Synthesis and Redox Activity of Polyenaminones for Sustainable Energy Storage Applications.

In the search for novel polymeric molecules that could be used as electroactive materials, seven novel polyenaminones were prepared in high yields by the transaminative polymerization of resorcinol-derived bis-enaminones with - and -phenylenediamine and with 2,5-diaminohydroquinone. The obtained polymers show very low solubility in organic solvents and absorb UV light and visible light at wavelengths below 500 nm. All the obtained polymeric products were tested for redox activity in a Li battery setup.

2-Bromopyridines as Versatile Synthons for Heteroarylated 2-Pyridones via Ru(II)-Mediated Domino C-O/C-N/C-C Bond Formation Reactions.

A novel methodology for the synthesis of 2-pyridones bearing a 2-pyridyl group on nitrogen and carbon atoms, starting from 2-bromopyridines, was developed employing a simple Ru(II)-KOPiv-NaCO catalytic system. Unsubstituted 2-bromopyridine was successfully converted to the penta-heteroarylated 2-pyridone product using this method. Preliminary mechanistic studies revealed a possible synthetic pathway leading to the multi-heteroarylated 2-pyridone products, involving consecutive oxygen incorporation, a Buchwald-Hartwig-type reaction, and C-H bond activation.

Synthesis of Bifunctional Amine-Squaramide Organocatalysts Derived from 3-((Dimethylamino)methylene)camphor.

Four bifunctional, noncovalent amine-squaramide organocatalysts were prepared from camphor in five steps. The stereochemistry of the prepared catalysts was thoroughly analyzed using various spectroscopic techniques. Their organocatalytic activity was investigated in the Michael addition of acetylacetone to trans-β-nitrostyrene.

Recent Advances in the Nickel-Catalyzed Alkylation of C-H Bonds.

Functionalization of C-H bonds has emerged as a powerful strategy for converting inert, nonfunctional C-H bonds into their reactive counterparts. A wide range of C-H bond functionalization reactions has become possible by the catalysis of metals, typically from the second row of transition metals. First-row transition metals can also catalyze C-H functionalization, and they have the merits of greater earth-abundance, lower cost and better environmental friendliness in comparison to their second-row counterparts.

Synthesis of Six-Membered -Heterocyclic Carbene Precursors Based on Camphor.

The - and --heterocyclic carbene precursors based on camphor were prepared diastereoselectively in five synthetic steps starting from (1)-(+)-ketopinic acid. The obtained -heterocyclic carbene precursors were investigated in an asymmetric benzoin reaction. All new compounds were fully characterized, and the absolute configurations were determined via X-ray diffraction and NOESY measurements.

Synthesis and Cholinesterase Inhibitory Activity of Selected Indole-Based Compounds.

Synthesis and anticholinesterase activity of 18 previously unpublished indole- and tryptophan-derived compounds are disclosed. These sp3-rich compounds containing an indole structural unit exhibit selective submicromolar inhibition of human butyrylcholinesterase (hBChE). The structures of the newly synthesized compounds were confirmed by 1H and 13C NMR, IR spectroscopy, and high-resolution mass spectrometry.

Catalytic Photoredox C-H Arylation of 4-Oxo-4-pyrido[1,2-]pyrimidine-3-diazonium Tetrafluoroborates and Related Heteroaryl Diazonium Salts.

Irradiation of mixtures of title diazonium salts and heteroarenes with green light (510 nm) in the presence of eosin Y disodium salt () as a photocatalyst furnished the corresponding arylation products in 8-63% yields. The proposed photocatalytic cycle is analogous to that proposed previously for closely related photoredox C-H arylations with aryl diazonium salts as aryl radical sources. This method has a broad substrate scope and represents a metal-free alternative for the synthesis of 3-heteroaryl-substituted 4-quinolizin-4-ones and azino- and azolo-fused pyrimidones with a bridgehead nitrogen atom.

Synthesis and Catalytic Activity of Bifunctional Phase-Transfer Organocatalysts Based on Camphor.

Ten novel bifunctional quaternary ammonium salt phase-transfer organocatalysts were synthesized in four steps from (+)-camphor-derived 1,3-diamines. These quaternary ammonium salts contained either (thio)urea or squaramide hydrogen bond donor groups in combination with either trifluoroacetate or iodide as the counteranion. Their organocatalytic activity was evaluated in electrophilic heterofunctionalizations of β-keto esters and in the Michael addition of a glycine Schiff base with methyl acrylate.

