Bismuth(III)-Catalyzed Regioselective Selenation of Indoles with Diaryl Diselenides: Synthesis of 3-Selanylindoles.

Heterocyclic aryl selenides have recently attracted considerable research interest owing to their applications in biological and pharmaceutical fields. Herein, we describe a simple and general synthesis of 3-selanylindoles via a novel regioselective C-H selenation of indoles using a bismuth reagent as a catalyst. The reactions of indoles with diselenides in the presence of 10 mol% BiI3 at 100 °C in DMF afforded the corresponding 3-selanylindoles in moderate-to-excellent yields. The reaction proceeded efficiently under aerobic conditions by adding only a catalytic amount of BiI3, which was non-hygroscopic and less toxic, and both selanyl groups of the diselenide were transferred to the desired products.

Sb-Phenyl-N-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine Induces Perlecan Core Protein Synthesis in Cultured Vascular Endothelial Cells.

Vascular endothelial cells synthesize and secrete perlecan, a large heparan sulfate proteoglycan that increases the anticoagulant activity of vascular endothelium by inducing antithrombin III and intensifying fibroblast growth factor (FGF)-2 activity to promote migration and proliferation in the repair process of damaged endothelium during the progression of atherosclerosis. However, the exact regulatory mechanisms of endothelial perlecan expression remain unclear. Since organic-inorganic hybrid molecules are being developed rapidly as tools to analyze biological systems, we searched for a molecular probe to analyze these mechanisms using a library of organoantimony compounds and found that the Sb-phenyl-N-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine (PMTAS) molecule promotes the expression of perlecan core protein gene without exhibiting cytotoxicity in vascular endothelial cells. In the present study, we characterized proteoglycans synthesized by cultured bovine aortic endothelial cells using biochemical techniques. The results indicated that PMTAS selectively induced perlecan core protein synthesis, without affecting the formation of its heparan sulfate chain, in vascular endothelial cells. The results also implied that this process is independent of the endothelial cell density, whereas in vascular smooth muscle cells, it occurred only at high cell density. Thus, PMTAS would be a useful tool for further studies on the mechanisms underlying perlecan core protein synthesis in vascular cells, which is critical in the progression of vascular lesions, such as those during atherosclerosis.

One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides.

The development of novel and efficient synthesis methods for 2-substituted benzazole derivatives is of interest as they are biologically active substances. Herein, a simple method for the synthesis of 2-aryl- and 2-alkyl-substituted benzazoles is described. The reaction of 2-aminophenols with thioamides at 60 °C in the presence of triphenylbismuth dichloride in 1,2-dichloroethane as a promoter afforded various 2-aryl- and 2-alkylbenzoxazoles in moderate to excellent yields under mild reaction conditions. This method could also be applied to the synthesis of benzimidazoles and benzothiazoles. This study presents the first use of triphenylbismuth dichloride to produce benzimidoyl chloride from thioamides by desulfurization and chlorination, as well as its application to the synthesis of 2-substituted benzazoles.

Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes.

Alkynyl selenides have attracted considerable research interest recently, owing to their applications in the biological and pharmaceutical fields. The Cu-catalyzed tandem reaction for the synthesis of novel alkynyl imidazopyridinyl selenides is presented. A one-pot synthesis route afforded alkynyl imidazopyridinyl selenides in moderate to good yields. This was achieved by a two-step reaction between terminal alkynes and diimidazopyridinyl diselenides, generated from imidazo[1,2-a]pyridines and Se powder, using 10 mol % of CuI and 1,10-phenanthroline as the catalytic system under aerobic conditions. The C(sp2)-Se and C(sp)-Se bond-formation reaction can be performed in one-pot by using inexpensive and easy to handle Se powder as the Se source. The reaction proceeded with terminal alkynes having various substitutions, such as aryl, vinyl, and alkyl groups. The obtained alkynyl imidazopyridinyl selenide was found to undergo nucleophilic substitution reaction on Se atom using organolithium reagents and 1,3-dipolar azide-alkyne cycloaddition based on the alkyne moiety.

