One-Pot Synthetic Approach to 3-Carboxyl- and 3-Ketopyridines in Aqueous Media.

We describe a one-pot strategy to access 3-carboxyl- and 3-ketopyridines from readily available alkynes and propargylamine via a hydroamination process. This one-pot protocol uses alkynes as starting materials, has a broad substrate scope, and operates in aqueous media and open-air conditions. A series of aryl- and alkyl-substituted pyridines were synthesized. This green methodology can be scaled to laboratory size and was used for the synthesis of the natural product core, 4-aza-fluorenone. Density-functional theory and control mechanistic studies support a domino hydroamination/pericyclic reaction, which includes the formation of the enaminone intermediate and its transformation through an aza-Claisen rearrangement to the desired pyridine product.

Simple Synthetic Approach to N-(Pyridin-2-yl)imidates from Nitrostyrenes and 2-Aminopyridines via the N-(Pyridin-2-yl)iminonitriles as Intermediates.

A facile, green, synthetic protocol of several substituted N-(pyridin-2-yl)imidates from nitrostyrenes and 2-aminopyridines via the corresponding N-(pyridin-2-yl)iminonitriles as intermediates is reported. The reaction process involved the in situ formation of the corresponding α-iminontriles under heterogeneous Lewis acid catalysis in the presence of Al2O3. Subsequently, α-iminonitriles were selectively transformed into the desired N-(pyridin-2-yl)imidates under ambient conditions and in the presence of Cs2CO3 in alcoholic media. Under these conditions, 1,2- and 1,3-propanediols also led to the corresponding mono-substituted imidates at room temperature. The present synthetic protocol was also developed on one mmol scale, providing access to this important scaffold. A preliminary synthetic application of the present N-(pyridin-2-yl)imidates was carried out for their facile conversion into the N-heterocycles 2-(4-chlorophenyl)-4,5-dihydro-1H-imidazole and 2-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine in the presence of the corresponding ethylenediamine and 1,3-diaminopropane.

Polyoxometalate-Driven Ease Conversion of Valuable Furfural to trans-N,N-4,5-Diaminocyclopenten-2-ones.

We investigated the catalytic efficacy of silicotungstic acid (H4SiW12O40) polyoxometalate (POM) toward the reaction between furfural and amines that selectively yields trans-N,N-4,5-substituted-diaminocyclopenten-2-ones (trans-DACPs). H4SiW12O40 facilitates the synthesis of a library of trans-DACPs with loadings as low as 0.05 mol %, in open air, without additives, in short times and good to high isolated yields. The protocol was applied to secondary amines as well as to aromatic primary amines with pKb higher than ca. 9. The present catalytic synthetic protocol has an extended substrate scope with high yields and represents, to the best of our knowledge, the first polyoxometalate-driven paradigm as an efficient method to produce cyclopentanone frameworks under mild reaction conditions.

Supported Gold Nanoparticle-Catalyzed Selective Reduction of Multifunctional, Aromatic Nitro Precursors into Amines and Synthesis of 3,4-Dihydroquinoxalin-2-Ones.

The synthesis of 3,4-dihydroquinoxalin-2-ones via the selective reduction of aromatic, multifunctional nitro precursors catalyzed by supported gold nanoparticles is reported. The reaction proceeds through the in situ formation of the corresponding amines under heterogeneous transfer hydrogenation of the initial nitro compounds catalyzed by the commercially available Au/TiO2-Et3SiH catalytic system, followed by an intramolecular C-N transamidation upon treatment with silica acting as a mild acid. Under the present conditions, the Au/TiO2-TMDS system was also found to catalyze efficiently the present selective reduction process. Both transfer hydrogenation processes showed very good functional-group tolerance and were successfully applied to access more structurally demanding products bearing other reducible moieties such as chloro, aldehyde or methyl ketone. An easily scalable (up to 1 mmol), low catalyst loading (0.6 mol%) synthetic protocol was realized, providing access to this important scaffold. Under these mild catalytic conditions, the desired products were isolated in good to high yields and with a TON of 130. A library analysis was also performed to demonstrate the usefulness of our synthetic strategy and the physicochemical profile of the derivatives.

Selective C-H Allylic Oxygenation of Cycloalkenes and Terpenoids Photosensitized by [Cu(Xantphos)(neoc)]BF4.

