Theoretical design of new ligands to boost reaction rate and selectivity in palladium-catalyzed aromatic fluorination.

The development of palladium-catalyzed fluorination with biaryl monophosphine ligands has faced two important problems that limit its application for bromoarenes: the formation of regioisomers and insufficient catalysis for heteroaryl substrates as bromothiophene derivatives. Overcoming these problems requires more ligand design. In this work, reliable theoretical calculations were used to elucidate important ligand features necessary for achieving more rate acceleration and selectivity. These features include increasing the ligand-substrate repulsion and creating a negative charge in the space around the fluoride ion bonded to the palladium. The investigated L5 ligand presents these features, and the calculations predict that this ligand completely suppresses the regioisomer formation in the difficult case of 4-bromoanisole. In addition, the free energy barriers are decreased by 2-3 kcal mol-1 in comparison with the catalysis involving the AlPhos ligand. Thus, the present study points out a direction for new developments in palladium-catalyzed fluorination.

A new thioglycolic ester ß-cyclodextrin/PdCl2 in water: An accessible catalyst for the Suzuki-Miyaura coupling reaction.

A novel, easily prepared and accessible water-soluble supramolecular catalyst for the Suzuki-Miyaura CC coupling reaction was synthesized and characterized by FTIR, NMR, XRD, SEM, and HR-TEM. An inexpensive Pd(II) source added to the resulting aqueous solution of thioglycolic ester ß-cyclodextrin (1-TGA-SH-ß-CD/PdCl2) showed Pd nanoclusters and efficient catalytic activity for Suzuki-Miyaura CC coupling reactions of aryl halides with aryl boronic acids, employing K2CO3 as base, in an environmentally benign aqueous solution prepared in open flasks. Organic aryl halides including chlorides can produce moderate to excellent yields with aryl boronic acids and a small catalytic amount (0.01 mol%) of 1-TGA-SH-ß-CD/PdCl2. This hydro-soluble catalyst stock solution was stable for long periods (more than three months) and could be reused in two runs until showing loss of catalytic activity. Some experiments to understand the mechanism were performed, with the results suggesting incorporation of aryl halide in the catalytic cavity.

New sustainable and robust catalytic supports for palladium nanoparticles generated from chitosan/cellulose film and corn stem biochar.

The production of sustainable catalytic supports for palladium nanoparticles is always desired, even more so through the recovery of biomass residues. In this sense, two different solids were investigated - chitosan/cellulose film and corn stem biochar - as catalytic supports of palladium nanoparticles. The solids were carefully characterized and tested in the Suzuki-Miyaura reaction, a typical cross-coupling reaction. The developed catalytic systems proved to be efficient and sustainable, promoted the formation of target products very well, and demanded green reactants under environmentally appropriate conditions. With the results shown in the manuscript, it is expected to contribute to the valorization of biomass and agro-industrial residues in the development of new catalysts for the chemical industry.

Bromo-Substituted Diazenyl-pyrazolo[1,5-a]pyrimidin-2-amines: Sonogashira Cross-Coupling Reaction, Photophysical Properties, Bio-interaction and HSA Light-Up Sensor.

A convenient synthesis of a broad series of thirteen examples of alkyne-spacer derivatives 2 from the well-known Sonogashira cross-coupling reaction on diazenyl-pyrazolo[1,5-a]pyrimidin-2-amine compounds 1 is reported. The reactivity of heterocycles 1 due the presence of selected electron-donor (EDG) and electron-withdrawing (EWG) groups attached to different alkynes was evaluated. Also, the reactional versatility due the position variation of the bromo atom at the scaffolds 1 was also investigated. In general, derivatives presented strong absorption bands at the 250-500 nm optical window and UV to cyan emission properties. Also, the redox analysis was recorded by electrochemical cyclic voltammetry technique. For HSA biomacromolecule assays, spectroscopic studies by UV-Vis, steady-state and time-resolved emission fluorescence, and molecular docking calculations evidenced the ability of each compound to establish interactions with human serum albumin (HSA). Finally, the behavior presented for this new class of heterocycles makes them a promising tool as optical sensors for albumins.

Nickel(II)-Based Building Blocks with Schiff Base Derivatives: Experimental Insights and DFT Calculations.

