Efficient access to diverse screening compounds with desirable, lead‐like properties can be a bottleneck in early drug discovery and chemical biology. Herein we present an efficient, rapid route to three structurally distinct classes of compounds (A–C) from a single precursor, which in turn is available through a one‐pot Petasis 3‐component reaction/Diels–Alder cascade reaction. We demonstrate the versatility of the approach through the synthesis of 35 exemplary compounds from the three classes, as well as by the production of 2188 final compounds, which have been included in the Joint European Compound Library of the European Lead Factory.

The aim of this work is to develop the first validated HPLC-UV method quantification in blood serum for a new endoplasmic reticulum (ER)-specific benzophenazine photosensitizer (OR-141). A fast solid phase extraction (SPE) cleaning sample procedure was achieved on C18 encapped (ec) SPE cartridges and the separation was performed on a RP-18e column(511,mu M) using an isocratic elution with methanol. The method has been fully validated according to accuracy profiles based on total error and tolerance intervals. Calibration was performed in the matrix and trueness (<4.25% relative bias), repeatability (<4.75% relative standard deviation (RSD)), intermediate precision (<5.37% RSD), selectivity, response function, linearity, and dilution effect were evaluated for both OR-141 regio-isomers. Afterwards the developed method was successfully applied to perform the quantitative determination of OR-141 in mouse blood serum samples in a preliminary pharmacokinetic study. (C) 2017 Elsevier B.V. All rights reserved.

A new library of N,N,N',N'-tetradentate pyrazoly compounds containing a pyrazole moiety was synthesized by the condensation of (3,5-dimethyl-1H-pyrazol-1-yl)methanol 2a or (1H-pyrazol-1-yl)methanol 2b with a series of primary diamines in refluxed acetonitrile for 6h. The antifungal activity against the budding yeast Saccharomyces cerevisiae, as well as the antibacterial activity against Escherichia coli of these new tetradentate ligands were studied. We found that these tetradentate ligands act specifically as antifungal agents and lack antibacterial activity. Their biological activities depend on the nature of the structure of the compounds.

A new series of combretastatin analogues with B-ring modifications were synthesized and evaluated for their cytotoxicity against one endothelial (HUVEC) and three tumor cell lines, e.g., the LoVo colon, the PC-3 prostate, and the U373 glioma cancer models. These new combretastatin analogues showed differential cytotoxic activities, cis derivatives 13 5-(2- Z -trimethoxyphenylethenyl)benzo[1,2-c]1,2,5-oxadiazole N 1 -oxide and 14 5-(2- Z -trimethoxyphenylethenyl)benzo[1,2,5]thiadiazole exhibiting interesting cytotoxicity both on endothelial and on tumor cells. Unlike the cis benzofurazan 12 5-(2- Z -trimethoxyphenylethenyl)benzo[1,2-c]1,2,5-oxadiazole, induction of apoptosis by 13 appeared to be through caspase-3 activation. Metabolic investigations showed a positive correlation between highly metabolized compounds and cytotoxic activity, suggesting that highly cytotoxic derivatives may act as pro-drug via a reductive metabolization to more active metabolites.

We report herein a versatile cooperative dual catalysis reaction based on a Cu(I)/Pd(0) system. Mechanistic investigation shows that every component plays a crucial role in determining the reaction outcome. The reaction is successfully extended to various substrates; such as α,β-unsaturated ketones, malonates and coumarins. The strategy tolerates different substitution patterns and affords good yields for each family of substrates.

Cooperative efforts: The catalytic coupling of the two organometallic intermediates is possible through a Cu/Pd-based dual catalysis (see scheme; LG=leaving group), in which the CuI catalytic cycle generates catalytically the starting material for the Pd0 catalytic cycle. Although reagents are present in stoichiometric amounts in the reaction mixture and are able to trap both active species, the desired reaction proceeds as planned. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The title reaction is carried out with acid chlorides as reactants in the presence of base to give the corresponding functionalized amides.

AbstractThe transformation proceeds via silyl enolates derived from cyclic enones.

The electrophilic trifluoromethylation of aniline with a range of trifluoromethyl sulfonium salts has been studied in ionic liquids as solvent. The best ionic liquid for this reaction was identified after extensive scrutiny of the influence of the cation's nature (imidazolium or pyridinium salts), the effect of the alkyl side chain length of the cation, as well as that of the counter anion. Recycling experiments have demonstrated that the purification protocol was greatly simplified over conventional reactions performed in DMF and that the solvent could be reused five times without significant loss of activity.

AbstractAn efficient synthesis of fluorinated N‐aryl sulfoximines (III) and (VI) is presented, involving the copper‐catalyzed N‐arylation of the corresponding sulfoximines (I) and (IV), resp., with aryl iodides or bromides.