We present herein for the first time the use of the [Cu(Xantphos)(neoc)]BF4 as a photocatalyst for the selective C-H allylic oxygenation of cycloalkenes into the corresponding allylic hydroperoxides or alcohols in the presence of molecular oxygen. The proposed methodology affords the products at good yields and has also been applied successfully to several bioactive terpenoids, such as geraniol, linalool, ß-citronellol, and phytol. A mechanistic study involving also kinetic isotope effects (KIEs) supports the proposed singlet oxygen-mediated reaction. On the basis of the high chemoselectivity and yields and the fast and clean reaction processes observed, the present catalytic system, [Cu(Xantphos)(neoc)]BF4, has also been applied to the synthesis, at a laboratory scale, of the cis-Rose oxide, a well-known perfumery ingredient used in rose and geranium perfumes.

Selective Reduction of Nitroarenes to Arylamines by the Cooperative Action of Methylhydrazine and a Tris(N-heterocyclic thioamidate) Cobalt(III) Complex.

We report an efficient catalytic protocol that chemoselectively reduces nitroarenes to arylamines, by using methylhydrazine as a reducing agent in combination with the easily synthesized and robust catalyst tris(N-heterocyclic thioamidate) Co(III) complex [Co(κS,N-tfmp2S)3], tfmp2S = 4-(trifluoromethyl)-pyrimidine-2-thiolate. A series of arylamines and heterocyclic amines were formed in excellent yields and chemoselectivity. High conversion yields of nitroarenes into the corresponding amines were observed by using polar protic solvents, such as MeOH and iPrOH. Among several hydrogen donors that were examined, methylhydrazine demonstrated the best performance. Preliminary mechanistic investigations, supported by UV-vis and NMR spectroscopy, cyclic voltammetry, and high-resolution mass spectrometry, suggest a cooperative action of methylhydrazine and [Co(κS,N-tfmp2S)3] via a coordination activation pathway that leads to the formation of a reduced cobalt species, responsible for the catalytic transformation. In general, the corresponding N-arylhydroxylamines were identified as the sole intermediates. Nevertheless, the corresponding nitrosoarenes can also be formed as intermediates, which, however, are rapidly transformed into the desired arylamines in the presence of methylhydrazine through a noncatalytic path. On the basis of the observed high chemoselectivity and yields, and the fast and clean reaction processes, the present catalytic system [Co(κS,N-tfmp2S)3]/MeNHNH2 shows promise for the efficient synthesis of aromatic amines that could find various industrial applications.

Direct and Indirect Chemiluminescence: Reactions, Mechanisms and Challenges.

Emission of light by matter can occur through a variety of mechanisms. When it results from an electronically excited state of a species produced by a chemical reaction, it is called chemiluminescence (CL). The phenomenon can take place both in natural and artificial chemical systems and it has been utilized in a variety of applications. In this review, we aim to revisit some of the latest CL applications based on direct and indirect production modes. The characteristics of the chemical reactions and the underpinning CL mechanisms are thoroughly discussed in view of studies from the very recent bibliography. Different methodologies aiming at higher CL efficiencies are summarized and presented in detail, including CL type and scaffolds used in each study. The CL role in the development of efficient therapeutic platforms is also discussed in relation to the Reactive Oxygen Species (ROS) and singlet oxygen (1O2) produced, as final products. Moreover, recent research results from our team are included regarding the behavior of commonly used photosensitizers upon chemical activation under CL conditions. The CL prospects in imaging, biomimetic organic and radical chemistry, and therapeutics are critically presented in respect to the persisting challenges and limitations of the existing strategies to date.

Mechanistic Studies on the Michael Addition of Amines and Hydrazines To Nitrostyrenes: Nitroalkane Elimination via a Retro-aza-Henry-Type Process.

In this article we report on the mechanistic studies of the Michael addition of amines and hydrazines to nitrostyrenes. Under the present conditions, the corresponding N-alkyl/aryl substituted benzyl imines and N-methyl/phenyl substituted benzyl hydrazones were observed via a retro-aza-Henry-type process. By combining organic synthesis and characterization experiments with computational chemistry calculations, we reveal that this reaction proceeds via a protic solvent-mediated mechanism. Experiments in deuterated methanol CD3OD reveal the synthesis and isolation of the corresponding deuterated intermediated Michael adduct, results that support the proposed slovent-mediated pathway. From the synthetic point of view, the reaction occurs under mild, noncatalytic conditions and can be used as a useful platform to yield the biologically important N-methyl pyrazoles in a one-pot manner, simple starting with the corresponding nitrostyrenes and the methylhydrazine.

