Green Synthesis of Electrophilic Alkenes Using a Magnesium Catalyst under Aqueous Conditions and Mechanistic Insights by Density Functional Theory.

A green approach for the synthesis of electrophilic alkenes has been developed via Knoevenagel condensation between active methylene compounds and carbonyl compounds using Mg powder under aqueous conditions. In this strategy, Mg(OH)2 acts as a catalyst, which was generated in situ by the reaction between metallic Mg (20 mol %) and water. Mg was found to be an efficient, nontoxic, and inexpensive metal catalyst system for producing a range of electrophilic alkenes in excellent yields (≤98%). A gram-scale synthesis of electrophilic alkenes has been developed, and Mg metal was recovered and recycled up to three times without an appreciable loss of catalytic activity. A catalytic cycle was proposed, and the reaction mechanism was investigated using density functional theory. The key steps are enolization of ethyl cyanoacetate, C-C bond formation, and then regeneration of the catalyst via metathesis with H2O. The overall reaction occurs easily with a maximum ΔG°â§§ value of 7.9 kcal/mol for the rate-determining C-C bond formation step. Our protocol has several advantages and can be further extended to one-pot sequential Knoevenagel condensation and Michael addition, and one-pot sequential Knoevenagel condensation and chemoselective reduction can be used for the synthesis of valuable precursors of pharmaceutical products under green and aqueous conditions.

How the structural properties of the indole derivatives are important in kinase targeted drug design?: A case study on tyrosine kinase inhibitors.

Kinases are considered as important signalling enzymes that illustrate 20% of the druggable genome. Human kinase family comprises >500 protein kinases and about 20 lipid kinases. Protein kinases are responsible for the mechanism of protein phosphorylation. These are necessary for regulation of various cellular activities including proliferation, cell cycle, apoptosis, motility, growth, differentiation, etc. Their deregulation leads to disruption of many cellular processes leading to different diseases most importantly cancer. Thus, kinases are considered as valuable targets in different types of cancer as well as other diseases. Researchers around the world are actively engaged in developing inhibitors based on distinct chemical scaffolds. Indole represents as a versatile scaffold in the naturally occurring and bioactive molecules. It is also used as a privileged scaffold for the target-based drug design against different diseases. This present article aim to review the applications of indole scaffold in the design of inhibitors against different tyrosine kinases such as epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), etc. Important structure activity relationships (SARs) of indole derivatives were discussed. The present work is an attempt to summarize all the crucial structural information which is essential for the development of indole based tyrosine kinase inhibitors with improved potency.

New Dual-Functional and Reusable Bimetallic Y2ZnO4 Nanocatalyst for Organic Transformation under Microwave/Green Conditions.

A novel bimetallic and reusable Y2ZnO4 nanocatalyst was synthesized by a simple coprecipitation method. The prepared nanocatalyst exhibited dual catalytic activity and was characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), energy-dispersive X-ray spectroscopy (EDX), and scanning electron microscopy (SEM). The average crystallite and grain sizes were found to be 17 ± 1 and 10 ± 2 nm, respectively. On the one hand, the catalytic activity of the nanocatalyst was studied for the Knoevenagel condensation reaction of aromatic aldehydes with active methylene compounds, such as ethyl cyanoacetate and malononitrile, under microwave irradiation and solvent-free conditions. On the other hand, the nanoparticles also showed faster photocatalytic activity against methyl orange (MO) compared to other dyes. The nanocatalyst was easily recoverable by a simple filtration method and was recycled without any significant loss of catalytic activity. The advantages of this nanocatalyst were a simple workup procedure, high reaction yields, solvent-free conditions, reusability, and a short reaction time under green reaction conditions.

Monte Carlo based modelling approach for designing and predicting cytotoxicity of 2-phenylindole derivatives against breast cancer cell line MCF7.

Breast cancer is one of the leading causes of cancers among the variety of cancers in woman all over the world. Compounds with phenylindole scaffold were found to execute promising cytotoxicity against breast cancer cell line MCF7. In the present study, a Monte Carlo based QSAR analysis was performed on a dataset containing 102 phenylindoles in order to accelerate the efforts to find out better cytotoxic phenylindoles against MCF7 cell line. The statistical qualities of the generated models were found to be quite good as far as the internal and external validation were concerned. The best models from each split (Split 1: R2 = 0.6944, Q2 = 0.6495; Split 2: R2 = 0.8202, Q2 = 0.7998; Split 3: R2 = 0.8603, Q2 = 0.8357) for the test set were selected and Y-scrambling test and applicability domain analysis were also performed to ensure the robustness of these models. Among these models, model from split 3 obtained by using hybrid descriptors (combination of SMILES and HSG with 0ECk connectivity) was used to identify and classify the structural attributes as promoters as well as hinderers of cytotoxicity for these 2-phenylindole derivatives. Results from the analysis were further used to design and predict some probable new 2-phenylindole derivatives having promising cytotoxicity (IC50 < 55 nM) against MCF7.

From Au-Thiolate Chains to Thioether Sierpinski Triangles: The Versatile Surface Chemistry of 1,3,5-Tris(4-mercaptophenyl)benzene on Au(111).

