Straightforward Synthesis of α-Chloromethylketimines Catalyzed by Gold(I). A Clean Way to Building Blocks.

α-Chloromethylketimines have been obtained through a gold-catalyzed hydroamination of aromatic and aliphatic 1-chloroalkynes with aromatic amines by using equimolar amounts of both reagents. This procedure has allowed the preparation and spectroscopic characterization of α-chloromethylketimines for the first time with a high degree of purity, complete conversion, and atom economy. The synthetic usefulness of the methodology has been demonstrated with the preparation of ß-chloroamines and indoles.

A Quantitative Model for Alkane Nucleophilicity Based on C-H Bond Structural/Topological Descriptors.

A first quantitative model for calculating the nucleophilicity of alkanes is described. A statistical treatment was applied to the analysis of the reactivity of 29 different alkane C-H bonds towards in situ generated metal carbene electrophiles. The correlation of the recently reported experimental reactivity with two different sets of descriptors comprising a total of 86 parameters was studied, resulting in the quantitative descriptor-based alkane nucleophilicity (QDEAN) model. This model consists of an equation with only six structural/topological descriptors, and reproduces the relative reactivity of the alkane C-H bonds. This reactivity can be calculated from parameters emerging from the schematic drawing of the alkane and a simple set of sums.

Measuring the Relative Reactivity of the Carbon-Hydrogen Bonds of Alkanes as Nucleophiles.

We report quantitative measurements of the relative reactivities of a series of C-H bonds of gaseous or liquid Cn H2n+2 alkanes (n=1-8, 29 different C-H bonds) towards in situ generated electrophiles (copper, silver, and rhodium carbenes), with methane as the reference. This strategy surpasses the drawback of previous model reactions of alkanes with strong electrophiles suffering from C-C cleavage processes, which precluded direct comparison of the relative reactivities of alkane C-H bonds.

SN1 reactions in supercritical carbon dioxide in the presence of alcohols: the role of preferential solvation.

Ethanol () inhibits SN1 reactions of alkyl halides in supercritical carbon dioxide (scCO2) and gives no ethers as products. The unexpected behaviour of alcohols in the reaction of alkyl halides with 1,3-dimethoxybenzene () in scCO2 under different conditions is rationalised in terms of Brønsted and Lewis acid-base equilibria of reagents, intermediates, additives and products in a singular solvent characterised by: (i) the strong quadrupole and Lewis acid character of carbon dioxide, which hinders SN2 paths by strongly solvating basic solutes; (ii) the weak Lewis base character of carbon dioxide, which prevents it from behaving as a proton sink; (iii) the compressible nature of scCO2, which enhances the impact of preferential solvation on carbon dioxide availability for the solvent-demanding rate determining step.

Competitive gold-activation modes in terminal alkynes: an experimental and mechanistic study.

The competition between π- and dual σ,π-gold-activation modes is revealed in the gold(I)-catalyzed heterocyclization of 1-(o-ethynylaryl)urea. A noticeable effect of various ligands in gold complexes on the choice of these activation modes is described. The cationic [Au(IPr)](+) (IPr=2,6-bis(diisopropylphenyl)imidazol-2-ylidene) complex cleanly promotes the π activation of terminal alkynes, whereas [Au(PtBu3 )](+) favors intermediate σ,π species. In this experimental and mechanistic study, which includes kinetic and cross-over experiments, several σ-gold, σ,π-gold, and other gold polynuclear reaction intermediates have been isolated and identified by NMR spectroscopy, X-ray diffraction, or MALDI spectrometry. The ligand control in the simultaneous or alternative π- and σ,π-activation modes is also supported by deuterium-labeling experiments.

Catalytic functionalization of methane and light alkanes in supercritical carbon dioxide.