Copper-Promoted Regioselective Synthesis of Polysubstituted Pyrroles from Aldehydes, Amines, and Nitroalkenes via 1,2-Phenyl/Alkyl Migration.

The facile copper-catalyzed synthesis of polysubstituted pyrroles from aldehydes, amines, and ß-nitroalkenes is reported. Remarkably, the use of α-methyl-substituted aldehydes provides efficient access to a series of tetra- and pentasubstituted pyrroles via an overwhelming 1,2-phenyl/alkyl migration. The present methodology is also accessible to non α-substituted aldehydes, yielding the corresponding trisubstituted pyrroles. On the contrary, the use of ketones, in place of aldehydes, does not promote the organic transformation, signifying the necessity of α-substituted aldehydes. The reaction proceeds under mild catalytic conditions with low catalyst loading (0.3-1 mol %), a broad scope, very good functional-group tolerance, and high yields and can be easily scaled up to more than 3 mmol of product, thus highlighting a useful synthetic application of the present catalytic protocol. Based on formal kinetic studies, a possible radical pathway is proposed that involves the formation of an allylic nitrogen radical intermediate, which in turn reacts with the nitroalkene to yield the desired pyrrole framework via a radical 1,2-phenyl or alkyl migration.

Cu(II) Coordination Polymers as Vehicles in the A3 Coupling.

A family of benzotriazole based coordination compounds, obtained in two steps and good yields from commercially available materials, formulated as [CuII(L1)2(MeCN)2]·2ClO4·MeCN (1), [CuII(L1)(NO3)2]·MeCN (2), [ZnII(L1)2(H2O)2]·2ClO4·2MeCN (3), [CuII(L1)2Cl2]2 (4), [CuII5(L1)2Cl10] (5), [CuII2(L1)4Br2]·4MeCN·CuII2Br6 (6), [CuII(L1)2(MeCN)2]·2BF4 (7), [CuII(L1)2(CF3SO3)2] (8), [ZnII(L1)2(MeCN)2]·2CF3SO3 (9), [CuII2(L2)4(H2O)2]·4CF3SO3·4Me2CO (10), and [CuII2(L3)4(CF3SO3)2]·2CF3SO3·Me2CO (11), are reported. These air-stable compounds were tested as homogeneous catalysts for the A3 coupling synthesis of propargylamine derivatives from aldehyde, amine, and alkyne under a noninert atmosphere. Fine tuning of the catalyst resulted in a one-dimensional (1D) coordination polymer (CP) (8) with excellent catalytic activity in a wide range of substrates, avoiding any issues that would inhibit its performance.

Controllable Synthesis of Mesoporous Iron Oxide Nanoparticle Assemblies for Chemoselective Catalytic Reduction of Nitroarenes.

Iron(III) oxide is a low-cost material with applications ranging from electronics to magnetism, and catalysis. Recent efforts have targeted new nanostructured forms of Fe2O3 with high surface area-to-volume ratio and large pore volume. Herein, the synthesis of 3D mesoporous networks consisting of 4-5 nm γ-Fe2O3 nanoparticles by a polymer-assisted aggregating self-assembly method is reported. Iron oxide assemblies obtained from the hybrid networks after heat treatment have an open-pore structure with high surface area (up to 167 m(2)g(-1)) and uniform pores (ca. 6.3 nm). The constituent iron oxide nanocrystals can undergo controllable phase transition from γ-Fe2O3 to α-Fe2O3 and to Fe3O4 under different annealing conditions while maintaining the 3D structure and open porosity. These new ensemble structures exhibit high catalytic activity and stability for the selective reduction of aryl and alkyl nitro compounds to the corresponding aryl amines and oximes, even in large-scale synthesis.

Green photocatalytic organic transformations by polyoxometalates vs. mesoporous TiO2 nanoparticles: selective aerobic oxidation of alcohols.