Self-assembly of 1,3,5-tris(4-mercaptophenyl)benzene (TMB), a 3-fold symmetric, thiol-functionalized aromatic molecule, was studied on Au(111) with the aim of realizing extended Au-thiolate-linked molecular architectures. The focus lay on resolving thermally activated structural and chemical changes by a combination of microscopy and spectroscopy. Thus, scanning tunneling microscopy (STM) provided submolecularly resolved structural information, while the chemical state of sulfur was assessed by X-ray photoelectron spectroscopy (XPS). Directly after room-temperature deposition, only less well ordered structures were observed. Mild annealing promoted the first structural transition into ordered molecular chains, partly organized in homochiral molecular braids. Further annealing led to self-similar Sierpinski triangles, while annealing at even higher temperatures again resulted in mostly disordered structures. Both the irregular aggregates observed at room temperature and the chains were identified as metal-organic assemblies, whereby two out of the three intermolecular binding motifs are energetically equivalent according to density functional theory (DFT) simulations. The emergence of Sierpinski triangles is driven by a chemical transformation, i.e., the conversion of coordinative Au-thiolate to covalent thioether linkages, and can be further understood by Monte Carlo simulations. The great structural variance of TMB on Au(111) can on one hand be explained by the energetic equivalence of two binding motifs. On the other hand, the unexpected chemical transition even enhances the structural variance and results in thiol-derived covalent molecular architectures.

Stereoselective synthesis of activated 2-arylazetidines via imino-aldol reaction.

A simple and efficient synthetic route to substituted N-sulfinyl and N-sulfonyl azetidines is described involving imino-aldol reaction of ester enolates with racemic and non-racemic aldimines for obtaining ß-amino esters as a key step. These ß-amino esters on subsequent reduction followed by TsCl/KOH mediated cyclization produced the corresponding racemic and non-racemic azetidines with high yield and stereoselectivity.

Adsorption structure determination of a large polyaromatic trithiolate on Cu(111): combination of LEED-I(V) and DFT-vdW.

The adsorption geometry of 1,3,5-tris(4-mercaptophenyl)benzene (TMB) on Cu(111) is determined with high precision using two independent methods, experimentally by quantitative low energy electron diffraction (LEED-I(V)) and theoretically by dispersion corrected density functional theory (DFT-vdW). Structural refinement using both methods consistently results in similar adsorption sites and geometries. Thereby a level of confidence is reached that allows deduction of subtle structural details such as molecular deformations or relaxations of copper substrate atoms.

Nonstatistical dynamic effects in the thermal C2-C6 Diels-Alder cyclization of enyne-allenes.

The Diels-Alder (DA) reaction channel of the thermal C(2)-C(6) (Schmittel) cyclization of enyne-allenes is studied computationally and experimentally evaluating the influence of temperature on product ratios. Remote substituents at the alkyne terminus influence the mechanism of the C(2)-C(6)/DA cyclization steering it either to a stepwise or a concerted course. Temperature independent product ratios, selectivity of product formation, and computational results obtained at (U)BLYP/6-31G(d) level unveil a mechanism that is strongly controlled by nonstatistical dynamics.

Extended two-dimensional metal-organic frameworks based on thiolate-copper coordination bonds.

Self-assembly and surface-mediated reactions of 1,3,5-tris(4-mercaptophenyl)benzene--a three-fold symmetric aromatic trithiol--are studied on Cu(111) by means of scanning tunneling microscopy (STM) under ultrahigh-vacuum (UHV) conditions. In order to reveal the nature of intermolecular bonds and to understand the specific role of the substrate for their formation, these studies were extended to Ag(111). Room-temperature deposition onto either substrate yields densely packed trigonal structures with similar appearance and lattice parameters. Yet, thermal annealing reveals distinct differences between both substrates: on Cu(111) moderate annealing temperatures (~150 °C) already drive the emergence of two different porous networks, whereas on Ag(111) higher annealing temperatures (up to ~300 °C) were required to induce structural changes. In the latter case only disordered structures with characteristic dimers were observed. These differences are rationalized by the contribution of the adatom gas on Cu(111) to the formation of metal-coordination bonds. Density functional theory (DFT) methods were applied to identify intermolecular bonds in both cases by means of their bond distances and geometries.

Enantioselective syntheses of morpholines and their homologues via S(N)2-type ring opening of aziridines and azetidines with haloalcohols.

A highly regio- and stereoselective strategy for the syntheses in high yield and enantioselectivity of a variety of substituted nonracemic morpholines and their homologues is described. The reaction proceeds via an S(N)2-type ring opening of activated aziridines and azetidines by suitable halogenated alcohols in the presence of Lewis acid followed by base-mediated intramolecular ring closure of the resulting haloalkoxy amine.

Lewis acid-mediated unprecedented ring-opening rearrangement of 2-aryl-N-tosylazetidines to enantiopure (E)-allylamines.

A highly efficient strategy for Cu(OTf)2-mediated ring-opening of 2-aryl-N-tosylazetidines in polar and coordinating solvents followed by an unprecedented rearrangement to substituted achiral and chiral (E)-allylamines (ee >99%) is reported. The methodology has been applied for the synthesis of gamma-unsaturated-beta-amino acids. A plausible mechanism for the rearrangement is also described.

Lewis acid-mediated highly regioselective SN2-Type ring-opening of 2-aryl-N-tosylazetidines and aziridines by alcohols.

Lewis acid-mediated highly regioselective SN2-type ring-opening of 2-aryl-N-tosylazetidines with alcohols to afford various 1,3-amino ethers in excellent yields with good enantiomeric excess is described. Similar SN2-type ring-opening of chiral 2-phenyl-N-tosylaziridine with various alcohols produces the corresponding nonracemic 1,2-amino ethers in excellent yields and good ee. The mechanism of the ring-opening of aziridines and azetidines via an SN2 pathway is supported by the formation of nonracemic amino ethers.