyzed reaction with intermolecular Michael and aza-Michael reactions allows the development of two- and three-step domino processes to synthesize diversely functionalized scaffolds from readily available starting materials. KEYWORDS: arylation; domino reactions; nitrogen heterocycles; palladium; sulfone