Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents

The synthesis of different 3,5-disubstituted isoxazoles and related isoxazolines using choline chloride:urea as deep eutectic solvent (DES) in a one-pot three step reaction has been accomplished successfully. The use of highly nucleophilic functionalized DES did not affect the process where highly electrophilic reagents or intermediates are involved. The presence of DES showed to be essential since the reaction in absence of this media did not proceed. The DES media could be reused up to five times without a detrimental effect on the yield of the reaction. To exemplify the synthetic potential of this methodology, the reaction was scaled up to the gram scale without any noticeable problem. Finally, different isoxazoles were easily transformed into β-aminoenones.This work was supported by the Spanish Ministerio de Economía y Competitividad (MICINN; Grant CTQ2011-24151) and University of Alicante. J.M.P. thanks the MICINN (FPI program) for her fellowship

Cross-dehydrogenative coupling reaction using copper oxide impregnated on magnetite in deep eutectic solvents

The synthesis of different tetrahydroisoquinolines using choline chloride : ethylene glycol as a deep eutectic solvent (DES) and copper(II) oxide impregnated on magnetite as a catalyst has been accomplished successfully. The copper catalyst amount is the lowest loading ever reported. The presence of DES showed to be essential since the reaction in the absence of this medium did not proceed. A direct proportional relationship was found between the conductivity of DES medium and the yield obtained. The DES and the catalyst could be reused up to ten times without any detrimental effect on the yield of the reaction, with the aerobic conditions making the protocol highly sustainable, where the only waste is water.This work was supported by the Spanish Ministerio de Economía y Competitividad (MICINN; CTQ2011-24151) and the University of Alicante. J. M. P. thanks the MICINN (FPI program) for her fellowship

Multicomponent Azide-Alkyne Cycloaddition Catalyzed by Impregnated Bimetallic Nickel and Copper on Magnetite

A new bimetallic catalyst derived from nickel and copper has been used successfully for the first time in the multicomponent reaction of terminal alkynes, sodium azide, and benzyl bromide derivatives. The presence of both metallic species on the surface of magnetite seems to have a positive and synergetic effect. The catalyst loading is the lowest ever published for a catalyst of copper anchored on any type of iron support. The catalyst could be easily removed from the reaction media just by magnetic decantation and it could be reused up to ten times without any negative effect on the initial results

Osmium impregnated on magnetite as a heterogeneous catalyst for the syn-dihydroxylation of alkenes

A new catalyst derived from osmium has been prepared, fully characterized and tested in the dihydroxylation of alkenes. The catalyst was prepared by wet impregnation methodology of OsCl3·3H2O on a commercial micro-magnetite surface. The catalyst allowed the reaction with one of the lowest osmium loadings for a heterogeneous catalyst and was selective for the monodihydroxylation of 1,5-dienes. Moreover, the catalyst was easily removed from the reaction medium by the simple use of a magnet. The selectivity of catalyst is very high with conversions up to 99%. Preliminary kinetics studies showed a first-order reaction rate with respect to the catalyst.This work was supported by the Spanish Ministerio de Economía y Competitividad (CTQ2011-24151). J. M. P. thanks the M.E.C. for a fellowship through the FPI program

Palladium(II) oxide impregnated on magnetite as a catalyst for the synthesis of 4-arylcoumarins via a Heck-arylation/cyclization process

Heck-arylation/cyclization was achieved using heterogeneous palladium(II) oxide impregnated on magnetite catalyst (2.5 mol%) with a lower catalyst loading than that reported for similar processes. Ethanol was used as a non-toxic and bio-renewable solvent. Good yields were afforded using a broad range of substrates (40–98%). The catalyst could be partially recycled, and analyses confirmed the almost total reduction of palladium(II) oxide to palladium(0) as well as the iodine poissoning effect, which is the main barrier to complete recyclability.The authors thank the Spanish Ministerio de Economía y Competitividad (MICINN; CTQ2011-24151), University of Alicante, Irish Research Council (RC) and Science Foundation Ireland (SFI/12/IP/1315 and SFI/12/RC/2275). J. M. P. thanks the MICINN (FPI program) for her fellowship

Impregnated Copper(II) Oxide on Magnetite as Catalyst for the Synthesis of Benzo[b]furans from 2-Hydroxyarylcarbonyl Derivatives and Alkynes

The coupling-allenylation-cyclization reaction sequence of o-hydroxybenzaldehydes with alkynes in the presence of 4-methylbenzenesulfonohydrazide was carried out in ethanol as a nontoxic biorenewable solvent and in the presence of impregnated copper(II) oxide on magnetite as a heterogeneous catalyst. The catalyst can be easily removed from the reaction medium by a simple magnetic decantation, and the reaction can be performed with a very low copper loading. The in situ reduction of the starting copper(II) oxide nanoparticles into copper(0) sheets made the recyclability of catalyst impossible. The versatility of the reaction was shown by employing different o-hydroxyacetophenones to give 2,3-disubstituted benzo[b]furans. The reaction can be carried out on a gram scale without any complications.This work was supported by the Spanish Ministerio de Educación y Ciencia (MEC), the Ministerio de Ciencia e Innovación (MICINN) (grant numbers CTQ2011-24151 and CTQ2015-66624-P) and the University of Alicante. J. M. P. thanks the Spanish Ministerio de Economía y Competitividad (MINECO) for her fellowship