Effects of Substitution on Cytotoxicity of Diphenyl Ditelluride in Cultured Vascular Endothelial Cells.

Among organic-inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.

Synthesis, Structural Characterization, and Optical Properties of Benzene-Fused Tetracyclic and Pentacyclic Stiboles.

The expectation that antimony (Sb) compounds should display phosphorescence emissions based on the "heavy element effect" prompted our interest in the introduction of antimony to a biaryl as the bridging atom in a fused heterole system. Herein, the synthesis, molecular structures, and optical properties of novel benzene-fused heteroacenes containing antimony or arsenic atoms are described. The stiboles and arsole were prepared by the condensation of dibromo(phenyl)stibane or dichloro(phenyl)arsine with dilithium intermediates derived from the corresponding dibromo compounds. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal analysis revealed that the linear pentacyclic stibole was highly symmetric in both the solution and crystal states. In contrast, the curved pentacyclic stibole adopted a helical structure in solution, and surprisingly, only M helical molecules were crystallized from the racemate. All synthesized compounds produced very weak or no emissions at room temperature or in the solid state. In contrast, the linear penta- and tetracyclic stiboles exhibited clear phosphorescence emissions in the CHCl3 frozen matrix at 77 K under aerobic conditions.

Synthesis, structural characterization, and optical properties of benzo[f]naphtho[2,3-b]phosphoindoles.

Phosphole-fused π-conjugated acenes have been attracting interest because of the attractive features of the phosphole moiety, such as fluorescence and chemically modifiable properties. Herein, 6-phenyl-6H-benzo[f]naphtho[2,3-b]phosphoindole was prepared by reacting dichlorophenylphosphine with a dilithium intermediate derived from 3,3'-dibromo-2,2'-binaphthyl. Various derivatives, such as a phospholium salt and a borane-phosphole complex with functional groups on the phosphorus atom were synthesized using the obtained phosphole as a common starting material. Single-crystal X-ray analysis of the parent benzo[f]naphtho[2,3-b]phosphoindole revealed that the pentacyclic ring is almost planar. Fluorescence spectroscopy data showed that the phosphole derivatives, such as phosphine oxide and the phospholium salt and borane complex exhibited photoluminescence in chloroform.

Synthesis of Nitriles via the Iodine-Mediated Dehydrosulfurization of Thioamides.

A simple general method for the synthesis of nitriles using the inexpensive and easy to handle iodine (I2) is described herein. The reaction of thioamides with I2 in the presence of triethylamine at room temperature under aerobic conditions afforded various nitriles bearing aryl, vinyl, and alkyl groups in good-to-excellent yields. This method was also effective for conversion from thioureas to cyanamides.

Palladium-Catalyzed C-H Arylation of Benzofurans with Triarylantimony Difluorides for the Synthesis of 2-Arylbenzofurans.

Pd-catalyzed regioselective C-H arylation is a useful tool for the chemical modification of aromatic heterocycles and 2-arylbenzofuran derivatives are of interest as biologically active substances. Herein, the reaction of triarylantimony difluorides with benzofurans under aerobic conditions in 1,2-DCE, using 5 mol% Pd (OAc)2 and 2 eq. of CuCl2 at 80 °C, produced a variety of 2-arylbenzofurans in moderate-to-high yields. The reaction is sensitive to the electronic nature of the substituents on the benzene ring of the triarylantimony difluorides: an electron-donating group showed higher reactivity than an electron-withdrawing group. Single crystal X-ray analysis of tri(p-methylphenyl) antimony difluoride revealed that the central antimony atom exhibits trigonal bipyramidal geometry.

Synthesis and anticancer activity of bis(2-arylimidazo[1,2-a]pyridin-3-yl) selenides and diselenides: the copper-catalyzed tandem C-H selenation of 2-arylimidazo[1,2-a]pyridine with selenium.

