Roberta Bernini

Copper-catalyzed C-C bond formation through C-H functionalization: synthesis of multisubstituted indoles from N-aryl enaminones.

Because of the economic attractiveness and good functional tolerance of copper-catalyzed methods and hence their potential in large-scale applications, during the past few years there have been remarkable advances in the use of copper catalysis in organic synthesis. An impressive number of Ullmann coupling reactions have been described starting from aryl halides and suitable reagents. Recent reports have shown that copper catalysis can also be used in the formation of C heteroatom and C C bonds through selective catalytic activation of aryl C H bonds, a topic of intense current interest that, for the most part, has witnessed the use of palladium-, rhodium-, and ruthenium-based catalysts. In particular, intramolecular copper-catalyzed ortho C H functionalizations through C N and C O bond-forming reactions have been shown to form benzimidazoles and benzoxazoles from amidines and anilides, respectively. Herein, we disclose a new synthesis of multisubstituted indoles from N-aryl enaminones that involves an intramolecular coppercatalyzed aryl C H functionalization through C C bond formation. The indole moiety is prevalent in a vast array of biologically active natural and nonnatural compounds. Consequently, despite the existence of numerous methods for the synthesis of indole derivatives, the development of new, more efficient procedures is a subject of great importance. N-Aryl enaminones 1 were readily prepared through Sonogashira cross-coupling of terminal alkynes with aroyl chlorides, followed by the conjugate addition of anilines with the resultant a,b-ynones. We initiated our study by examining whether the enaminone 1a could be converted into the corresponding indole 2a. Reactions were usually carried out under an atmosphere of air. After an initial screen of copper catalysts (CuSO4, CuCl2, CuI), we found that 2 a could be isolated in 63 % yield by using CuI, Li2CO3, and 1,10-phenanthroline (phen) in dimethyl acetamide (DMA) after 48 h (Table 1, entry 1). Optimization studies were then performed that varied the

Perfluoro-tagged, phosphine-free palladium nanoparticles supported on silica gel: application to alkynylation of aryl halides, Suzuki–Miyaura cross-coupling, and Heck reactions under aerobic conditions

The utilization of perfluoro-tagged palladium nanoparticles immobilized on fluorous silica gel through fluorous–fluorous interactions (Pdnp–A/FSG) or through covalent bonding to silica gel (Pdnp–B) in the alkynylation of aryl halides, in the Suzuki–Miyaura cross-coupling, as well as in the Heck reaction between methyl acrylate and aryl iodides is described. The reactions are carried out under aerobic and phosphine-free conditions with excellent to quantitative product yields in each case. The catalysts are easily recovered and reused several times without significant loss of activity. The alkynylation of aryl halides (under copper-free conditions) and the Suzuki–Miyaura cross-coupling are carried out in water. The Heck reaction of methyl acrylate with aryl iodides is best performed in MeCN. The utilization of Pdnp–B in the synthesis of 2,3-disubstituted indoles from 2-(alkynyl)trifluoroacetanilides and aryl halides is also reported.

Convenient synthesis of hydroxytyrosol and its lipophilic derivatives from tyrosol or homovanillyl alcohol.

Hydroxytyrosol, a naturally occurred o-phenolic compound exhibiting antioxidant properties, was synthesized by a three-step high-yielding procedure from natural and low-cost compounds such as tyrosol or homovanillyl alcohol. First, the efficient chemoselective protection of the alcoholic group of these compounds was performed by using dimethyl carbonate (DMC) as reagent/solvent; second, the oxidation with 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane reagent (DMP) and in situ reduction with sodium dithionite (Na2S2O4) allowed the preparation of carboxymethylated hydroxytyrosol; finally, by a mild hydrolytic step, hydroxytyrosol was obtained in high yield and purity, as confirmed by NMR spectra and HPLC profile. By using a similar methodology, lipophilic hydroxytyrosol derivatives, utilized as additives in pharmaceutical, food, and cosmetic preparations, were prepared. In fact, at first the chemoselective protection of the alcoholic group of tyrosol and homovanillyl alcohol was performed by using acyl chlorides without any catalyst to obtain the corresponding lipophilic derivatives, and then these compounds were converted in good yield and high purity into the hydroxytyrosol derivatives by oxidative/reductive pathway with IBX or DMP and Na2S2O4.