The development of catalytic methods for the effective functionalization of methane yet remains a challenge. The best system known to date is the so-called Catalytica Process based on the use of platinum catalysts to convert methane into methyl bisulfate with a TOF rate of 10(-3) s. In this contribution, we report a series of silver complexes containing perfluorinated tris(indazolyl)borate ligands that catalyze the functionalization of methane into ethyl propionate upon reaction with ethyl diazoacetate (EDA) by using supercritical carbon dioxide (scCO2) as the reaction medium. The employment of this reaction medium has also allowed the functionalization of ethane, propane, butane, and isobutane.

FeCl3·6H2O-catalyzed Mukaiyama-aldol type reactions of enolizable aldehydes and acetals.

Mukaiyama-aldol type reactions of acetals derived from enolizable aldehydes with FeCl3·6H2O, an eco-friendly, low-cost, and stable catalyst, lead to ß-methoxycarbonyl compounds with nearly quantitative yields. The methodology is extended to the parent aldehydes as starting materials, leading to the corresponding aldols with lower yields, but efficiently. Different alkyl and aryl substituted acetals and aldehydes have been tested in the reaction with linear and cyclic silyl enol ethers. Reactions are carried out in an open air atmosphere, and additives are not required. Acetals can be considered activating groups of the carbonyl moiety rather than a protecting group in this type of FeCl3·6H2O-catalyzed condensation.

Inverse solvent effects in the heterogeneous and homogeneous epoxidation of cis-2-heptene with [2-percarboxyethyl]-functionalized silica and meta-chloroperbenzoic acid.

The rate constants for the epoxidation of cis-2-heptene with [2-percarboxyethyl]-functionalized silica (1a) and meta-chloroperbenzoic acid (mCPBA) (1b) in different solvents have been determined at temperatures in the -10 to 40 °C range. The heterogeneous epoxidation exhibits a dependence of the reaction rate on solvent polarity opposite to its homogeneous counterpart and anomalous activation parameters in n-hexane, which are interpreted in terms of the surface-promoted solvent structure at the solid-liquid interface. The results show that highly polar solvents can strongly inhibit heterogeneous reactions performed with silica-supported reagents or catalysts.

Epoxidation of olefins with a silica-supported peracid.

Anhydrous [2-percarboxyethyl] functionalized silica (2a) is an advantageous oxidant for performing the epoxidation of olefins 1. Epoxides 3 do not undergo the ring-opening reactions catalyzed by the acidic silica surface, except for particularly activated cases such as styrene oxide. The hydrophilic and acidic character of the silica surface does not interfere with the directing effects exerted by allylic H-bond acceptor substituents. The alkenes 1 carrying hydroxyl groups react with silica-supported peracid 2a faster than unsubstituted alkenes, thus reversing the trend known for reactions with soluble peracids. These results are attributed to the H-bond interactions of substrate 1 with the silanol and carboxylic acid groups bonded to the silica surface.

Switchable palladium-catalyst reaction of bromomethyl sulfoxides, CO, and N-nucleophiles: aminocarbonylation at Csp3 versus oxidative carbonylation of amines.

The palladium-catalyzed reaction of α-bromomethyl sulfoxides, carbon monoxide, and N-nucleophiles follows different reaction pathways according to the catalytic system and the reaction conditions. The Pd-xantphos catalyst affords high yields of α-sulfinyl amides by an aminocarbonylation process and is the first example of this type of transformation for a nonbenzylic sp(3)-hybridized carbon. On the other hand, the oxidative carbonylation of amines occurs with α-bromomethyl sulfoxides, carbon monoxide, and catalytic Pd(PPh(3))(4) under aerobic conditions, yielding ureas and oxalamides from either primary or secondary amines. The reaction with ambident nucleophiles such as amino alcohols was highly selective and took place exclusively at the amino group despite the presence of the alcohol functionality. In parallel to the reaction paths for simple amines, amino alcohols were converted into hydroxy sulfinyl amides when the reaction was catalyzed by Pd-xantphos, while Pd(PPh(3))(4) catalyst afforded cyclic carbamates. The alkoxycarbonylation reaction of bromomethyl sulfoxides with simple alcohols and CO leading to the corresponding sulfinyl esters is also described.