Most heteroaryl selenides and diselenides are biologically active, with some reported to act as antioxidants and show activities that are medicinally relevant; hence, the development of efficient methods for their synthesis is an important objective. Herein, a simple method for the synthesis of selenides and diselenides bearing imidazo[1,2-a]pyridine rings and their anticancer activity are described. The double C-H selenation of imidazo[1,2-a]pyridine with Se powder was catalyzed by CuI (10 mol %) ligated with 1,10-phenanthroline (10 mol %) at 130 °C under aerobic conditions. The selenides or diselenides were prepared almost selectively using selenium powder in an appropriate quantity under otherwise identical reaction conditions. The prepared selenides and diselenides bearing two imidazo[1,2-a]pyridine rings were all novel compounds. Among the prepared diselenides and selenides that exhibited cytotoxicity against cancer cells, bis[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl] diselenide showed an excellent anticancer activity and low cytotoxicity toward noncancer cells, suggesting that this diselenide is a potential lead compound for anticancer therapy.

Synthesis of benzo[d]imidazo[2,1-b]benzoselenoazoles: Cs2CO3-mediated cyclization of 1-(2-bromoaryl)benzimidazoles with selenium.

The synthesis of benzimidazo[2,1-b]benzoselenoazoles is described. The novel ring-closure reaction of 1-(2-bromoaryl)benzimidazoles with Se powder is promoted by Cs2CO3 (2 equiv) in DMF at 150 °C. Moreover, the obtained tetracyclic heterocycles are all novel compounds. Single-crystal X-ray analysis of the parent benzimidazo[2,1-b]benzoselenoazole revealed that the tetracyclic ring is almost planar. Absorption spectroscopy data of the benzimidazo[2,1-b]benzoselenoazoles showed the λmax was dependent on the number of rings.

Synthesis, antitumor activity, and cytotoxicity of 4-substituted 1-benzyl-5-diphenylstibano-1H-1,2,3-triazoles.

Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4a-f). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) and their 5-unsubstituted 1,2,3-triazoles (4a-f) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3a-f) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4a-f) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3a-f). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3a-f), but not all 5-unsubstituted 1,2,3-triazoles (4a-f), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3b-e) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future.

Microwave-Assisted Debromination of α-Bromoketones with Triarylstibanes in Water.

Several α-bromoarylketones were reacted with triarylstibanes under microwave irradiation in water to obtain the corresponding debrominated ketones. Under similar reaction conditions, 1,2-elimination of vic-dibromides in water afforded the corresponding E-olefins. This reaction is the first example of organoantimony compounds utilized for organic transformation in water.

Synthesis and photophysical properties of novel benzophospholo[3,2-b]indole derivatives.

The parent benzophospholo[3,2-b]indole was prepared by the reaction of dichlorophenylphosphine with a dilithium intermediate, which was prepared in two steps from 2-ethynyl-N,N-dimethylaniline. Using the obtained benzophosphole-fused indole as a common starting material, simple modifications were carried out at the phosphorus center of the phosphole, synthesizing various functionalized analogs. The X-ray structure analysis of trivalent phosphole and phosphine oxide showed that the fused tetracyclic moieties are planar. The benzophosphole-fused indoles, such as phosphine oxide, phospholium salt, and borane complex, exhibited strong photoluminescence in dichloromethane (Φ = 67-75%).

Transcriptional Induction of Metallothionein by Tris(pentafluorophenyl)stibane in Cultured Bovine Aortic Endothelial Cells.

Vascular endothelial cells cover the luminal surface of blood vessels and contribute to the prevention of vascular disorders such as atherosclerosis. Metallothionein (MT) is a low molecular weight, cysteine-rich, metal-binding, inducible protein, which protects cells from the toxicity of heavy metals and active oxygen species. Endothelial MT is not induced by inorganic zinc. Adequate tools are required to investigate the mechanisms underlying endothelial MT induction. In the present study, we found that an organoantimony compound, tris(pentafluorophenyl)stibane, induces gene expression of MT-1A and MT-2A, which are subisoforms of MT in bovine aortic endothelial cells. The data reveal that MT-1A is induced by activation of both the MTF-1-MRE and Nrf2-ARE pathways, whereas MT-2A expression requires only activation of the MTF-1-MRE pathway. The present data suggest that the original role of MT-1 is to protect cells from heavy metal toxicity and oxidative stress in the biological defense system, while that of MT-2 is to regulate intracellular zinc metabolism.