We have recently reported a series of neutral square planar tridentate Schiff base (L) complexes of the general formula [(L)M(py)], showing relatively high first-order hyperpolarizabilities and NLO redox switching behavior. In the present study, new members of this family of compounds have been prepared with the objective to investigate their potential as building blocks in the on-demand construction of D-π-A push-pull systems. Namely, ternary nickel(II) building blocks of general formula [(LA/D)Ni(4-pyX)] (4-7), where LA/D stands for an electron accepting or donating dianionic O,N,O-tridentate Schiff base ligand resulting from the monocondensation of 2-aminophenol or its 4-substituted nitro derivative and ß-diketones R-C(=O)CH2C(=O)CH3 (R = methyl, anisyl, ferrocenyl), and 4-pyX is 4-iodopyridine or 4-ethynylpyridine, were synthesized and isolated in 60-78% yields. Unexpectedly, the Sonogashira cross-coupling reaction between the 4-iodopyridine derivative 6 and 4-ethynylpyridine led to the formation of the bis(4-pyridyl) acetylene bridged centrosymmetric dimer [{(LD)Ni}2(µ2-py-C≡C-py)] (8). Complexes 4-8 were characterized by elemental analysis, FT-IR and NMR spectroscopy, single crystal X-ray diffraction and computational methods. In each compound, the four-coordinate Ni(II) metal ion adopts a square planar geometry with two nitrogen and two oxygen atoms as donors occupying trans positions. In 8, the Ni…Ni separation is of 13.62(14) Å. Experimental results were proved and explained theoretically exploiting Density Functional Theory calculations.

Application of palladium-catalyzed cross-coupling between bile acids and 2-furanylboronic acid to the synthesis of 24-(2'-furanyl)-24-oxo steroids.

Palladium-catalyzed cross-coupling of bile acids with 2-furanylboronic acid produced steroid furanyl ketones in low yields. Unambiguous assignments of the NMR signals were made with the aid of combined 1D and 2D NMR techniques.

Room Temperature Coupling of Aryldiazoacetates with Boronic Acids Enhanced by Blue Light Irradiation.

A visible-light-promoted photochemical protocol is reported for the coupling of aryldiazoacetates with boronic acids. This photochemical reaction shows great enhancement compared to the same protocol performed in the absence of light. Except for a few cases, the room temperature coupling in the dark (thermal process) generally does not work. When it does, it is likely to also involve free carbenes as key intermediates. Alternatively, photochemical reactions show a broad scope, can be performed under air and tolerate a wide variety of functional groups. Reaction-evolution monitoring, DFT calculations and control experiments have been used to evaluate the main aspects of this intricate mechanistic scenario. Biologically active molecules Adiphenine, Benactyzine and Aprophen have been prepared as examples of synthetic applications.

[18F]Amylovis as a Potential PET Probe for ß-Amyloid Plaque: Synthesis, In Silico, In vitro and In vivo Evaluations.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice. METHODS: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice. RESULTS: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aß-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aß peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aß plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model. CONCLUSION: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aß senile plaques.

Carbonylative negishi-type coupling of 2-Iodoglycals with alkyl and aryl halides

C-Glycosides are valuable organic compounds in the field of medicinal chemistry due to their ubiquity inside living systems and pronounced biological activity. Herein, we describe an approach to alkyl-ketones bearing glycal units via the Pd-catalyzed carbonylative coupling of 2-iodoglycals and alkyl and aryl halides. Examples bearing a variety of functional groups are presented as well as a mechanistic proposal for this transformation.

Suzuki-Type Cross-Coupling Reaction of Unprotected 3-Iodoindazoles with Pinacol Vinyl Boronate: An Expeditive C-3 Vinylation of Indazoles under Microwave Irradiation.

Herein we report an expeditive C-3 vinylation of unprotected 3-iodoindazoles under microwave irradiation. Ten C-5 substituted 3-vinylindazole derivatives, nine of them novel, were synthesized through this method, which proceeds in moderate to excellent yields starting from C-5 substituted 3-iodoindazole derivatives. In all cases, the C-3 vinylated derivative was the only isolated product. This methodology allows access to 3-vinylated indazoles selectively and directly without the need of N-protection. 3-Vinylindazoles could be interesting synthetic intermediates allowing access to biologically active molecules.

Synthesis of a Tyr-Tyr Dipeptide Library and Evaluation Against Tumor Cells.

BACKGROUND: Structural component of proteins and peptides, amino acids have been used as building blocks in the synthesis of more complex molecules with antitumor activity against several types of cancer. OBJECTIVE: The search for new anticancer compounds is ongoing, especially for cancers that are very aggressive and have poor prognoses, such as leukemia. METHOD: Here, we report a method to synthesize Tyr-Tyr dipeptides via sonochemistry reactions followed by functionalization of these Tyr-Tyr dipeptides with Suzuki-Miyaura and Sonogashira crosscoupling reactions in good yields. Twelve different Tyr-Tyr dipeptides were investigated against three cell lines: HaCaT; Jurkat-E6; and A2058. RESULTS: Some of the Tyr-Tyr dipeptides showed activity against Jurkat-E6 leukaemia cells at low concentration, decreasing their viability, but not against non-tumor HaCaT cells, suggesting a cytotoxicity specific to tumor cells. CONCLUSION: All dipeptides were able to decrease the viability of Jurkat cell line, however the A2058 cell line did not respond well to treatment with the peptides. Some of the modified Tyr-Tyr dipeptides presented selective activity on leukemic tumor cells.