Epoxidation of olefins with a silica-supported peracid in supercritical carbon dioxide under flow conditions.

Anhydrous 2-percarboxyethyl-functionalized silica (2b), a recyclable supported peracid, is a suitable reagent to perform the epoxidation of alkenes 1 in supercritical carbon dioxide at 250 bar and 40 °C under flow conditions. This procedure simplifies the isolation of the reaction products and uses only carbon dioxide as a solvent under mild conditions. The solid reagent 2b can be easily recycled by a reaction with 30% hydrogen peroxide in an acid medium.

Selective "one-pot" synthesis of functionalized cyclopentenones.

Double addition (1,2-1,4) of vinyl magnesium bromide to squaric acid derivatives allows the preparation of polyoxygenated cyclopentenones (8) in a "one-pot" procedure. The reaction occurs through the intermediate formation of octatetraenes (6). Protonation of this latter intermediate at -78 °C with TFE occurs selectively at the vinyl CH(2) closer to the metallic centers. DFT studies of the cyclization step justify the observed diastereoselectivity.

Reactions at interfaces: oxygenation of n-butyl ligands anchored on silica surfaces with methyl(trifluoromethyl)dioxirane.

The oxygenation of n-butyl and n-butoxy chains bonded to silica with methyl(trifluoromethyl)dioxirane (1) revealed the ability of the silica matrix to release electron density toward the reacting C(2)-H σ-bond through the Si-C(1) and Si-O(1) σ-bonds connecting the alkyl chain to the surface (silicon ß-effect). The silica surface impedes neither the alkyl chain adopting the conformation required for the silicon ß-effect nor dioxirane 1 approaching the reactive C(2) methylene group. Reaction regioselectivity is insensitive to changes in the solvation of the reacting system, the location of organic ligands on the silica surface, and the H-bonding character of the silica surface. Reaction rates are faster for those organic ligands either within the silica pores or bonded to hydrophilic silica surfaces, which evidence the enhanced molecular dynamics of confined dioxirane 1 and the impact of surface phenomena on the reaction kinetics. The oxygenation of n-butyl and n-butoxy chains carrying trimethylsilyl, trimethoxysilyl, and tert-butyl groups with dioxirane 1 under homogeneous conditions confirms the electronic effects of the silyl substituents and the consequences of steric hindrance on the reaction rate and regioselectivity. Orthosilicic acid esters react preferentially at the methylene group adjacent to the oxygen atom in clear contrast with the reactivity of the carboxylic or sulfonic acid alkyl esters, which efficiently protect this position toward oxidation with 1.

Antimicrobial peptides and their superior fluorinated analogues: structure-activity relationships as revealed by NMR spectroscopy and MD calculations.

The conformations of two synthetic pentapeptides with antimicrobial activity and their 4-fluorophenylalanine (Pff)-containing analogues (ArXArXAr-NH(2); Ar=Phe, Pff; X=Lys, Arg) have been studied. NMR experiments carried out both in aqueous fluoroalcohol solutions and SDS micelles permitted their interactions with membrane-like environments to be explored. WaterLOGSY experiments and Mn(2+)-based paramagnetic probes were also applied to assess their orientations with respect to the SDS micelles. In addition, pulse-field gradient (PFG) diffusion NMR spectroscopy studies were conducted, under different experimental conditions (i.e., concentration, temperature) to characterize the possible changes in the peptides' aggregation states as a putative critical factor for their antimicrobial activity. Finally, molecular dynamics simulations on a variety of conformations showed the intrinsic flexibility of these peptides in both aqueous solutions and membrane-mimetic systems.

Competitive and selective Csp3-Br versus Csp2-Br bond activation in palladium-catalysed Suzuki cross-coupling: an experimental and theoretical study of the role of phosphine ligands.