Synthesis of Optically and Redox Active Polyenaminones from Diamines and α,α'-Bis[(dimethylamino)methylidene]cyclohexanediones.

New oligo- and polyenaminones with ~ 7-50 KDa were prepared in high yields by transaminative amino-enaminone polymerization of regioisomeric bis[(dimethylamino)methylidene]cyclohexanediones with alkylene and phenylenediamines. The polymers obtained are practically insoluble in aqueous and organic solvents and exhibit film-forming properties, UV light absorption at wavelengths below 500 nm, and redox activity. These properties indicate a promising application potential of these polymers, which could find use in optical and optoelectronic applications and in energy storage devices.

Regioselective Synthesis of 5- and 3-Hydroxy--Aryl-1-Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Dihydroorotate Dehydrogenase.

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of (DHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones.

A Set of Experimentally Validated Decoys for the Human CC Chemokine Receptor 7 (CCR7) Obtained by Virtual Screening.

We present a state-of-the-art virtual screening workflow aiming at the identification of novel CC chemokine receptor 7 (CCR7) antagonists. Although CCR7 is associated with a variety of human diseases, such as immunological disorders, inflammatory diseases, and cancer, this target is underexplored in drug discovery and there are no potent and selective CCR7 small molecule antagonists available today. Therefore, computer-aided ligand-based, structure-based, and joint virtual screening campaigns were performed.

From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series.

Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp-rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold). Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme).

Visible-Light Driven Selective C-N Bond Scission in -Bimane-Like Derivatives.

In the present study, we report the photochemical transformation of pyrazolo[1,2-]pyrazolone substrates that reach an excited state upon irradiation with visible light to initiate the homolytic C-N bond cleavage process that yields the corresponding N1-substituted pyrazoles. Moreover, chemoselective heterolytic C-N bond cleavage is possible in the pyrazolo[1,2-]pyrazole core in the presence of bromomalonate.

Regioselective Ru(II)/Pd(0) Dual Catalysis: One-Pot C-H Diarylation of Five-Membered Heterocyclic Derivatives.

Herein, we report a one-pot site-selective dual metal catalyzed C-H diarylation reaction for the synthesis of multiarylated thiophene and furan derivatives in yields up to 92%. The regioselectivity of the developed methodology was achieved with the sequential use of two metal catalysts within a single vessel, starting with a Ru(II)-catalyzed C3 arylation assisted by an azine directing group, followed by a Pd(0)-catalyzed C-H functionalization on the C5-position of the five-membered heterocycle. Furthermore, the kinetic studies support that the position of the nitrogen atom within the azine moiety exhibits an evident effect on the efficiency of the ruthenium-catalyzed arylation step.

Synthesis of 6,7-Dihydro-1,5-pyrazolo[1,2-]pyrazoles by Azomethine Imine-Alkyne Cycloadditions Using Immobilized Cu(II)-Catalysts.

A series of 12 silica gel-bound enaminones and their Cu(II) complexes were prepared and tested for their suitability as heterogeneous catalysts in azomethine imine-alkyne cycloadditions (CuAIAC). Immobilized Cu(II)-enaminone complexes showed promising catalytic activity in the CuAIAC reaction, but these new catalysts suffered from poor reusability. This was not due to the decoordination of copper ions, as the use of enaminone ligands with additional complexation sites resulted in negligible improvement.

Structure-activity relationship study of tryptophan-based butyrylcholinesterase inhibitors.

A series of tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors was designed and synthesized. Compounds were optimized in terms of potency, selectivity, and synthetic accessibility. The crystal structure of the inhibitor 18 in complex with BChE revealed the molecular basis for its low nanomolar inhibition (IC = 2.

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts.

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1)-(+)-ketopinic acid and (1)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature isomeric diversity in terms of regioisomeric attachment of the primary and the tertiary amine function and the -isomerism. Diamines were transformed into the corresponding noncovalent bifunctional thiourea organocatalysts, which have been evaluated for catalytic activity in the conjugative addition of 1,3-dicarbonyl nucleophiles (dimethyl malonate, acetylacetone, and dibenzoylmethane) to -β-nitrostyrene.