Novel tripodal derivatives with a triphenylamine core and that bear "superacidifiers" (i.e., fluorinated sulfoximinyl blocks) or novel sulfiliminyl moieties as peripheral groups were synthesized. These new chromophores show strong absorption in the near-UV region and emission in the visible region. The fluorinated sulfoximinyl moieties were found to behave as potent auxochromic and electron-withdrawing (EW) groups, thus leading to redshifted absorption and emission. These moieties promote a core-to-periphery intramolecular charge transfer (ctp-ICT) transition, the energy of which was found to be correlated to their EW strength. In this study, we provide evidence of a linear correlation between the Hammett constant (σ(p)) values and the electronic gap between the ground and first excited state of the three-branched derivatives. This in turn was used to derive σ(p) values of fluorinated sulfoximinyl moieties. These EWGs show unprecedentedly high σ(p) values, up to 1.45 relative to 0.8 for NO(2). Also, by using this method, the sulfiliminyl moiety was shown to exhibit similar EW strength as NO(2) , while promoting improved transparency and solubility. Finally, the superior EW strength of the fluorinated sulfoximine peripheral moieties was shown to induce significant enhancement of the two-photon absorption responses in the red near-IR region of the three-branched derivatives relative to similar octupoles that bear more usual strong EW groups. These characteristics (improved nonlinear responses or transparency) open new routes for the design of nonlinear optical (NLO) chromophores for optical limiting or electro-optical modulation. Such building blocks could also be of interest for optoelectronic applications, including the development of solar cells.

The introduction of a perfluoroalkyl group, with emphasis on the trifluoromethyl moiety, is a challenging topic. Of the synthetic methods available in the repertoire of chemists, electrophilic introduction was until recently the least developed. In five years, however, a renaissance of this chemistry has happened. This renewal has been made possible thanks to reports both of numerous new reagents (stable, easy tohandle and to prepare) and of easier preparation of older reagents. Their availability rapidly inspired highly original works involving their use, in particular with the help of catalysis. This virtuous spiral, as well as all these exciting new developments, is described in this microreview.

AbstractThe electrophilic trifluoromethylation of aniline with sulfonium salts like (II) proceeds efficiently in [bdmim]BF4 as solvent.

A high yielding, simple, and flexible copper-based system for N-arylation of fluorinated sulfoximines is reported. Best results were achieved using copper iodide in combination with DMEDA and Cs2CO3 to provide a wide range of N-arylated perfluoroalkylated sulfoximines. These conditions tolerate a great number of substituents on either aromatic cycle, including heteroaromatic rings, for the N-functionalization.

We investigated the behavior of the extensively used system trifluoromethanesulfonic anhydride/sulfoxide in the absence of any added nucleophilic species. We show here, with the help of 19 F NMR spectroscopy, that in the case of trifluoromethyl sulfoxides this results initially in the net reduction of the sulfoxide to a sulfane. We propose a mechanism involving sulfoxide itself as the reducing agent.

We have successfully extended our previously described methodology for the preparation of trifluoromethyl N-acyl sulfilimines to the case of bromodifluoro- and dichlorofluoromethyl derivatives. Attempts to convert such N-acyl sulfilimines to free NH-sulfilimines failed. However, a strategy based on the reaction of their direct ditriflyl ketal precursor with amines allows the isolation of either original sulfilimino iminium salts using secondary amines or of free NH-sulfilimines using primary amines. The latter were further easily N-functionalized with electron-withdrawing groups giving structures close to those of efficient perfluoroalkylating agents. Preliminary experiments showed that these new sulfilimine-based compounds have poor perfluoroalkylating abilities, demonstrating that the sulfilimine function is not sufficiently activating for that purpose, contrary to sulfur(VI) reagents.

Trifluoromethyl sulfonium salts are widely used for the introduction of a trifluoromethyl group through reaction with a wide range of nucleophiles. Nevertheless, the reaction mechanism is far from obvious and has been the subject of various literature discussions. In this Letter, we show, through trapping experiments with a radical probe that, at least in the case of nucleophiles such as enol silyl ethers, the reaction proceeds by SET.

[1007264-00-6] C9H11F4NO3S (MW 289.25) InChI = 1S/C8H11FN.CHF3O3S/c1-6-4-7(2)10(9)8(3)5-6;2-1(3,4)8(5,6)7/h4-5H,1-3H3;(H,5,6,7)/q+1;/p-1 InChIKey = PRIGFEJKMMRJSF-UHFFFAOYSA-M (electrophilic fluorinating reagent) Alternate Name: 1-fluoro-2,4,6-trimethylpyridinium triflate. Physical Data: mp 162 °C; stable crystals that remained intact after 5 h at 150 °C but melted and decomposed within a few minutes at 190 °C. Solubility: soluble in polar solvents such as CH3CN and even in water without decomposition after 30 days at room temperature, but insoluble or hardly soluble in nonpolar organic solvents. Form Supplied in: commercially available as a light yellow solid. Preparative Methods: 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate can be prepared by fluorination of the corresponding pyridine with molecular fluorine (diluted in nitrogen) at low temperature in the presence of metal triflate salts (sodium, potassium, or lithium).1-3 Purification: recrystallization from CH3CN–diethyl ether at room temperature. Handling, Storage, and Precautions: irritant; handle with caution and minimize exposure. This compound must be stored in a cool and shaded area. Keep away from heat and oxidizing agents.