Impregnated palladium on magnetite as catalyst for direct arylation of heterocycles

Palladium impregnated on magnetite is an efficient, cheap and easy to prepare catalyst for the direct arylation of heterocycles. Good yields are afforded under relatively mild conditions and a broad substrate scope is evident. The catalyst is regioselective in many cases, affording arylated products, at the C2- or C3-position (depending of the heterocycle used). The methodology can be extended to prepare chromenes through an intramolecular direct arylation reaction. Some evidence is provided for two catalyst deactivation pathways, which prevents efficient recycling.The authors thank the Irish Research Council (RC), Science Foundation Ireland (SFI/12/IP/1315 and SFI/12/RC/2275), Spanish Ministerio de Economía y Competitividad (MICINN; CTQ2011-24151, University of Alicante and MICINN FPI program (JMP)

Impregnated palladium on magnetite as a water compatible catalyst for the cycloisomerization of alkynoic acid derivatives

This work describes the catalytic activity of palladium(II) species in the cycloisomerization of alkynoic acids and their derivatives in aqueous media as well as in Deep Eutectic Solvents (DESs), with one of the lowest metal catalyst loadings reported so far in the literature. Different substrates such as terminal and internal alkynes or alkynyl sulfonylimides were studied, obtaining selectivity either to the cyclic compound or the hydrolysed keto derivative. This new system avoids the use of harmful solvents and employs very efficient and recoverable heterogeneous catalysts.This work was supported by the University of Alicante (UAUSTI16-10, VIGROB-173), and the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P). B. S. thanks the Generalitat Valenciana (ACIF/2017/211) for a fellowship. M. J. R.-A and J. G.-A. are indebted to the MINECO of Spain (CTQ2016-81797-REDC and CTQ2016-75986-P) and the Gobierno del Principado de Asturias (project GRUPIN14-006) for financial support. J. G.-A. thanks the Fundación BBVA for the award of a “Beca Leonardo a Investigadores y Creadores Culturales 2017”

Matrix Metalloproteinase-9 Expression Is Associated with the Absence of Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients

Triple-negative breast cancer (TNBC) is particularly challenging due to the weak or absent response to therapeutics and its poor prognosis. The effectiveness of neoadjuvant chemotherapy (NAC) response is strongly influenced by changes in elements of the tumor microenvironment (TME). This work aimed to characterize the residual TME composition in 96 TNBC patients using immunohistochemistry and in situ hybridization techniques and evaluate its prognostic implications for partial responders vs. non-responders. Compared with non-responders, partial responders containing higher levels of CD83+ mature dendritic cells, FOXP3+ regulatory T cells, and IL-15 expression but lower CD138+ cell concentration exhibited better OS and RFS. However, along with tumor diameter and positive nodal status at diagnosis, matrix metalloproteinase-9 (MMP-9) expression in the residual TME was identified as an independent factor associated with the impaired response to NAC. This study yields new insights into the key components of the residual tumor bed, such as MMP-9, which is strictly associated with the lack of a pathological response to NAC. This knowledge might help early identification of TNBC patients less likely to respond to NAC and allow the establishment of new therapeutic targets

Prognostic Implications of the Residual Tumor Microenvironment after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients without Pathological Complete Response

Simple Summary Triple-negative breast cancer (TNBC) is currently in the clinical research spotlight because of the tumor's aggressive and invasive nature and the scarcity of therapeutic targets. Despite recent advances in identifying reliable prognostic biomarkers in the tumor microenvironment (TME), rigorous evaluation of their predictive capacity remains challenging. We describe the immune cellular and genetic profile of the residual tumor of TNBC that does not achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). A high concentration of lymphocytes and dendritic cells, as well as genetic TME markers such as MUC-1 and CXCL13 in the residual tumor, are valuable prognostic factors of survival and relapse in TNBC patients. From a clinical health perspective, a thorough understanding of the composition of the TME and its prognostic implications might yield relevant immunological information and reveal key predictive biomarkers. This could ultimately help substantially improve the outcomes of residual cancer-burdened TNBC patients after NAC. With a high risk of relapse and death, and a poor or absent response to therapeutics, the triple-negative breast cancer (TNBC) subtype is particularly challenging, especially in patients who cannot achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Although the tumor microenvironment (TME) is known to influence disease progression and the effectiveness of therapeutics, its predictive and prognostic potential remains uncertain. This work aimed to define the residual TME profile after NAC of a retrospective cohort with 96 TNBC patients by immunohistochemical staining (cell markers) and chromogenic in situ hybridization (genetic markers). Kaplan-Meier curves were used to estimate the influence of the selected TME markers on five-year overall survival (OS) and relapse-free survival (RFS) probabilities. The risks of each variable being associated with relapse and death were determined through univariate and multivariate Cox analyses. We describe a unique tumor-infiltrating immune profile with high levels of lymphocytes (CD4, FOXP3) and dendritic cells (CD21, CD1a and CD83) that are valuable prognostic factors in post-NAC TNBC patients. Our study also demonstrates the value of considering not only cellular but also genetic TME markers such as MUC-1 and CXCL13 in routine clinical diagnosis to refine prognosis modelling