A General and Highly Versatile Heterogeneous Pd-Catalyzed Oxidative Aminocarbonylation of Alkynes with Aromatic and Aliphatic Amines.

An efficient heterogeneous catalytic system for the oxidative aminocarbonylation of alkynes and amines in the presence of CO/O2 to afford substituted propiolamides has been developed. The active nanocatalyst, [Pd/Mg3Al-LDH]-300(D), is composed by Pd nanoaggregates (2-3 nm average particle size) stabilized over a partially dehydrated [Mg3Al-LDH] matrix. The methodology has resulted widely applicable, being the first catalytic system, either homogeneous or heterogeneous, able to activate not only aliphatic amines but also poorly-nucleophilic aromatic amines. In fact, >60 substituted propiolamides have been synthesized in good to excellent isolated yields through this methodology, being 27 novel compounds. An important characterization effort (XRD, 27Al MAS NMR, TGA, TPD-CO2, BET area, XPS, HAADF-HRSTEM and HRTEM) and optimization of the synthesis conditions of the optimal catalyst has been performed. This study, together with a series of kinetic and mechanistic essays, indicates that the optimal catalyst is composed by Pd(0) species stabilized in a partially dehydrated/dehydroxylated LDH material with a Mg/Al molar ratio of 3 and a small crystallite size. All the experimental data indicates that the in situ formation of [PdI2] active species in the material surface together with the presence of a matrix with the optimal acid/base properties are key aspects of this process.

Silver Supported Nanoparticles on [Mg4 Al-LDH] as an Efficient Catalyst for the α-Alkylation of Nitriles, Oxindoles and Other Carboxylic Acid Derivatives with Alcohols.

An efficient heterogeneous silver-catalyzed α-alkylation of nitriles and oxindoles using alcohols via borrowing hydrogen strategy has been developed for the first time. The active nanostructured material, namely [Ag/Mg4 Al-LDH], composed by silver nanoparticles (3-4 nm average particle size) homogeneously stabilized onto a [Mg4 Al-LDH] support with suitable Brønsted basic properties, constitutes a stable catalyst for the sustainable building of novel C-C bonds from alcohols and C-nucleophiles. By applying this catalyst, a broad range of α-functionalized nitriles and oxindoles has been accessed with good to excellent isolated yields and without the addition of external bases. Moreover, the novel silver nanocatalyst has also demonstrated its successful application to the cyclization of N-[2-(hydroxymethyl)phenyl]-2-phenylacetamides to afford 3-arylquinolin-2(1H)-ones, through a one-pot dehydrogenation and intramolecular α-alkylation. Control experiments, kinetic studies, and characterization data of a variety of [Ag/LDH]-type materials confirmed the silver role in the dehydrogenation and hydrogenation steps, while [Mg4 Al-LDH] matrix is able to catalyze condensation. Interestingly, these studies suggest as key point for the successful activity of [Ag/Mg4 Al-LDH], in comparison with other [Ag/LDH]-type nanocatalysts, the suitable acid-base properties of this material.

Catalytic Reductive Alcohol Etherifications with Carbonyl-Based Compounds or CO2 and Related Transformations for the Synthesis of Ether Derivatives.

Ether derivatives have myriad applications in several areas of chemical industry and academia. Hence, the development of more effective and sustainable protocols for their production is highly desired. Among the different methodologies reported for ether synthesis, catalytic reductive alcohol etherifications with carbonyl-based moieties (aldehydes/ketones and carboxylic acid derivatives) have emerged in the last years as a potential tool. These processes constitute appealing routes for the selective production of both symmetrical and asymmetrical ethers (including O-heterocycles) with an increased molecular complexity. Likewise, ester-to-ether catalytic reductions and hydrogenative alcohol etherifications with CO2 to dialkoxymethanes and other acetals, albeit in less extent, have undergone important advances, too. In this Review, an update of the recent progresses in the area of catalytic reductive alcohol etherifications using carbonyl-based compounds and CO2 have been described with a special focus on organic synthetic applications and catalyst design. Complementarily, recent progress made in catalytic acetal/ketal-to-ether or ester-to-ether reductions and other related transformations have been also summarized.

Homogeneous and heterogeneous catalytic reduction of amides and related compounds using molecular hydrogen.

