Facile synthesis and characterization of novel bis(2-S-alkylpyridines) and bis(3-aminothieno[2,3-b]pyridines) incorporating 1,3-diarylpyrazole moiety

3-(4-Hydroxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (1) is condensed with acetophenone to afford the corresponding unsaturated carbonyl compound 4 whose potassium salt is reacted with 1,4-dibromobutane to afford the bis-unsaturated carbonyl compound 3. Both carbonyl compounds 3 and 4 are reacted with 2-cyanoethanethioamide, through Michael addition reaction followed by cyclocondensation, to prepare the starting materials bis(pyridine-2(1H)-thione) derivative 5 and pyridine-2(1H)-thione derivative 8. Two synthetic routes to synthesize the target materials 7 and 14 are described to get the most efficient method for preparation and maximum yield%. The first route came from the direct alkylation of the bis(pyridine-2(1H)-thione) derivative 5 using iodomethane (6a) and benzyl chloride (6b) to afford the corresponding bis(2-S-alkylpyridine) derivatives 7a,b. The reaction of 5 with halo-containing compounds 10a–d to synthesize the target materials bis(3-aminothieno[2,3-b]pyridine) derivatives 14a–d failed under various reaction conditions. The second route involves the reaction of pyridine-2(1H)-thione derivative 8 with 6a,b and 10a–d to afford the corresponding 2-S-alkylpyridine derivatives 9a,b and 3-aminothieno[2,3-b]pyridine derivatives 13a–d, through the formation of 2-S-alkylpyridine derivatives 12a–d followed by a Thrope-Ziegler reaction, whose potassium salts reacted with 1,4-dibromobutane to afford the corresponding target materials 7a,b and 14a–d, respectively. The structures of target molecules were elucidated using elemental analyses and spectral data.     

β-Aminocrotononitrile in heterocyclic synthesis: Synthesis of polysubstituted pyridines as precursors to bicycles and polycycles

β-aminocrotononitrile (1) reacted with either cyanothioacetamide to give (3) or malononitrile to afford an anion (5). Pyridine-2(1H)-thione (4) was obtained by boiling of (3) in ethanol and Et ₃N or treatment of (5) with H ₂S, respectively. The reaction of anion 5 with isothiocyanates (6) gave N-substituted pyridine-2(1H)-thiones (7). N-Substituted pyridine-2(1H)-thiones (7) can be used for the preparation of pyrido[2,3-d]pyrimidines (8a–e) and (10a–e), or the preparation of pyrido[1,2-a]pyrimidines (12a–d). 1,8-Naphthyridine derivatives (14a–d) and (16a–e) can also be obtained from pyridine-2(1H)-thione (7). Finally, 1,8-naphthyridine derivatives (16a–e) can be used for the preparation of tetracyclic compounds 17a–c and 18a,b.     

The behavior of some Wittig reagents toward 4,5,6,7-tetrahydro-3H-1,2-benzo[1,2]dithiole-3-thione

ABSTRACT

Novel synthetic route for phosphanylidene-benzothiophenethione, benzothiaphosphinine-4-thione, triphenylphosphoranylidenecyclobutane and benzodithiolylidenephosphonate derivatives has been proposed through reactions of 4,5,6,7-tetrahydro-3H-1,2-benzodithiole-3-thione with different Wittig and Wittig–Horner reagents. All new synthesized compounds were fully characterized with elemental and spectroscopic analysis.     

Tautomerism and Reactions of 1H-1,2,4-Triazole-5-thiones with Hydrazonoyl Halides

The acid dissociation constants (K_a) of a series of 3,4-diaryl-1H-1,2,4-triazole-5-thiones ( 1 ) were determined and were found to correlated linearly with Hammett substituent constants; log K_a = 1.06 σ_x − 11.01. Such a result indicates that 1 exists essentially in one tautomeric form namely the thione form. Reactions of 1 with hydrazonoyl chlorides 2 gave the thiohydrazides 5 . Similiar reaction of 3-phenyl-1H(4H)- 1,2,4-triazole-5-thione 1g with 2a gave the thiohydrazide 5h which was converted into 1,3,5-triphenyl-1,2,4-triazolo[3,4-c]-1,2,4-triazole ( 9 ). The latter was also prepared from 3-phenyl-5-methylthio-4H-1,2,4-triazole ( 6 ) and 2a . The mechanism of the reaction of 1 with 2 is discussed.     

Construction of a 3D luminescent cadmium(II) network with an unusual deprotonated 1,3-imidazolidine-2-thione ligand

A novel three-dimensional (3D) polymer [Cd(SC₃H₅N₂)₂]_n (SC₃H₅N₂ = deprotonated 1,3-imidazolidine-2-thione) (1) was synthesized. The deprotonated 1,3-imidazolidine-2-thione ligand has been found at cadmium for the first time. The single-crystal X-ray diffraction shows that the deprotonated 1,3-imidazolidine-2-thione ligand contributes greatly to the formation of the 3D framework and the helical structure. Compound 1 exhibits blue fluorescence at 494 nm in the solid state upon excitation at 372 nm.     

A computational investigation on the molecular structure,electronic properties and intramolecular hydrogen bonding interaction of 1,1,1-trifluoro-4-mercaptobut-3-ene-2-thione in ground and electronic excited state

The hydrogen bond (HB) strength, geometry optimization, vibrational frequencies and several well-established indices of aromaticity in 1,1,1-trifluoro-4-mercaptobut-3-ene-2-thione and its 15 derivatives in two positions, R1 and R2, have been investigated by means of the density functional theory (DFT) method with 6-311++G** basis set in the gas phase. The obtained results show that the HB strength is mainly governed by resonance variations inside the chelate ring induced by the substituent groups. The following substituents have been taken into consideration: NO₂, SCF₃, Ph, PhOCH₃, SCOCH₃, CH₂OCH₃ and CH₂OH. The strongest S–H···S HBs belong to PhOCH₃-substituted system in both positions, whereas NO₂ and H substitutions in R1 and R2 positions, respectively, produce the weakest S–H···S hydrogen bridges. The excited-state properties of intramolecular hydrogen bonding in substituted systems have been investigated theoretically using the time-dependent DFT method. Natural bond orbital analysis is also performed for a better understanding of the nature of intramolecular interactions. The electron density and Laplacian (?²ρ) properties, estimated by atoms in molecule calculations, indicate that the H···S bond possesses low ρ, positive ?² ρ and H_C<0, which are in agreement with the partially covalent character of HBs.     

Horseradish‐Peroxidase‐Catalyzed Tyrosine Click Reaction

The efficiency of protein chemical modification on tyrosine residues with N‐methylluminol derivatives was drastically improved by using horseradish peroxidase (HRP). In the previous method, based on the use of hemin and H₂O₂, oxidative side reactions such as cysteine oxidation were problematic for functionalization of proteins selectively on tyrosine residues. Oxidative activation of N‐methylluminol derivatives with a minimum amount of H₂O₂ prevented the occurrence of oxidative side reactions under HRP‐catalyzed conditions. As probes for HRP‐catalyzed protein modification, N‐methylluminol derivatives showed much higher efficiency than tyramide without inducing oligomerization of probe molecules. Tyrosine modification also proceeded in the presence of β‐nicotinamide adenine dinucleotide (NADH, H₂O₂‐free conditions).     

Synthesis of heterocyclic phosphonato esters by reaction between triphenyl phosphite and acetylenic diesters in the presence of sulfur-containing heterocyclic compounds

The reaction between triphenyl phosphite and acetylenic esters in the presence of some heterocyclic compounds such as oxazolo[4,5-b]pyridine-2(3H)-thione, 2-mercaptobenzothiazole or 2-mercaptopyrimidine led to the formation of phosphonato esters in high yield.     

Silylated thiocarbonyl S-methanides as key intermediates in one-pot olefination reactions leading to ferrocenyl-substituted ethenes and dibenzofulvenes

(Trimethylsilyl)diazomethane (TMS-CHN₂) reacts smoothly with cycloaliphatic thioketones as well as with fluorene-9-thione at low temperature to give the corresponding 1,3,4-thiadiazole derivatives as product of a regioselective [3?+?2]-cycloaddition. In the first case, the obtained cycloadducts are relatively stable and eliminate N₂ upon heating at 40°C. In the second case, N₂-extrusion occurs already at ?40°C. The silylated thiocarbonyl S-methanides generated thereby can be trapped regioselectively with ferrocenyl hetaryl thioketones to give the sterically crowded 2-silylated 4,4,5,5-tetrasubstituted 1,3-dithiolanes. Without isolation, these products are desilylated with tetrabutylammonium fluoride and tetrasubstituted ethenes or dibenzofulvenes are obtained as final products via cycloelimination (‘[3?+?2]-cycloreversion’) of the intermediate 1,3-dithiolane carbanion.     

Use of chitosan for removal of bisphenol A and bisphenol derivatives through tyrosinase‐catalyzed quinone oxidation

In this study, the availability of chitosan was systematically investigated for removal of bisphenol A (BPA, 2,2‐bis(hydroxyphenyl)propane) through the tyrosinase‐catalyzed quinone oxidation and subsequent quinone adsorption on chitosan beads. In particular, the process parameters, such as the hydrogen peroxide (H₂O₂)‐to‐BPA ratio, pH value, temperature, and tyrosinase dose, were discussed in detail for the enzymatic quinone oxidation. Tyrosinase‐catalyzed quinone oxidation of BPA was effectively enhanced by adding H₂O₂ and the optimum conditions for BPA at 0.3 mM were determined to be pH 7.0 and 40°C in the presence of H₂O₂ at 0.3 mM ([H₂O₂]/[BPA] = 1.0). Removal of BPA from aqueous solutions was accomplished by adsorption of enzymatically generated quinone derivatives on chitosan beads. The use of chitosan in the form of beads was found to be more effective because heterogeneous removal of BPA with chitosan beads was much faster than homogeneous removal of BPA with chitosan solutions, and the removal efficiency was enhanced by increasing the amount of chitosan beads dispersed in the BPA solutions and BPA was completely removed by quinone adsorption in the presence of chitosan beads more than 0.10 cm³/cm³. In addition, a variety of bisphenol derivatives were completely or effectively removed by the procedure constructed in this study, although the enzyme dose or the amount of chitosan beads was further increased as necessary for some of the bisphenol derivatives used. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Yield of benzothiazine derivatives and catalysis by heteropolyacids

An efficient heteropolyacid-catalyzed reaction for the synthesis of benzothiazine derivatives is reported. In this transformation, H₃PW₁₂O₄₀ was employed as a catalyst in a reaction involving 2-aminobenzenethiols, acetylenic esters, and malonate esters. Optimum conditions are developed in i-PrOH at 50?C for 7?h.     

Structural correlations in nickel(II)–thiodiacetato complexes: molecular and crystal structures and properties of [Ni(tda)(H2O)3]

Triaqua(thiodiacetato)nickel(II) has been synthesized and studied by X-ray crystallography, thermal, spectral and magnetic methods. The compound crystallizes in the triclinic system, space group , in contrast to the related compound [Ni(tda)(H₂O)₃] · H₂O (orthorhombic) reported long time ago. As in other four Ni–tda derivatives, the metal atom exhibits an octahedral coordination and tda ligand adopts a fac-tridentate chelating role. The studied compound is closely related to [Zn(tda)(H₂O)₃]. In addition, a structural comparison of the binary and ternary Ni–tda derivatives reveals that auxiliary N-donor ligands bind the metal atom using the trans-positions towards the Ni–O(carboxylato) bonds, but not in trans to the Ni–S(thioether) bond.     