Cubane Cross-Coupling and Cubane-Porphyrin Arrays.

Herein, an improved methodology for aryl-cubane cross-coupling is reported. The peculiarities of the cubane core and its behavior during cross-coupling conditions were analyzed, while the versatility of this adapted Baran cross-coupling methodology was demonstrated by the synthesis of various aryl-cubane systems, including coupling products of cubanes and porphyrins. Furthermore, arm extension of alkynyl-cubanes by Sonogashira reactions is demonstrated, showcasing the first proof of the stability of the cubane core in the presence of palladium catalysts.

Direct, Metal-free C(sp2 )-H Chalcogenation of Indoles and Imidazopyridines with Dichalcogenides Catalysed by KIO3.

Herein, we report a greener protocol for the synthesis of 3-Se/S-indoles and imidazo[1,2-a]pyridines through direct C(sp2 )-H bond chalcogenation of heteroarenes with half molar equivalents of different dichalcogenides, using KIO3 as a non-toxic, easy-to-handle catalyst and a stoichiometric amount of glycerol. The reaction features are high yields, based on atom economy, easy performance on gram-scale, metal- and solvent-free conditions as well as applicability to different types of N-heteroarenes.

Synthesis of a Tyr-Tyr dipeptide library and evaluation against tumor cells

BACKGROUND:Structural component of proteins and peptides, amino acids have been used as building blocks in the synthesis of more complex molecules with antitumor activity against several types of cancer. OBJECTIVE:The search for new anticancer compounds is ongoing, especially for cancers that are very aggressive and have poor prognoses, such as leukemia. METHOD:Here, we report a method to synthesize Tyr-Tyr dipeptides via sonochemistry reactions followed by functionalization of these Tyr-Tyr dipeptides with Suzuki-Miyaura and Sonogashira crosscoupling reactions in good yields. Twelve different Tyr-Tyr dipeptides were investigated against three cell lines: HaCaT; Jurkat-E6; and A2058. RESULTS:Some of the Tyr-Tyr dipeptides showed activity against Jurkat-E6 leukaemia cells at low concentration, decreasing their viability, but not against non-tumor HaCaT cells, suggesting a cytotoxicity specific to tumor cells. CONCLUSION:All dipeptides were able to decrease the viability of Jurkat cell line, however the A2058 cell line did not respond well to treatment with the peptides. Some of the modified Tyr-Tyr dipeptides presented selective activity on leukemic tumor cells.

Copper-Catalyzed Synthesis of Unsymmetrical Diorganyl Chalcogenides (Te/Se/S) from Boronic Acids under Solvent-Free Conditions.

The efficient and mild copper-catalyzed synthesis of unsymmetrical diorganyl chalcogenides under ligand- and solvent-free conditions is described. The cross-coupling reaction was performed using aryl boric acids and 0.5 equiv. of diorganyl dichalcogenides (Te/Se/S) in the presence of 3 mol % of CuI and 3 equiv. of DMSO, under microwave irradiation. This new protocol allowed the preparation of several unsymmetrical diorganyl chalcogenides in good to excellent yields.

Small-Molecule Kinase-Inhibitors-Loaded Boron Cluster as Hybrid Agents for Glioma-Cell-Targeting Therapy.

The reported new anilinoquinazoline-icosahedral borane hybrids have been evaluated as glioma targeting for potential use in cancer therapy. Their anti-glioma activity depends on hybrids' lipophilicity; the most powerful compound against glioma cells, a 1,7-closo-derivative, displayed at least 3.3 times higher activity than the parent drug erlotinib. According to the cytotoxic effects on normal glia cells, the hybrids were selective for epidermal growth factor receptor (EGFR)-overexpressed tumor cells. These boron carriers could be used to enrich glioma cancer cells with boron for cancer therapy.

Tirosina, substrato em reações de acoplamento cruzado: síntese de dipeptídeos Tyr-Tyr, heterociclos e investigação da atividade biollógica contra células cancerígenas e parasitárias / Tyrosine, a building block in cross-coupling reactions: synthesis of dipeptides Tyr-Tyr, heterocycles and biological activity investigations against cancer cells and parasidic cells

