Practical synthesis and elaboration of methyl 7-chloroindole-4-carboxylate

A synthesis of a previously unknown indole derivative is presented. The route reported herein allows for the preparation of multihundred gram quantities of material without any chromatographic purification. Conditions are presented for the Pd-catalyzed elaboration of one of the "diversity generating elements" of this important pharmacophore.     

Indium-mediated beta-allylation,beta-propargylation,and beta-allenylation onto alpha,beta-unsaturated ketones: reactions of in-situ-generated 3-tert-butyldimethylsilyloxyalk-2-enylsulfonium salts with in-situ-generated organoindium reagents

3-tert-Butyldimethylsilyloxyalk-2-enylsulfonium salts, generated in situ from the reaction of alpha,beta-enones with dimethyl sulfide in the presence of TBSOTf, underwent a novel nucleophilic substitution with allylindiums to give silyl enol ethers of delta,epsilon-alkenyl ketones in good yields, which correspond to formal Michael addition products. In a similar manner, 1,4-propargylation of propargylindiums onto the sulfonium salts produced the corresponding silyl enol ethers of delta,epsilon-alkynyl ketones in good yields. Organoindium reagents derived from gamma-substituted propargyl bromide and indium afforded the corresponding silyl enol ethers of beta-allenyl ketones in good yields. The reaction proceeds via an addition-substitution mechanism involving the formation of allylic sulfonium salts. The presence of the intermediate sulfonium salt was confirmed by observation of the low-temperature (1)H NMR spectra.     

Production from ilmenite of TiO2-supported catalysts for selective catalytic reduction of NO with NH3

Economic production of titanium dioxide (yield >98 %) from ilmenite has been achieved by use of a modified sulfate reduction process. A series of samples were prepared by varying the concentration of titanium dioxide nuclei (0.2, 0.3, and 0.6 %) and further impregnation with antimony and vanadia. The structural and acidic properties of the samples were comprehensively studied by X-ray diffraction (XRD), transmission electron microscopy, BJH pore size distribution, and temperature-programmed desorption of NH₃. The XRD results revealed the presence of intense peaks from anatase titanium dioxide. Enhancement of surface area was observed for second-time filtered samples, possibly because of loss of iron from the bulk. As a result, formation of additional micropores was apparent from N₂ adsorption and desorption isotherms. Among all the antimony and vanadia-doped samples, the first-time filtered sample with the low concentration of nuclei (0.2 %) had the highest catalytic activity at low temperatures, owing to its larger pore size and abundant acidic species.     

W(CO)5(L)-catalyzed endo-selective cyclization of allenyl silyl enol ethers: an efficient method for the cyclopentene annulation onto alpha,beta-unsaturated ketones

[reaction: see text] Indium-mediated allenylation of alpha,beta-unsaturated ketones in the presence of tert-butyldimethylsilyl triflate and dimethyl sulfide gives 6-siloxy-1,2,5-trienes, which undergo W(CO)(5)(L)-catalyzed 5-endo cyclization to give the corresponding cyclopentene derivatives in good yield. Furthermore, this novel W(CO)(5)(L)-catalyzed cyclization of allenyl silyl enol ethers proceeds in a 6-endo manner when 5-siloxy-1,2,5-trienes are employed as a substrate. In these reactions, effective electrophilic activation of allenyl compounds for attack by silyl enol ethers is achieved using a catalytic amount of W(CO)(6).     

Measuring intracellular calcium fluxes in high throughput mode

The measurement of intracellular calcium fluxes in real time is widely applied within the pharmaceutical industry to measure the activation of G-protein coupled receptors (GPCRhyp;s), either for pharmacological characterisation or to screen for new surrogate ligands. Initially restricted to G(q) coupled GPCRs, the introduction of promiscuous and chimeric G-proteins has further widened the application of these assays. The development of new calcium sensitive dyes and assays has provided sensitive, homogeneous assays which can be readily applied to high throughput screening (HTS). In this paper we describe the full automation of this assay type using a fluorometric imaging plate reader (FLIPR ) integrated into a Beckman/Sagian system to establish a simple robotic system that is well suited for the current medium throughput screening in this area of lead discovery. Using a recently completed HTS we discuss important determinants for FLIPR based screening, highlight some limitations of the current approach, and look at the requirements for future automated systems capable of keeping up with expanding compound files.     

Synthesis of 5-Alkyl- and 5-Phenylamino-Substituted Azothiazole Dyes with Solvatochromic and DNA-Binding Properties

A series of new 5-mono- and 5,5′-bisamino-substituted azothiazole derivatives was synthesized from the readily available diethyl azothiazole-4,4′-dicarboxylate. This reaction most likely comprises an initial Michael-type addition by the respective primary alkyl and aromatic amines at the carbon atom C5 of the substrate. Subsequently, the resulting intermediates are readily oxidized by molecular oxygen to afford the amino-substituted azothiazole derivatives. The latter exhibit remarkably red-shifted absorption bands (λ_abs=507–661 nm) with high molar extinction coefficients and show a strong positive solvatochromism. As revealed by spectrometric titrations and circular and linear dichroism studies, the water-soluble, bis-(dimethylaminopropylamino)-substituted azo dye associates with duplex DNA by formation of aggregates along the phosphate backbone at high ligand–DNA ratios (LDR) and by intercalation at low LDR, which also leads to a significant increase of the otherwise low emission intensity at 671 nm.     

Gold-catalyzed hydrosilyloxylation driving tandem aldol and mannich reactions

The chemoselective formation of an enolate from alkyne in the presence of a carbonyl and imine group was realized, which constructed a variety of structural motifs under exceedingly mild reaction conditions in a tandem process. Reaction driving tandem hydrosilyloxylation/aldol reactions was achieved through the formation of enol silyl ethers catalytically generated in situ from readily available alkynes. These reactions were expanded to obtain β-amino enol silyl ethers in good yields via the tandem hydrosilyloxylation/isomerization/Mannich reaction.