Self-Assembly of Multinuclear Sandwich Silver(I) Complexes by Cooperation of Hexakis(azaheteroaryl)benzene Ligands, Argentophilic Interactions, and Fluoride Inclusion.

Self-assembly of AgOTf and AgF with the hexatopic ligands hexakis(pyridin-2-yl)benzene () and 2,4,6-tris(pyridin-2-yl)-1,3,5-tris(quinolin-2-yl)benzene () affords the discrete sandwich-shaped complexes [AgF()](OTf), [AgF()](OTf), and [AgF()](OTf). The solid-state structures of the complexes were characterized by single-crystal X-ray diffraction analysis, which revealed that the fluoride anion is coordinated in the center of the Ag-square or Ag-pentagon units which are positioned between two molecules of the hexakis(azaheteroaryl)benzene. The generation of complexes is dictated by a unique cooperation of ligand coordination, argentophilicity, and fluoride anion inclusion.

Tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylates as inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.

The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo[1,2-a]pyrazole-1-carboxylates as mixtures of syn- and anti-diastereomers. Testing for inhibition of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH) revealed high activity of some anti-isomers of the methyl esters, while the corresponding carboxylic acids and carboxamides were not active. The most active representative, methyl (1S*,3S*,5R*)-1,5-dimethyl-7-oxo-3-phenyltetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylate (IC = 2.

Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease.

We have identified tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors. They are defined according to their chemical modularity, novel binding mode revealed by five solved crystal structures with human BChE, low cytotoxicity, and predicted permeability of the blood-brain barrier. Altogether, these factors indicate their potential as unique lead compounds for symptomatic therapy against Alzheimer's disease.

Ruthenium(II)-Catalyzed Microwave-Promoted Multiple C-H Activation in Synthesis of Hexa(heteroaryl)benzenes in Water.

A series of hexa(heteroaryl)benzenes were synthesized by the Ru(II)-carboxylate-catalyzed multiple C-H activation of benzenes carrying pyridyl, pyrimidyl, or pyrazolyl directing groups using N-heteroaryl bromides as coupling partners. The reactions proceeded with high selectivity under microwave irradiation in water. Iterative penta-arylation could be implemented via activation of C-H bonds of generated intermediates by cascade chelation assistance of in situ installed pyridyl groups.

Asymmetric Bio- and Chemoreduction of 2-Benzylidenecyclopentanone Derivatives.

Highly efficient asymmetric reduction of 2-benzylidenecyclopentanone derivatives to give the respective exocyclic allylic alcohols in ee's up to 96% was performed with chiral oxazaborolidine-based catalysts. Complete enantioselectivity furnishing (S)-configured alcohol product could be achieved by bioreduction of 2-(4-chlorobenzylidene)cyclopentanone with Daucus carota root. The synthesized compounds may be used as enantiomerically enriched standards for the monitoring of the enzyme-catalyzed redox processes.

Synthesis of Novel 5-(N-Boc-N-Benzyl-2-aminoethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides and Their Inhibition of Cathepsins B and K.

Eight novel 5-(N-Boc-N-benzyl-2-aminoethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides were prepared in three steps from methyl 3-amino-1H-pyrazole-4-carboxylate and methyl 5-(benzyl(tert-butoxycarbonyl)amino)-3-oxopentanoate. The synthetic procedure comprises cyclocondensation of the above starting compounds, hydrolysis of the ester, and bis(pentafluorophenyl) carbonate (BPC)-mediated amidation. Title carboxamides were tested for inhibition of cathepsins K and B.

Synthesis and Reduction of 10-Phthalimidocamphor Oxime.

10-Phthalimidocamphor oxime was prepared from easily available 10-iodocamphor in two steps. Reduction of the oxime functionality resulted in the formation of two novel polycyclic isoindolinone heterocycles, the attempted preparation of the primary amine failed. The structures of novel heterocycles were unambiguously confirmed by single crystal X-ray diffraction as well as NMR techniques.

Synthesis of Novel 3D-Rich α-Amino Acid-Derived 3-Pyrazolidinones.

Synthetic approaches towards novel 3-pyrazolidinone derivatives functionalized at positions N(1) and/or C(5) were studied. 5-Aminoalkyl-3-pyrazolidinones were prepared in four steps from N-protected glycines via Masamune-Claisen homologation, reduction, O-mesylation, and cyclisation with a hydrazine derivative. The free amines were prepared by acidolytic deprotection.