Tirosina, um aminoácido proteinogênico, de fundamental importância para nossa sobrevivência, foi objeto de estudo para a confecção da presente tese. Investigado frente às três reações de acoplamento cruzado mais exploradas nos últimos anos, Suzuki-Miyaura, Heck e Sonogashira, a 3-iodotirosina comportou-se como um excelente substrato na formação de unidades biarílicas, derivados estilbeno, formação de heterociclos do tipo 1,2,3-triazóis, quinolinas, benzofuranos e flavonas, bem como a formação de dipeptídeos Tyr-Tyr. A reação entre a 3-iodotirosina com diferentes nucleófilos de boro via reação de Suzuki- Miyaura, além de dar origem às unidades biarílicas, forneceu derivados do estilbeno, usados como substratos na construção de quinolinas, alcançadas por meio da reação multicomponente de Povarov, com catálise de prata em apenas 40 minutos sob irradiação de micro-ondas. Alguns desses derivados estilbeno, apresentaram ainda uma acentuada fluorescência, a qual foi medida em diferentes polaridades. Ao explorarmos a reação entre a 3-iodotirosina e acetilenos, derivados alquinílicos puderam ser convenientemente preparados, permitindo seu uso como materiais de partida na reação de cicloadição de Huisgen, no preparo de anéis triazólicos. Produtos provenientes da adição estereosseletiva de oxa-Michael, entre o anel fenólico da tirosina e aldeídos propargílicos, forneceram compostos carbonílicos α,ß-insaturados capazes de reagirem via acoplamento intramolecular de Heck, levando a derivados 2-aril-3- formil-5-alanilbenzofuranos ou ainda, apenas alterando a atmosfera inerte de nitrogênio por monóxido de carbono, a formação de 2-aril-6-alanilflavonas via acilação intramolecular redutiva. Além da metodologia de síntese explorada na tese, alguns dos compostos obtidos apresentaram atividade biológica seletiva contra células de melanoma e leucemia, bem como atividade antiparasitária frente ao Plasmodium falciparum, não afetando a proliferação de células sadias. Dessa forma, os resultados apresentados, agregam ainda mais valor sintético e biológico ao aminoácido tirosina, explorados de forma inédita

Tyrosine, a proteinogenic amino acid of fundamental importance for life, was the object of study for the research that is presented in this thesis. When 3-iodotyrosine was used in the three different types of cross-coupling reactions that have been exploited the most in recent years, namely the Suzuki-Miyaura, Heck and Sonogashira coupling reactions, 3-iodotyrosine as an excellent substrate for the formation of biaryl units, stilbene derivatives, 1,2,3-triazoletype heterocycles, quinolines, benzofurans and flavones, and Tyr-Tyr dipeptides. This work is organized into sections in order to facilitate ease of reading. The reaction between 3-iodotyrosine and different boron nucleophiles via the Suzuki- Miyaura coupling reaction, in addition to giving the biaryl units, also provided stilbene derivatives, which were used as substrates for the construction of quinolines via multicomponent Povarov reactions. The Povarov was performed with silver catalysis under 40 minutes of microwave irradiation. Some of these stilbene derivatives showed a marked fluorescence, which was measured in solvents with different polarities. By exploring the Sonogashira coupling reaction between 3-iodotyrosine and acetylenes, alkynyl derivatives could be conveniently prepared, which in turn could be used as starting materials in Huisgen cycloaddition reactions to synthesize1,2,3-triazole rings. Products from the stereoselective addition of oxa-Michael, between the phenolic ring of tyrosine and propargyl aldehydes, provided 945;,946;-unsaturated carbonyl compounds capable of reacting via Heck intramolecular coupling, leading to 2-aryl-3-formyl-5-alanylbenzofurans or by simply changing the inert atmosphere of nitrogen by carbon monoxide, the formation of 2- aryl-6-alanylflavones via reductive intramolecular acylation. In addition to the synthesis methodology explored in the thesis, some of the compounds showed selective biological activity against melanoma and leukemia cells, as well as antiparasitic activity against Plasmodium falciparum, without affecting the proliferation of healthy cells. In this way, the presented results add even more synthetic and biological value to the amino acid tyrosine, explored in an unprecedented way

Photoredox Catalysis in Nickel-Catalyzed Cross-Coupling.

The traditional transition metal-catalyzed cross-coupling reaction, although well suited for C(sp2)-C(sp2) cross-coupling, has proven less amenable toward coupling of C(sp3)-hybridized centers, particularly using functional group tolerant reagents and reaction conditions. The development of photoredox/Ni dual catalytic methods for cross-coupling has opened new vistas for the construction of carbon-carbon bonds at C(sp3)-hybridized centers. In this chapter, a general outline of the features of such processes is detailed.

Chemoselective and Sequential Palladium-Catalyzed Couplings for the Generation of Stilbene Libraries via Immobilized Substrates.

A versatile palladium-catalyzed tandem synthetic sequence to afford E-stilbenes libraries has been developed. Excellent regio- and stereocontrol have been achieved by means of the sequence of Hiyama and Heck cross-couplings. Undesirable homocoupling byproducts were avoided employing immobilized substrates.

Tandem C(sp3)-H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones.

Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of the isoindolinones with aryl bromides (22 examples) using a Pd(OAc)2/NIXANTPHOS-based catalyst system. Additionally 3-aryl 3-hydroxy isoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxyl group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials.