Transition Metal Catalyzed Reductive Cyclization Reactions of Nitroarenes and Nitroalkenes

Nitroarenes are the entry point for the production of most nitrogen-containing aromatic compounds. Thus, any transformation that leads directly from them to the final product allows saving one or more synthetic steps. This review deals with homogeneously catalyzed reactions leading to the formation of N-heterocyclic compounds from nitroarenes or nitroalkenes in one pot. Reactions that lead to the intermediate formation of amines are not considered. Carbon monoxide is the most often employed reductant because it allows selective reactions, is cheap, and only produces CO2 as stoichiometric byproduct. However, the difficulty in handling pressurized CO has stimulated in recent years the development of CO-surrogates, that is molecules able to liberate CO during the reaction. The use of phosphines and diols has also been developed in conjunction with molybdenum catalysts. The review focusses in more detail on the literature in the period 2006\u20132018, but reference to earlier work is made when necessary to put recent results in a more general context

Palladium Catalyzed Reductive Cyclization of Nitrobiphenyls Using Formate Esters as CO Surrogates

Palladium complexes with phenanthroline ligands are so far the most effective catalysts for the reductive cyclization of nitroarenes by carbon monoxide to yield a variety of heterocyclic compounds.[1] Despite the high efficiency and the high atom-economical character of many of these reactions, they have not become of widespread use. This is mainly attributed to the need for pressurized CO and pressure equipment (requiring CO safety measures). In the aim of turning this kind of reaction into a \u201cgeneral tool\u201d for the synthetic chemist, we developed a procedure based on the use of phenyl formate as an in situ source of CO. The reaction can be performed in a glass pressure tube, a cheap equipment accessible to every laboratory. Our previous work was mainly focused on the synthesis of indoles by reductive cyclization of o-nitrostyrenes[2] and oxazines by the hetero Diels-Alder condensation of a conjugated diene with a nitrosoarene formed in situ by the reduction of the starting nitroarene.[3] However, the application of the previously developed method to the reductive cyclization of 2-nitrobiphenyls to carbazoles (Scheme 1) afforded only moderate yields even under harsher conditions and higher catalyst loadings. The result is not totally unexpected since this reductive cyclization is known to be more difficult than the other previously studied. Here we report the results of our investigations on this reaction aimed at both improving the catalytic performance and better understanding the reaction mechanism

Synthesis of Oxazines by Palladium Catalyzed Reductive Cyclization of Nitroarenes and Dienes Using Phenyl Formate as CO Surrogate

The synthesis of hetero-Diels-Alder adducts derived from nitrosoarenes as dienophiles (oxazines) has been the focus of much attention in recent years, since these products have pharmacological activity themselves or can be easily transformed into other products. 1 However, their usual synthesis requires problematic intermediate isolation of nitroso compounds. We have previously reported a method for oxazines synthesis in up to 91% yields in one pot by the reaction of unfunctionalized dienes with nitroarenes and carbon monoxide.2 Despite the high efficiency of this synthetic procedure, it has not become of widespread use by the chemical community. This is mostly because it involves the use of pressurized CO, requiring safety measures that are not available in most synthetic organic laboratories. To overcome this limitation, we started investigating the use of molecules capable of releasing CO in situ, thus avoiding the need for high-pressure equipment and CO lines. Recently, we have reported3 an efficient, convenient and general synthetic procedure to produce nitrogen heterocycles from nitro compounds in presence of a Pd catalyst employing phenyl formate as the CO releasing agent. In this study, we take advantage of this general procedure in the synthesis of oxazines from dienes and nitroarenes (Figure 1). First, due to its high cost, the amount of the diene was optimized down to 1:4 nitroarene to diene ratio. The reaction works well for nitroarenes bearing either electron-donating or electron-withdrawing substituents, a moderate steric hindrance on the nitroarene is well tolerated and yields up to 99% in one pot were reached. In addition, variation in the diene were also investigated using 2,3-dimethoxy-1,3-butadiene, isoprene and myrcene affording the corresponding oxazines in good yields

Palladium/iodide catalyzed oxidative carbonylation of aniline to diphenylurea: Effect of ppm amounts of iron salts