Pathways and Substrate Specificity of DMSP Catabolism in Marine Bacteria of the Roseobacter Clade

The volatiles released by Phaeobacter gallaeciensis, Oceanibulbus indolifex and Dinoroseobacter shibae have been investigated by GC‐MS, and several MeSH‐derived sulfur volatiles have been identified. An important sulfur source in the oceans is the algal metabolite dimethylsulfoniopropionate (DMSP). Labelled [²H₆]DMSP was fed to the bacteria to investigate the production of volatiles from this compound through the lysis pathway to [²H₆]dimethylsulfide or the demethylation pathway to [²H₃]‐3‐(methylmercapto)propionic acid and lysis to [²H₃]MeSH. [²H₆]DMSP was efficiently converted to [²H₃]MeSH by all three species. Several DMSP derivatives were synthesised and used in feeding experiments. Strong dealkylation activity was observed for the methylated ethyl methyl sulfoniopropionate and dimethylseleniopropionate, as indicated by the formation of EtSH‐ and MeSeH‐derived volatiles, whereas no volatiles were formed from dimethyltelluriopropionate. In contrast, the dealkylation activity for diethylsulfoniopropionate was strongly reduced, resulting in only small amounts of EtSH‐derived volatiles accompanied by diethyl sulfide in P. gallaeciensis and O. indolifex, while D. shibae produced the related oxidation product diethyl sulfone. The formation of diethyl sulfide and diethyl sulfone requires the lysis pathway, which is not active for [²H₆]DMSP. These observations can be explained by a shifted distribution between the two competing pathways due to a blocked dealkylation of ethylated substrates.     

Novel,Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B

Annelated purinedione derivatives have been shown to act as possible multiple-target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido- and diazepino[2,1-f]purinedione derivatives were designed as dual-target-directed ligands combining A_2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. This allowed 9-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione ( 13 e ; K_i human A_2AAR: 264 nM and IC₅₀ human MAO-B: 243 nM) to be identified as the most potent dual-acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure-activity relationships was complemented by molecular-docking studies based on previously published X-ray structures of the protein targets. Such dual-acting ligands, by selectively blocking A_2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO-B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease     

From Overcrowded Polycyclic Aromatic Enes to Semifullerenes

Abstract

Overcrowded polycyclic aromatic enes (1), e.g., bi-9H-fluoren-9-ylidene (2) and bi-4H-cyclopenta[def]-phenanthren-4-ylidene (3) are potential starting materials for the preparation of bowl-shaped fragments of fullerenes. Semiempirical MNDO-PM3 calculations of C₂₆ H_n and C₃₀ H_n (n = 12,14,16) species 2–14 are used to analyze energetic and steric effects on the dehydrocyclization and isomerization reactions of these molecules. the out-of-plane bending and pyramidalization in these species are ascribed to intramolecular overcrowding in the fjord and cove regions and to strain introduced by C5 rings in the PAH skeleton. Oxidative photocyclization reactions on Z-2,2′-bridged derivatives of 2 and 3 are briefly outlined.     

Polybenzimidazole (PBI) molecular weight and Mark‐Houwink equation

The molecular weight, and intrinsic viscosity of polybenzimidazole (PBI) and its phosphonylated derivatives are reported. The relationship between intrinsic viscosity [η] and weight average molecular weight (M_w) for PBI has been established in H₂SO₄ and DMF‐LiCl. The Mark Houwink constants K_w of 5.2 × 10^?3 mL/g, α of 0.92 for H₂SO₄ solvent systems and, K_w of 3.2 × 10^?2 mL/g, α of 0.754 for DMF‐LiCl solvent system have been determined at M_w < 65,000. The intrinsic viscosity of PBI determined by the Huggins–Kraemer method was compared with a single point method, and found that both methods fit well for PBI in relatively low concentration solvent system, giving ～ 99% accuracy. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Rhodium‐Catalyzed Hydrogenation of Alkenes by Rhodium/Tris(fluoroalkoxy)phosphane Complexes in Fluorous Biphasic System

The reaction of [Ir(μ‐Cl)(COD)]₂ with various fluorous derivatives of triphenylphosphane containing a para‐, meta‐, or ortho‐(1H,1H‐perfluoroalkoxy)‐substituted fluorous phosphane P(C₆H₄‐ORf)₃ (Rf=CH₂C₇F₁₅, CH₂CH₂CH₂C₈F₁₇) and CO (1 atm) gives the corresponding trans‐[Ir(μ‐Cl)(CO){P(C₆H₄ORf)₃}₂]. The IR ν_CO values of these complexes give some information on the donor/acceptor properties of the phosphanes. These fluorous derivatives of triphenylphosphane, as well as a phosphane bearing two (1H,1H‐perfluoroalkyloxy) chains at the 3,5‐positions, were used in association with [Rh(μ‐Cl)(COD)]₂ or [Rh(COD)₂]PF₆ in the reduction of methyl cinnamate, 2‐cyclohexen‐1‐one, cinnamaldehyde, and methyl α‐acetamidocinnamate in a two‐phase system D‐100/ethanol under 1 bar hydrogen at room temperature. Some differences in catalytic activity were observed in the reduction of methyl cinnamate, the most active catalyst being the rhodium complex containing the phosphane with the p‐fluorous ponytail. Recycling of the fluorous catalyst was possible, particularly using the p‐substituted phosphane, where no significant loss of catalyst or activity was observed, and generally with very low leaching of rhodium or phosphane in the organic phase.     

Addition of alkyllithiums to 3H-quinazoline-4-thione and various substituted quinazoline derivatives; application in synthesis

Reaction of 3H-quinazoline-4-thione (1) with two mole equivalents of an alkyllithium (t-BuLi, n-BuLi or MeLi) at?78 ^°C in dry THF gave the corresponding 2-alkyl-1,2-dihydro-3H-quinazoline-4-thione (4, 5 or 6) in high yield. Similarly, reactions of 4-(methylthio)quinazoline (7), 4-(ethylthio)quinazoline (8) and 4-methoxyquinazoline (9) with alkyllithiums (one mole equivalent) gave the corresponding 4-substitued 2-alkyl-1,2-dihydroquinazolines 11–18. On the other hand, blocking position 2 with a phenyl group in 4-(methylthio)-2-phenylquinazoline (20) and 4-methoxy-2-phenylquinazoline (21) resulted in reaction with two mole equivalents of alkyllithiums to give 4,4-dialkyl-2-phenyl-3,4-dihydroquinazolines 22–24.     

Darstellung und Reaktionen von 2-Mercapto-6-thioxo-thiopyran-3-carbonsäure-Derivaten

Synthesis and Reactions of 2-Mercapto-6-thioxo-thiopyran-3-carboxylate derivatives 6-Amino-thiopyran-2-thiones ( 1 ) react with dihydrogen sulfide in the presence of pyridine and triethyl amine to yield 6-thioxo-thiopyran-2-thiolates ( 2 ). Methylation of 2 gives the methylthio compounds 3 and 4 . Further methylation of 3a and 4a yields the thiapyrylium salt ( 7 ). The reaction of 2-imino-thiopyran ( 6 ) with carbon disulfide represents another route to the 6-methylthio-thiopyran-2-thione ( 4a ). The 2-methylthio-thiopyran-6-thione ( 3a ) undergoes substitution of the methylthio group with amines to 8 or reacts with phenylhydrazine to phenylhydrazono-thiopyrane ( 9c ). 6-Thioxo-thiophen-2-thiolates ( 2a , b ) react with hydrazine hydrate to give hydrazono-thiopyranes ( 10a , b ) which can be S-methylated. On the contrary 2c gives with hydrazine hydrate under ring transformation the pyridine-2-thiolate ( 11 ). N,S-Acetals ( 12 ) and 1,3,4-thiadiazoles ( 15 ), which give rise to new pyridine derivatives ( 14 ) and ( 17 ), can be obtained from 1-Amino-pyridin-2-thiolate ( 11 ).     

Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism

Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M₁-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M₁ positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.