Catalytic hydrogenation of amides is of great interest for chemists working in organic synthesis, as the resulting amines are widely featured in natural products, drugs, agrochemicals, dyes, etc. Compared to traditional reduction of amides using (over)stoichiometric reductants, the direct hydrogenation of amides using molecular hydrogen represents a greener approach. Furthermore, amide hydrogenation is a highly versatile transformation, since not only higher amines (obtained by C-O cleavage), but also lower amines and alcohols, or amino alcohols (obtained by C-N cleavage) can be selectively accessed by fine tuning of reaction conditions. This review describes the most recent advances in the area of amide hydrogenation using H2 exclusively and molecularly defined homogeneous as well as nano-structured heterogeneous catalysts, with a special focus on catalyst development and synthetic applications.

Self-Assembly of Catalytically Active Supramolecular Coordination Compounds within Metal-Organic Frameworks.

Supramolecular coordination compounds (SCCs) represent the power of coordination chemistry methodologies to self-assemble discrete architectures with targeted properties. SCCs are generally synthesized in solution, with isolated fully coordinated metal atoms as structural nodes, thus severely limited as metal-based catalysts. Metal-organic frameworks (MOFs) show unique features to act as chemical nanoreactors for the in situ synthesis and stabilization of otherwise not accessible functional species. Here, we present the self-assembly of PdII SCCs within the confined space of a pre-formed MOF (SCCs@MOF) and its post-assembly metalation to give a PdII-AuIII supramolecular assembly, crystallography underpinned. These SCCs@MOFs catalyze the coupling of boronic acids and/or alkynes, representative multi-site metal-catalyzed reactions in which traditional SCCs tend to decompose, and retain their structural integrity as a consequence of the synergetic hybridization between SCCs and MOFs. These results open new avenues in both the synthesis of novel SCCs and their use in heterogeneous metal-based supramolecular catalysis.

Catalytic Reductive N-Alkylations Using CO2 and Carboxylic Acid Derivatives: Recent Progress and Developments.

N-Alkylamines are key intermediates in the synthesis of fine chemicals, dyes, and natural products, and hence are highly valuable building blocks in organic chemistry. Consequently, the development of greener and more efficient procedures for their production continues to attract the interest of both academic and industrial chemists. Reductive procedures such as reductive amination or N-alkylation through hydrogen autotransfer by employing carbonyl compounds or alcohols as alkylating agents have prevailed for the synthesis of amines. In the last few years, carboxylic/carbonic acid derivatives and CO2 have been introduced as alternative and convenient alkylating sources. The safety, easy accessibility, and high stability of these reagents makes the development of new reductive transformations with them as N-alkylating agents a useful alternative to existing procedures. In this Review, we summarize reported examples of one-pot reductive N-alkylation methods that use carboxylic/carbonic acid derivatives or CO2 as alkylating agents.

Cobalt-catalysed reductive C-H alkylation of indoles using carboxylic acids and molecular hydrogen.

The direct CH-alkylation of indoles using carboxylic acids is presented for the first time. The catalytic system based on the combination of Co(acac)3 and 1,1,1-tris(diphenylphosphinomethyl)-ethane (Triphos, L1), in the presence of Al(OTf)3 as co-catalyst, is able to perform the reductive alkylation of 2-methyl-1H-indole with a wide range of carboxylic acids. The utility of the protocol was further demonstrated through the C3 alkylation of several substituted indole derivatives using acetic, phenylacetic or diphenylacetic acids. In addition, a careful selection of the reaction conditions allowed to perform the selective C3 alkenylation of some indole derivatives. Moreover, the alkenylation of C2 position of 3-methyl-1H-indole was also possible. Control experiments indicate that the aldehyde, in situ formed from the carboxylic acid hydrogenation, plays a central role in the overall process. This new protocol enables the direct functionalization of indoles with readily available and stable carboxylic acids using a non-precious metal based catalyst and hydrogen as reductant.

Unprecedented selective homogeneous cobalt-catalysed reductive alkoxylation of cyclic imides under mild conditions.