In this study, the catalytic activity of decatungstate (W10O32(4-)) supported on mesoporous TiO2 nanoparticle assemblies (DT-MTA) was compared with that of homogeneous [Bu4N]4W10O32 catalysts under mild conditions. Our experiments showed that both catalytic systems achieve exceptionally high activity and selectivity under UV-visible light oxidation of various para-substituted aryl alcohols, using molecular oxygen as a "green" oxidant. The chemoselective transformation of aryl alcohols into the corresponding ketones was investigated with gas chromatography (GC) and NMR spectroscopy. Product analysis and kinetic results also indicated that these photooxidation reactions proceed via both electron transfer (ET) and hydrogen atom transfer (HAT) mechanisms over the DT-MTA catalyst, with the former one as the predominant, whereas a HAT route was adopted to account for the decatungstate homogeneous catalyzed reactions.

Synergy of redox-activity and hemilability in thioamidato cobalt(III) complexes for the chemoselective reduction of nitroarenes to anilines: catalytic and mechanistic investigation.

Reduction of nitro-compounds to amines is one of the most often employed and challenging catalytic processes in the fine and bulk chemical industry. Herein, we present two series of mononuclear homoleptic and heteroleptic Co(III) complexes, i.e., [Co(LNS)3] and [Co(LNS)2L1L2]x+, respectively (x = 0 or 1, LNS = pyrimidine- or pyridine-thioamidato, L1/L2 = thioamidato, phosphine or pyridine), which successfully catalyze the transformation of nitroarenes to anilines by methylhydrazine. The catalytic reaction can be accomplished for a range of electronically and sterically diverse nitroarenes, using mild experimental conditions and low catalyst loadings, resulting in the corresponding anilines in high yields, with high chemoselectivity, and no side-products. Electronic and steric properties of the ligands play pivotal role in the catalytic efficacy of the respective complexes. In particular, complexes bearing ligands of high hemilability/lability and being capable of stabilizing lower metal oxidation-states exhibit the highest catalytic activity. Mechanistic investigations suggest the participation of the Co(III) complexes in two parallel reaction pathways: (a) coordination-induced activation of methylhydrazine and (b) reduction of nitroarenes to anilines by methylhydrazine, through the formation of Co(I) and Co-hydride intermediates.

Biological Response of Human Cancer Cells to Ionizing Radiation in Combination with Gold Nanoparticles.

In the context of improving radiation therapy, high-atomic number (Z) metallic nanoparticles and, more importantly, gold-based nanostructures are developed as radiation enhancers/radiosensitizers. Due to the diversity of cell lines, nanoparticles, as well as radiation types or doses, the resulting biological effects may differ and remain obscure. In this multiparameter study, we aim to shed light on these effects and investigate them further by employing X-irradiation and three human cancer cell lines (PC3, A549, and U2OS cells) treated by multiple techniques. TEM experiments on PC3 cells showed that citrate-capped AuNPs were found to be located mostly in membranous structures/vesicles or autophagosomes, but also, in the case of PEG-capped AuNPs, inside the nucleus as well. The colony-forming capability of cancer cells radiosensitized by AuNPs decreased significantly and the DNA damage detected by cytogenetics, γH2AX immunostaining, and by single (γH2AX) or double (γH2AX and OGG1) immunolocalization via transmission electron microscopy (TEM) was in many cases higher and/or persistent after combination with AuNPs than upon individual exposure to ionizing radiation (IR). Moreover, different cell cycle distribution was evident in PC3 but not A549 cells after treatment with AuNPs and/or irradiation. Finally, cellular senescence was investigated by using a newly established staining procedure for lipofuscin, based on a Sudan Black-B analogue (GL13) which showed that based on the AuNPs' concentration, an increased number of senescent cells might be observed after exposure to IR. Even though different cell lines or different types and concentrations of AuNPs may alter the levels of radiosensitization, our results imply that the complexity of damage might also be an important factor of AuNP-induced radiosensitization.

Oxidative cycloaddition of 1,1,3,3-tetramethyldisiloxane to alkynes catalyzed by supported gold nanoparticles.

Gold nanoparticles supported on TiO(2) (0.1-1% mol) catalyze at room temperature and at extremely mild conditions the unprecedented oxidative cycloaddition of 1,1,3,3-tetramethyldisiloxane to alkynes, forming substituted 2,5-dihydro-1,2,5-oxadisiloles, with concomitant evolution of hydrogen gas. For the majority of the substrates, the yields are exceptional (up to 99%). The reaction proceeds at room temperature, tolerates a variety of functional groups, and can be performed in several solvents.

Functionalized 3(2H)-furanones via photooxygenation of (ß-keto)-2-substituted furans: application to the biomimetic synthesis of merrekentrone C.