Phosphine-Free Perfluoro-Tagged Palladium Nanoparticles Supported on Fluorous Silica Gel: Application to the Heck Reaction†

The immobilization of phosphine-free perfluoro-tagged palladium nanoparticles Pd-1 on fluorous silica gel (FSG) and their utilization in the Heck reaction have been investigated. High yields of vinylic substitution products have been obtained. Recycling studies have shown that the solid-supported palladium catalyst can be readily recovered and reused several times without significant loss of activity. Reactions and recovery of the solid-supported palladium catalyst system can be carried out in the presence of air, without any particular precaution.

Conversion of naringenin and hesperetin by heterogeneous catalytic Baeyer-Villiger reaction into lactones exhibiting apoptotic activity

Naringenin and hesperetin were converted into the corresponding lactones by hydrogen peroxide activated by poly(4-vinylpiridine)-supported methyltrioxorhenium in t-butanol, an environmentally friendly catalytic system. The products showed a marked apoptotic activity in the genetic tests.

Synthesis of a novel ester of hydroxytyrosol and α-lipoic acid exhibiting an antiproliferative effect on human colon cancer HT-29 cells

A novel ester of hydroxytyrosol and α-lipoic acid was synthesized in satisfactory yield by original and simple procedures and evaluated about its antiproliferative activity on the human colorectal adenocarcinoma HT-29 cell line. The compound exhibited a cell growth inhibitory activity significantly more potent than the corresponding parent natural compounds, very likely due to the induction of cell cycle arrest in the G2/M phase. These data suggest that the novel ester might exert a more effective antitumour activity than hydroxytyrosol and α-lipoic acid.

A new and efficient Baeyer–Villiger rearrangement of flavanone derivatives by the methyltrioxorhenium/H2O2 catalytic system

Abstract The catalytic Baeyer–Villiger rearrangement of flavanones is described by the use of the homogeneous methyltrioxorhenium (MTO)/H2O2 system. In these experimental conditions 3,4-dihydro-4-phenyl-1,5-benzodioxepin-2-ones and previously not reported para-quinone derivatives have been obtained in mild experimental conditions from acceptable to good yields.

Synthesis and Structure/Antioxidant Activity Relationship of Novel Catecholic Antioxidant Structural Analogues to Hydroxytyrosol and Its Lipophilic Esters

A large panel of novel catecholic antioxidants and their fatty acid or methyl carbonate esters has been synthesized in satisfactory to good yields through a 2-iodoxybenzoic acid (IBX)-mediated aromatic hydroxylation as the key step. The new catechols are structural analogues of naturally occurring hydroxytyrosol (3,4-DHE). To evaluate structure/activity relationships, the antioxidant properties of all catecholic compounds were evaluated in vitro by ABTS assay and on whole cells by DCF fluorometric assay and compared with that of the corresponding already known hydroxytyrosyl derivatives. Results outline that all of the new catechols show antioxidant capacity in vitro higher than that of the corresponding hydroxytyrosyl derivatives. Less evident positive effects have been detected in whole cells experiments. Cytotoxicity experiments, using MTT assay, on a representative set of compounds evidenced no influence in cell survival.

Naturally occurring hydroxytyrosol: synthesis and anticancer potential.

Several epidemiological and animal studies have suggested that polyphenols, a group of secondary plant metabolites occurring mainly in the plant kingdom, may have a protective effect against some chronic degenerative diseases such as cancer. Polyphenols are part of the human diet, being present in vegetal food and beverages. Among them, an olive biophenol named hydroxytyrosol [2-(3,4- dihydroxyphenyl)ethanol, HTyr] has recently received particular attention because of its antioxidant, antiproliferative, pro-apoptotic, and anti-inflammatory activities, which have the potential to specifically counteract all cancer hallmarks, thus representing the expectant biological activities underlying the anti-tumor properties of this polyphenol. After a description of the synthetic procedures to prepare pure HTyr, this review takes into consideration the chemopreventive and chemotherapeutic potential of HTyr as the result of its antioxidant, antiproliferative and anti-inflammatory activities. In particular, the review is focused on the current knowledge of the main cellular and molecular mechanisms used by HTyr to affect carcinogenesis, highlighting the specific oncogenic and inflammatory signaling pathways potentially targeted by HTyr.

Alkynylation of aryl halides with perfluoro-tagged palladium nanoparticles immobilized on silica gel under aerobic, copper- and phosphine-free conditions in water

The utilization of perfluoro-tagged palladium nanoparticles immobilized on fluorous silica gel through fluorous-fluorous interactions (Pd(np)-/FSG) or linked to silica gel by covalent bonds (Pd(np)-) in the alkynylation of terminal alkynes with aryl halides under aerobic, copper- and phosphine-free conditions in water, and their recovery and re-utilization, is described.