The first general and efficient non-noble metal-catalysed reductive C2-alkoxylation of cyclic imides (phthalimides and succinimides) is presented. Crucial for the success is the use of [Co(BF4)2·6H2O/triphos (L1)] combination and no external additives are required. Using the optimal cobalt-system, the hydrogenation of the aromatic ring of the parent phthalimide is avoided and only one of the carbonyl groups is selectively functionalized. The resulting products, N- and aryl-ring substituted 3-alkoxy-2,3-dihydro-1H-isoindolin-1-one and N-substituted 3-alkoxy-pyrrolidin-2-one derivatives, are prepared under mild conditions in good to excellent isolated yields. Intramolecular reductive couplings can also be performed affording tricyclic compounds in a one-step process. The present protocol opens the way to the development of new base-metal processes for the straightforward synthesis of functionalized N-heterocyclic compounds of pharmaceutical and biological interest.

A General and Highly Selective Cobalt-Catalyzed Hydrogenation of N-Heteroarenes under Mild Reaction Conditions.

Herein, a general and efficient method for the homogeneous cobalt-catalyzed hydrogenation of N-heterocycles, under mild reaction conditions, is reported. Key to success is the use of the tetradentate ligand tris(2-(diphenylphosphino)phenyl)phosphine). This non-noble metal catalyst system allows the selective hydrogenation of heteroarenes in the presence of a broad range of other sensitive reducible groups.

Low-Temperature Hydrogenation of Carbon Dioxide to Methanol with a Homogeneous Cobalt Catalyst.

Herein we describe the first homogeneous non-noble metal catalyst for the hydrogenation of CO2 to methanol. The catalyst is formed in situ from [Co(acac)3 ], Triphos, and HNTf2 and enables the reaction to be performed at 100 °C without a decrease in activity. Kinetic studies suggest an inner-sphere mechanism, and in situ NMR and MS experiments reveal the formation of the active catalyst through slow removal of the acetylacetonate ligands.

Selective Hydrogenation of Nitriles to Primary Amines by using a Cobalt Phosphine Catalyst.

A general procedure for the catalytic hydrogenation of nitriles to primary amines by using a non-noble metal-based system is presented. Co(acac)3 in combination with tris[2-(dicyclohexylphosphino)ethyl]phosphine efficiently catalyzes the selective hydrogenation of a wide range of (hetero)aromatic and aliphatic nitriles to give the corresponding amines.

Evaluation of the Novel Antichagasic Activity of [1,2,3]Triazolo[1,5-a]pyridine Derivatives.

BACKGROUND: Trypanosoma cruzi is the causative agent of Chagas disease. This parasite is vulnerable to the effects of ROS as its main defense mechanism against exogenous agents trypanothione is also another weakness of the parasite that investigated related to the inhibition of enzymes belonging P450 system, mainly CYP51. In our group we have synthesized a series of triazoles known as [1,2,3]triazolo[1,5-a]pyridyl ketones, and pyridyl ketones. These families have shown interesting structural features due to the presence of electron withdrawing moieties attached to the main heterocycle (triazoles and/or pyridines) and are proposed as potential target in the parasite, by the presence of the carbonyl group being able to be reduced and form a free radical that could interact with molecular oxygen generating ROS in the parasite. Furthermore, the triazole ring and pyridines have been considered as potent inhibitors of sterol biosynthesis, the lock being part CYP51. RESULT: Our results showed that the series is capable of generating a stable radical species and generate ROS in the parasite. On the other hand these molecules are potent inhibitors of enzymes belonging to the complex P450. We have focused on the inhibition of ergosterol biosynthesis demonstrating that triazole/ pyridine families are able to affect this pathway being observed the accumulation of squalene and lanosterol.

Esters, Including Triglycerides, and Hydrogen as Feedstocks for the Ruthenium-Catalyzed Direct N-Alkylation of Amines.

Triglycerides are used for the direct N-alkylation of amines with molecular hydrogen for the first time. A broad range of interesting and industrially relevant secondary and tertiary amines are obtained in the presence of an in situ formed Ru/Triphos complex. Notably, plant oil can be efficiently applied in this single-step process. Moreover, a variety of other methyl esters can be used as N-alkylation agents in the presence of hydrogen for the synthesis of more advanced building blocks.

NNP-Type Pincer Imidazolylphosphine Ruthenium Complexes: Efficient Base-Free Hydrogenation of Aromatic and Aliphatic Nitriles under Mild Conditions.

A series of seven novel N(Im)N(H)P-type pincer imidazolylphosphine ruthenium complexes has been synthesized and fully characterized. The use of hydrogenation of benzonitrile as a benchmark test identified [RuHCl(CO)(N(Im)N(H) P(tBu))] as the most active catalyst. With its stable Ru-BH4 analogue, in which chloride is replaced by BH4, a broad range of (hetero)aromatic and aliphatic nitriles, including industrially interesting adiponitrile, has been hydrogenated under mild and base-free conditions.

Efficient Rh-catalyzed C-H borylation of arene derivatives under photochemical conditions.

Photocatalysis allows innovations in organic synthesis. Among the various catalytic reactions, CH-functionalizations offer valuable possibilities for the refinement of easily available building blocks. In this respect, catalytic borylation is of interest, too. So far, most of the catalytic borylation reactions are performed under thermal conditions at comparably high temperatures. Here, we describe a new synthetic route for efficient borylation reactions of arenes using a photocatalytic pathway. This novel approach allows the synthesis of a broad variety of borylated arenes and heteroarenes under mild conditions. Applying trans-[Rh(PMe3)2(CO)Cl] as an active photocatalyst and HBPin as an boron source, we achieved high TON. A catalytic cycle that relies on a Rh(I)-Rh(III) interconversion is proposed.

Triazolopyridopyrimidines: an emerging family of effective DNA photocleavers. DNA binding. Antileishmanial activity.

Triazolopyridopyrimidines 3-phenyl-6,8-di(2-pyridyl)-[1,2,3]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine (1a), 6,8-di(pyridin-2-yl)-[1,2,3]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (1b) and 3-methyl-6,8-di(2-pyridyl)-[1,2,3]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine (1c) were prepared and their electrochemical and luminescence properties were studied in depth. The DNA binding ability of this series of compounds has been investigated by means of UV-vis absorption and fluorescence titrations, steady-state emission quenching with ferrocyanide as well as viscosity measurements. Results have shown that triazolopyridopyrimidine 1a interacts strongly at DNA grooves. This compound also displays preferential binding to GC-rich sequences and the ability to photooxidize guanine. Moreover, these studies have revealed the key role of the phenyl substituent at the triazole ring in the binding affinity of 1a-c. Compounds 1b and 1c did not show appreciable propensity for DNA binding, however these triazolopyridopyrimidines demonstrated to present photoinduced DNA cleavage activity, 1b being more active than 1c. DNA photocleavage mediated by these compounds takes place mainly through single strand scission events and, in a minor extent, through double strand cuts. Mechanistic investigations using radical scavengers showed that both 1b and 1c generate reactive oxygen species (singlet oxygen, superoxide and hydroxyl radicals) upon irradiation. Both type I and type II mechanisms are involved in the photocleavage process. Furthermore, compounds 1a-c were tested for their antiprotozoal activity against four different Leishmania spp. (L. infantum, L. braziliensis, L. guyanensis and L. amazonensis). Triazolopyridopyrimidines 1a and 1c resulted to be more active and selective than the reference drug (miltefosine) in vitro against L. infantum amastigotes. Compound 1a exhibited high leishmanicidal activity against L. infantum spleen forms in the in vivo test.

Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction.

A new series of triazolopyridyl pyridyl ketones has been synthetized by regioselective lithiation of the corresponding [1,2,3]triazolo[1,5-a]pyridine at 7 position followed by reaction with different electrophiles. The in vitro antileishmanial activity of these compounds was evaluated against Leishmaniainfantum, Leishmaniabraziliensis, Leishmaniaguyanensis and Leishmaniaamazonensis. Compounds 6 and 7 were found to be the most active leishmanicidal agents. Both of them showed activities at micromolar concentration against cultured promastigotes of Leishmania spp. (IC50=99.8-26.8 µM), without cytotoxicity on J774 macrophage cells. These two compounds were also tested in vivo in a murine model of acute infection by L. infantum. The triazolopyridine derivative 6 was effective against both spleen and liver parasites forms, while 7 was inactive against liver parasites. Mechanistic aspects of the antileishmanial activity were investigated by means of DNA binding studies (UV-titration and viscosimetry). Results have revealed that these active ligands are able to interact strongly with DNA [Kb=1.14 × 10(5)M(-1) (6) and 3.26 × 10(5)M(-1) (7)]. Moreover, a DNA groove binding has been proposed for both 6 and 7. To provide more insight on the mode of action of compounds 6 and 7 under biological conditions, their interaction with bovine serum albumin (BSA) was monitored by fluorescence titrations and UV-visible spectroscopy. The quenching constants and binding parameters were determined. Triazolopyridine ketones 6 and 7 have exhibited significant affinity towards BSA [Kb=2.5 × 10(4)M(-1) (6) and 1.9 × 10(4)M(-1) (7)]. Finally, to identify the binding location of compounds 6 and 7 on the BSA, competitive binding experiments were carried out, using warfarin, a characteristic marker for site I, and ibuprofen as one for site II. Results derived from these studies have indicated that both compounds interact at BSA site I and, to a lesser extent, at site II.

Detecting Ni(II) in aqueous solution by 3-(2-pyridyl)-[1,2,3]triazolo[1,5-a]pyridine and dimethyl-ß-cyclodextrin.

A new supramolecular sensitizer for nickel(II) ion in aqueous solution based on a pyridyltriazolopyridine-cyclodextrin inclusion complex is proposed. The inclusion complexation behavior, characterization and binding ability of pyridyltriazolopyridine (PTP) with dimethyl-ß-cyclodextrin (DMßCD) has been investigated both in solution and solid state by means of absorption, fluorescence, (1)H NMR, DSC, and molecular modeling methods. The stoichiometry of the inclusion complex is 1:1, and the thermodynamic studies indicate that the inclusion of PTP is mainly an entropic driven process. The 2D NMR studies revealed that the pyridyl-triazolopyridine is included by both sides of cyclodextrin which are in good agreement with the docking results. The fluorescence changes upon addition of divalent cations to the inclusion complex indicate a high selectivity and sensitivity for Ni(2+) by fluorescence quenching in neutral aqueous solution.

An efficient one pot transfer hydrogenation and N-alkylation of quinolines with alcohols mediated by Pd/C/Zn.

A Pd/C/Zn mixture with alcohols has been revealed to be an efficient transfer hydrogenation system to quinolines. Furthermore, the metals mixture is able to activate alcohols as N-alkylating agents in a hydrogen autotransfer process. 1,2,3,4-Tetrahydroquinolines and N-alkylated tetrahydroquinolines from quinolines have been obtained with excellent yields in one step.

Expanding the 3d-4f heterometallic chemistry of the (py)2CO and pyCOpyCOpy ligands: structural, magnetic and Mössbauer spectroscopic studies of two Fe(II)-Gd(III) complexes.

Complex [Fe(II)Gd(III){pyCO(OEt)pyCOH(OEt)py}(3)](ClO(4))(2) (1) crystallizes in the Cc space group and contains one hexacoordinate ferrous ion and one enneacoordinate Gd(III) ion. Complex [Fe(2)(II)Gd(III){pyCO(OEt)py}(4)(NO(3))(H(2)O)][Gd(NO(3))(5)](0.5)(ClO(4)) (2) crystallizes in the C2/c space group and contains two hexacoordinate ferrous ions and one octacoordinate Gd(III) ion. Both complexes have been prepared by the metal-assisted ethanolysis of ligands di-2,6-(2-pyridylcarbonyl)pyridine (pyCOpyCOpy, dpcp) and di-2-pyridyl ketone ((py)(2)CO, dpk), which exhibit similar structures. Mössbauer spectroscopic studies of 2 revealed the presence of two quadrupole-split doublets of equal intensities, each assigned to a ferrous site. These doublets exhibit similar isomer shifts (δ(1) = 1.14 mm s(-1), δ(2) = 1.11 mm s(-1)) but quite different quadrupole splittings (ΔE(Q1) = 3.55 mm s(-1), ΔE(Q2) = 2.74 mm s(-1)). Magnetic studies revealed weak ferromagnetic Fe(II)-Gd(III) interactions for both complexes (J(FeGd) = +0.68 cm(-1), D(Fe) = 12.0 cm(-1) for 1 and J(FeGd) = +0.03 cm(-1), J(FeFe) = -1.73 cm(-1) for 2, according to the -JS(i)S(j) spin-Hamiltonian formalism).