Photooxygenation of (ß-keto)-2-substituted furans leads, in a one pot operation, to functionalized 3(2H)-furanones with good to excellent yields. This methodology was applied as a key-step to the concise and biomimetic synthesis of the sesquiterpene merrekentrone C. The precursor to merrekentrone C, keto difuran, was synthesized using a cross coupling of α-iodo-3-acetylfuran with an alkenyl furan under Fenton-type conditions.

Selective Mild Oxidation of Anilines into Nitroarenes by Catalytic Activation of Mesoporous Frameworks Linked with Gold-Loaded Mn3 O4 Nanoparticles.

This work reports the synthesis and catalytic application of mesoporous Au-loaded Mn3 O4 nanoparticle assemblies (MNAs) with different Au contents, i. e., 0.2, 0.5 and 1 wt %, towards the selective oxidation of anilines into the corresponding nitroarenes. Among common oxidants, as well as several supported gold nanoparticle platforms, Au/Mn3 O4 MNAs containing 0.5 wt % Au with an average particle size of 3-4 nm show the best catalytic performance in the presence of tert-butyl hydroperoxide (TBHP) as a mild oxidant. In all cases, the corresponding nitroarenes were isolated in high to excellent yields (85-97 %) and selectivity (>98 %) from acetonitrile or greener solvents, such as ethyl acetate, after simple flash chromatography purification. The 0.5 % Au/Mn3 O4 catalyst can be isolated and reused four times without a significant loss of its activity and can be applied successfully to a lab-scale reaction of p-toluidine (1 mmol) leading to the p-nitrotulene in 83 % yield. The presence of AuNPs on the Mn3 O4 surface enhances the catalytic activity for the formation of the desired nitroarene. A reasonable mechanism was proposed including the plausible formation of two intermediates, the corresponding N-aryl hydroxylamine and the nitrosoarene.

Skeletally Tunable Seven-Membered-Ring Fused Pyrroles.

We describe a copper-mediated method that enables the synthesis of seven-membered-ring fused pyrroles (7-mrFPs). The protocol proceeds via an in situ spiro-intermediate ring expansion and tolerates a library of 7-mrFP derivatives with a broad range of functional groups in a simple step with tangible parameters and substrate adaptations. These rare 7-mrFPs are now accessible on a millimolar scale, and selected examples exhibit high antioxidant activity.

Decatungstate as an efficient photocatalyst in organic chemistry.

In view of its unique photocatalytic properties, decatungstate (W(10)O(32)(4-)) is rapidly emerging as a promising tool in organic chemistry. This tutorial review surveys recent developments in the chemistry of decatungstate, including mostly synthetic, and to a lesser extent mechanistic aspects. We have chosen to present several representative examples that illustrate the diverse uses of decatungstate in organic synthesis. Thus, the decatungstate-mediated radical functionalization of several classes of organic compounds such as alkanes, alkenes, alcohols, aldehydes and sulfides, under both aerobic and anaerobic conditions, represents reactions of fundamental and practical interest in academia and industry. Several new discoveries concerning the heterogenization of decatungstate for the development of sustainable methods with broad applications in catalysis, such as the photooxidation or photodegradation of various organic substrates, are also presented.

Selective Synthesis of Benzimidazoles from o-Phenylenediamine and Aldehydes Promoted by Supported Gold Nanoparticles.

We investigated the catalytic efficacy of supported gold nanoparticles (AuNPs) towards the selective reaction between o-phenylenediamine and aldehydes that yields 2-substituted benzimidazoles. Among several supported gold nanoparticle platforms, the Au/TiO2 provides a series of 2-aryl and 2-alkyl substituted benzimidazoles at ambient conditions, in the absence of additives and in high yields, using the mixture CHCl3:MeOH in ratio 3:1 as the reaction solvent. Among the AuNPs catalysts used herein, the Au/TiO2 containing small-size nanoparticles is found to be the most active towards the present catalytic methodology. The Au/TiO2 can be recovered and reused at least five times without a significant loss of its catalytic efficacy. The present catalytic synthetic protocol applies to a broad substrate scope and represents an efficient method for the formation of a C-N bond under mild reaction conditions. Notably, this catalytic methodology provides the regio-isomer of the anthelmintic drug, Thiabendazole, in a lab-scale showing its applicability in the efficient synthesis of such N-heterocyclic molecules at industrial levels.