Benzylidene Ring Research Articles

3-Methoxybenzaldehyde thiosemicarbazone

The title compound, C9H11N3OS, was prepared by the reaction of 3-methoxy­benzaldehyde and thio­semicarbazide. The benzyl­idene ring and the thio­semicarbazone fragment are slightly twisted, making a dihedral angle of 14.1 (1)°. A weak intra­molecular N—H⋯N hydrogen bond may influence the conformation of the mol­ecule. Inter­molecular N—H⋯S hydrogen bonds build up a three-dimensional network.

Phytogrowth Activity of 3-(3-Chlorobenzyl)-5-arylidenefuran-2(5H)-ones

Nine new 3-(3-chlorobenzyl)-5-arylidenefuran-2(5H)-ones were prepared in 20 - 87% yields by reaction of 3-(3-chlorobenzyl)furan-2(5H)-one with pertinent aldehydes. All compounds were fully characterized by IR and NMR spectroscopy as well asMS spectrometry. The phytotoxic properties of the synthesized lactones were evaluated as the ability to interfere with the growth of Sorghum bicolor and Cucumis sativus seedlings at 10 ppm and 100 ppm. Lactone 12, at 10 ppm, was the most active and selective, inhibiting the S. bicolor and C. sativus root growth by 70.7% and 10.7%, respectively. At 10 ppm, lactone 14 caused the larger effect on the inhibition (41.9%) of C. sativus. In general, the results indicate the influence of the benzylidene ring substitution on the phytotoxic activity

Synthesis and Characterization of New Polyamides with Substitutions in the Pendent Benzylidene Rings

Aromatic polyamides with azomethine groups present in the polymer with –Cl, –OCH3, –N(CH3)2 and –OH substitutions in the pendent benzylidene rings were synthesized through polycondensation of new aromatic dicarboxylic acids with aromatic diamines using the phosphorylation technique in DMF. Direct polymerization of the monomers benzylidenamino phenyl 2,5-dicarboxylic acid (M1), 4′-hydroxy benzylidenamino phenyl 2,5-dicarboxylic acid (M2), 4′-methoxy benzylidenamino phenyl 2,5-dicarboxylic acid (M3), 4′-chloro benzylidenamino phenyl 2,5-dicarboxylic acid (M4) and (N,N-dimethylamino) benzylidenamino phenyl 2,5-dicarboxylic acid (M5) was carried out with commercial diamines, 4,4′-methylenedianilene and 4,4-diaminobiphenyl, at 140°C. FT-IR and 1H-NMR spectroscopic analysis were used to characterize the monomers and polymers. The inherent viscosity values of polyamides are in the range 0.39–0.68. Due to the substitutions in the pendent benzylidene rings, the polymers show enhanced solubility. The thermal stability of the polyamides was evaluated using thermogravimetric analysis, and the thermogravimetric curves show the dependence of thermal stability on the nature of the substitutions in the benzylidene rings.

Dimethoxyaurones: Potent inhibitors of ABCG2 (breast cancer resistance protein)

A series of 4,6-dimethoxyaurones were synthesized by reacting 4,6-dimethoxybenzofuran-3(2 H)-one with various benzaldehydes in a base-catalyzed aldol reaction. A Z configuration was assigned to the aurones based on spectroscopic and crystallographic data. The aurones were tested for their ability to modulate ABCG2 (breast cancer resistance protein)-mediated multidrug resistance in vitro. Several members (0.5 μM) increased the accumulation of mitoxantrone (MX) in human breast cancer cells (MDA-MB-231) transfected with ABCG2 and re-sensitized these cells to the cytotoxic effects of MX. In the re-sensitization assay, aurones at 0.5 μM reduced the resistance of the transfected cells to MX to just twice that of the parental cells, exceeding fumitremorgin C (FTC) tested at the same concentration. The aurones (10 μM) also increased calcein-AM accumulation in MDCKII/MDR1 cells that were transfected with ABCB1 (P-glycoprotein), at levels comparable to verapamil tested at the same concentration. Structure–activity analysis showed that substitution of the benzylidene ring B of the aurone template was less important for ABCG2 inhibition, with little variation in activity noted for compounds with an unsubstituted ring B or one that was substituted. In contrast, substitution of ring B gave rise to better inhibitors of ABCB1. A preference for the 3′ position of ring B was noted. There was also some indication from the data that aurones with good ABCG2 inhibitory activity were poor ABCB1 inhibitors and vice versa, but further confirmation would be required. Limited antiproliferative activity (>70% cell survival) was observed for many aurones on four different cell lines. Thus, functionalized 4,6-dimethoxyaurones are promising ABCG2 inhibitors that combine good activity at submicromolar concentrations with limited antiproliferative activity.

Sulindac Derivatives That Activate the Peroxisome Proliferator-activated Receptor γ but Lack Cyclooxygenase Inhibition

A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARγ). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as any other in the series with an EC50 of 0.1 μM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPARγ was demonstrated by the displacement of [3H]troglitazone, a PPARγ agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPARγ to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARγ target genes. Taken together, these compounds represent potential leads in the development of novel PPARγ agonists.