Phosphine ligands have been demonstrated to have an effect on reactivity and selectivity in the competitive intramolecular palladium-catalysed Suzuki-Miyaura coupling of dibromo sulfoxide 1a possessing two different hybridised electrophilic carbons. It was found that the bromine bond to the sp(3)-hybridised carbon is selectively replaced in the presence of unhindered phosphines such as PPh(3) or xantphos. The use of hindered phosphine ligands such as P(o-tol)(3) and P(1-naphthyl)(3) reversed the selectivity, conducting the cross-coupling at the Csp(2)-Br. Identical trends were observed in external competition experiments carried out with bromomethyl sulfoxide and different substituted bromoarenes. DFT and DFT/MM calculations showed that the selectivity observed is mainly due to the different facility of the ligands to dissociate. Bisphosphine catalysts favour coupling at the sp(3) carbon, whereas monophosphine catalysts prefer the sp(2) carbon.

Osmium(III) complexes with POP pincer ligands: preparation from commercially available OsCl(3)·3H(2)O and their X-ray structures.

Complexes OsCl(3){dbf(P(i)Pr(2))(2)} [1; dbf(P(i)Pr(2))(2) = 4,6-bis(diisopropylphosphino)dibenzofuran], OsCl(3){xant(P(i)Pr(2))(2)} [2; xant(P(i)Pr(2))(2) = 9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene], and OsCl(3){xant(PPh(2))(2)} [3; xant(PPh(2))(2) = 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] have been obtained in high yield by the reaction of the corresponding diphosphine with OsCl(3)·3H(2)O. The ruthenium(III) counterparts RuCl(3){dbf(P(i)Pr(2))(2)} (4), RuCl(3){xant(P(i)Pr(2))(2)} (5), and RuCl(3){xant(PPh(2))(2)} (6) are similarly obtained from RuCl(3)·3H(2)O in moderate yields. The X-ray structures of dbf(P(i)Pr(2))(2) and complexes 1-3 are also reported.

Why is the Suzuki-Miyaura cross-coupling of sp3 carbons in alpha-bromo sulfoxide systems fast and stereoselective? A DFT study on the mechanism.

The stereoselectivity-determining oxidative addition step in the Suzuki-Miyaura cross-coupling of alpha-bromo sulfoxides is analyzed computationally through DFT calculations on a model system defined by Pd(PMe(3))(2) and CH(3)SOCH(2)Br. Both monophospine and bisphosphine complexes have been considered, different reaction pathways being characterized through location of the corresponding transition states. The lowest energy transition states correspond to nucleophilic substitution mechanisms, which imply inversion of configuration at the carbon, in good agreement with experimental data on the process. The energy-lowering and stereodirecting role of the sulfinyl substituent is explained through its attractive interactions with the palladium center, which are only possible in the most favored mechanisms.

Regioselectivity in the ligand-assisted addition of vinylmagnesium bromide: an experimental and theoretical study on the gamma-alkoxycyclobutenone model.

Compounds 2 (M = Mg) obtained in the mono addition of vinylmagnesium bromide to squarates are attractive structural models to determine the influence of complexation between magnesium(II) and the alkoxide group on the regioselectivity of the 1,2- versus 1,4-addition of organomagnesium by complex induced proximity effects (CIPE). The 1,4-addition is observed almost exclusively in the case of vinylmagnesium in THF solution with formation of hydroxyketones type 5, which are always side or minor products in the known reaction of alkenyllithium derivatives. A comparative study on the reactivity of alkenyllithium and magnesiun derivatives is reported. The high regioselectivitity observed in the 1,4-addition of vinylmagnesium bromide is fully understood by computational studies of compounds 2 (M = Mg) at the DFT level with the density functional B3LYP.

Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma.

Inhibition of cancer growth by resveratrol (trans-3,5,4'-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.