Copper-catalyzed [3 + 2] cycloaddition of (phenylethynyl)di-p-tolylstibane with organic azides.

Trisubstituted 5-stibano-1H-1,2,3-triazoles were synthesized in moderate to excellent yields by the Cu-catalyzed [3 + 2] cycloaddition of a ethynylstibane with organic azides in the presence of CuBr (5 mol %) under aerobic conditions. The reaction of 5-stibanotriazole with HCl, I2, and NOBF4 afforded 1-benzyl-4-phenyltriazole, 1-benzyl-5-iodo-4-phenyltriazole, and a pentavalent organoantimony compound, respectively.

Pd-catalyzed P-arylation of triarylantimony dicarboxylates with dialkyl H-phosphites without a base: synthesis of arylphosphonates.

The reaction of triarylantimony diacetates [Ar3Sb(OAc)2] with dialkyl H-phosphites [H-PO(OR)2] in the presence of a Pd(PPh3)4 (5 mol%) catalyst led to the formation of arylphosphonates in moderate to excellent yield under base-free conditions. This reaction is the first example of carbon-phosphorus bond formation by using an organoantimony compound as a pseudo-halide.

Novel mono substituted pyridoimidazoisoquinoliniums via a silver-catalyzed intramolecular cyclization and their applications in cellular imaging.

Cationic heterocycles, an important class of organic compounds soluble in polar solvents, have been gaining attention in the construction of fluorescent probes. This paper reports the quick synthesis of novel pyrido[1',2';2,3]imidazo[5,1-a]isoquinoliniums starting from 2-(2-ethynylphenyl)imidazo[1,2-a]pyridines at room temperature via intramolecular cyclization by employing a catalytic amount of silver trifluoromethanesulfonate in addition to lithium trifluoromethanesulfonate and silica gel as the counter anion source and additive, respectively. The designed pyridoimidazoisoquinoliniums consisted of an imidazo[1,2-a]pyridine fused isoquinolinium. The X-ray diffraction results revealed that pyrido[1',2';2,3]imidazo[5,1-a]isoquinolinium trifluoromethanesulfonate contained considerable planar parent skeletons and interacted by π-π stacking with neighbouring molecules. Furthermore, in a methanol solution the designed 6-phenyl derivative exhibited strong fluorescence in the 420-450 nm region in addition to strong mitochondrial specificity in a cell staining assay.

Aluminepin: aluminum analogues of borepin and gallepin.

We report synthesis of dibenzoaluminepin as the first aluminepin, an aluminum analogue of borepin and gallepin. This compound contains one molecule of ethereal solvent on the Al atom, which adopts a tetrahedral geometry. The central 7-membered aluminepin ring has a boatlike conformation and was characterized by single-crystal X-ray diffraction, (1)H/(13)C NMR, and DFT studies. In addition, NICS, NBO, and theoretical calculations provide insight into the nature of the bonding and aromaticity of aluminepins.

Silver-catalyzed three-component reaction of uracils, arylboronic acids, and selenium: synthesis of 5-arylselanyluracils.

Herein, we describe a simple and general multi-component synthesis of 5-arylselanyluracils by the regioselective C-H selenation of uracils. Reactions of uracils with arylboronic acid and Se powder in the presence of AgNO3 (10 mol%) at 120 °C under aerobic conditions afforded various 5-arylselanyluracils. The source of the introduced selanyl group was prepared from a commercially available arylboronic acid and Se powder in the reaction system, thereby ensuring a simple and efficient protocol. This reaction represents the first example of the synthesis of a 5-arylselanyluracil in a multi-component system.