The palladium/iodide couple is the most investigated catalytic system for the oxidative carbonylation of amines to give ureas or carbamates. In reinvestigating it, we found that the most prominent role of iodide is to etch the stainless steel of the autoclave employed in most of previous works, releasing in solution small amounts of iron salts. The latter are much better promoters than iodide itself. Iron and iodide have a complex interplay and, depending on relative ratios, can even deactivate each other. The presence of a halide is beneficial, but chloride is better than iodide in this respect. The ideal Fe/Pd ratio is around 10, but even an equimolar amount of iron with respect to palladium (0.02 mol% with respect to aniline, corresponding to 12 ppm Fe with respect to the whole solution) is sufficient to boost the activity of the catalytic system. Such small amount may also come from Fe(CO)5 impurities present in the CO gas when stored in steel tanks. The role of the solvent has also been investigated. It was found that the reason for the better selectivity in some cases is at least in part due to a hydrolysis of the solvent itself, which removes the coproduced water

Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review

[EN] Purpose: To systematically review evidence regarding the association of multi-parametric biomarkers with clinical outcomes and their capacity to explain relevant subcompartments of gliomas. Materials and Methods: Scopus database was searched for original journal papers from January 1st, 2007 to February 20th , 2017 according to PRISMA. Four hundred forty-nine abstracts of papers were reviewed and scored independently by two out of six authors. Based on those papers we analyzed associations between biomarkers, subcompartments within the tumor lesion, and clinical outcomes. From all the articles analyzed, the twenty-seven papers with the highest scores were highlighted to represent the evidence about MR imaging biomarkers associated with clinical outcomes. Similarly, eighteen studies defining subcompartments within the tumor region were also highlighted to represent the evidence of MR imaging biomarkers. Their reports were critically appraised according to the QUADAS-2 criteria. Results: It has been demonstrated that multi-parametric biomarkers are prepared for surrogating diagnosis, grading, segmentation, overall survival, progression-free survival, recurrence, molecular profiling and response to treatment in gliomas. Quantifications and radiomics features obtained from morphological exams (T1, T2, FLAIR, T1c), PWI (including DSC and DCE), diffusion (DWI, DTI) and chemical shift imaging (CSI) are the preferred MR biomarkers associated to clinical outcomes. Subcompartments relative to the peritumoral region, invasion, infiltration, proliferation, mass effect and pseudo flush, relapse compartments, gross tumor volumes, and high-risk regions have been defined to characterize the heterogeneity. For the majority of pairwise cooccurrences, we found no evidence to assert that observed co-occurrences were significantly different from their expected co-occurrences (Binomial test with False Discovery Rate correction, alpha=0.05). The co-occurrence among terms in the studied papers was found to be driven by their individual prevalence and trends in the literature. Conclusion: Combinations of MR imaging biomarkers from morphological, PWI, DWI and CSI exams have demonstrated their capability to predict clinical outcomes in different management moments of gliomas. Whereas morphologic-derived compartments have been mostly studied during the last ten years, new multi-parametric MRI approaches have also been proposed to discover specific subcompartments of the tumors. MR biomarkers from those subcompartments show the local behavior within the heterogeneous tumor and may quantify the prognosis and response to treatment of gliomas.This work was supported by the Spanish Ministry for Investigation, Development and Innovation project with identification number DPI2016-80054-R.Oltra-Sastre, M.; Fuster García, E.; Juan -Albarracín, J.; Sáez Silvestre, C.; Perez-Girbes, A.; Sanz-Requena, R.; Revert-Ventura, A.... (2019). 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Rebuttal to: Polemic against conclusions drawn in “Palladium/iodide catalyzed oxidative carbonylation of aniline to diphenylurea: Effect of ppm amounts of iron salts” (J. Catal. 369 (2019) 257–266)

In a recent paper on this Journal (J. Catal. 369 (2019) 257-266), we reported on the effect of ppm amounts of iron compounds on the palladium/iodide (and even palladium/chloride) catalytic system for the oxidative carbonylation of aniline to diphenylurea. In a "Polemic" against our work, Gabriele and coworkers argued against some of the conclusions we had drawn and even against our experimental practice. Here, we reply in detail to this polemic. Some of the content of the latter is due to some misunderstanding, whereas some assertions are untenable and in contrast with experimental data

Palladium-Phenanthroline Complexes as Catalysts for the Synthesis of Oxazines by Reductive Cyclization of Nitroarenes and Dienes Using Phenyl Formate as CO Surrogate

Our previous work was mainly focused on the synthesis of indoles by reductive cyclization of o-nitrostyrenes and oxazines by the hetero Diels-Alder condensation of a conjugated diene with a nitrosoarene formed in situ by the reduction of the starting nitroarene. However, the application of the previously developed method to the reductive cyclization of 2-nitrobiphenyls to carbazoles afforded only moderate yields even under harsher conditions and higher catalyst loadings. The result is not totally unexpected since this reductive cyclization is known to be more difficult than the other previously studied. Here we report the results of our investigations on this reaction aimed at improving the catalytic performance