Activation of C–H and C–Br bonds in cyclopalladation reactions of Schiff base ligands: Influence of the benzylidene ring substituents

Reaction of Pd(AcO) 2 with the Schiff base ligands 2-Br-4,5-(OCH 2O)C 6H 2C(H) N(Cy) ( a) and 4,5-(OCH 2CH 2)C 6H 3C(H) N(Cy) ( b) leads to the cyclometallated compounds [Pd{2-Br-4,5-(OCH 2O)C 6HC(H) N(Cy)- C6, N}(μ-O 2CMe)] 2 ( 1a) and [Pd{4,5-(OCH 2CH 2)C 6H 2C(H) N(Cy)- C6, N}(μ-O 2CMe)] 2 ( 1b), respectively, via C–H activation. Treatment of a with Pd 2(dba) 3 gave [Pd{4,5-(OCH 2O)C 6H 2C(H) N(Cy)- C2, N}(μ-Br)] 2 ( 6a), via C–Br activation. The metathesis reaction of 1a and 1b with aqueous sodium chloride gave the corresponding cyclopalladated dimers with bridging chloride ligands, 2a and 2b, respectively. Treatment of the halogen-bridged compounds with tertiary tri- and diphosphines in the appropriate molar ratio gave the mono and dinuclear compounds 3a– 5a, 7a– 9a and 3b– 5b. The structure of compounds 3a, 4a, 5a, 8a, 2b, 3b and 5b has been determined by X-ray diffraction analysis.

Substituent Cross-Interaction Effects on the Electronic Character of the CN Bridging Group in Substituted Benzylidene Anilines − Models for Molecular Cores of Mesogenic Compounds. A13C NMR Study and Comparison with Theoretical Results

13C NMR chemical shifts delta(C)(C=N) were measured in CDCl3 for a wide set of mesogenic molecule model compounds, viz. the substituted benzylidene anilines p-X-C6H4CH=NC6H4-p-Y (X = NO2, CN, CF3, F, Cl, H, Me, MeO, or NMe2; Y = NO2, CN, F, Cl, H, Me, MeO, or NMe2). The substituent dependence of delta(C)(C=N) was used as a tool to study electronic substituent effects on the azomethine unit. The benzylidene substituents X have a reverse effect on delta(C)(C=N): electron-withdrawing substituents cause shielding, while electron-donating ones behave oppositely, the inductive effects clearly predominating over the resonance effects. In contrast, the aniline substituents Y exert normal effects: electron-withdrawing substituents cause deshielding, while electron-donating ones cause shielding of the C=N carbon, the strengths of the inductive and resonance effects being closely similar. Additionally, the presence of a specific cross-interaction between X and Y could be verified. The electronic effects of the neighboring aromatic ring substituents systematically modify the sensitivity of the C=N group to the electronic effects of the benzylidene or aniline ring substituents. Electron-withdrawing substituents on the aniline ring decrease the sensitivity of delta(C)(C=N) to the substitution on the benzylidine ring, while electron-donating substituents have the opposite effect. In contrast, electron-withdrawing substituents on the benzylidene ring increase the sensitivity of delta(C)(C=N) to the substituent on the aniline ring, while electron-donating substituents act in the opposite way. These results can be rationalized in terms of the substituent-sensitive balance of the electron delocalization (mesomeric effects). The present NMR characteristics are discussed as regards the computational literature data. Valuable information has been obtained on the effects of the substituents on the molecular core of the mesogenic model compounds.

Effect of substituents on the 13C chemical shifts of the azomethine carbon atom of N-(substituted phenylmethylene)-3- and -4-aminobenzoic acids

13C chemical shifts of the azomethine carbon atom for N-(substituted phenylmethylene)-3- and -4-aminobenzoic acids having a wide range of substituent effects, were determined in deuterated DMSO solution. Good Hammett correlations of the 13C NMR chemical shifts of azomethine carbons with electrophilic substituent constants σ p + for electron-donor substituents for both series of acids indicate an important resonance interaction of the substituents on the benzylidene ring with the azomethine carbon atom. On the other hand, good correlations of the 13C NMR chemical shifts of azomethine carbon atom of both series of acids with inductive substituent constants for electron-acceptor substituents in benzylidene ring indicates that the chemical shifts are influenced only by inductive effect of the substituents. The demand for electrons by the azomethine carbon atom in both investigated series have been compared, discussing the mode of transmission of substituent effects, both inductive and resonance, in relation to the geometry of investigated imines.

Effects at a distance in α7 nAChR selective agonists: benzylidene substitutions that regulate potency and efficacy

Anabaseine is a marine worm toxin that is a relatively non-selective nicotinic agonist, activating both muscle-type and neuronal nicotinic acetylcholine receptors (nAChR) with varying efficacy. While anabaseine has significant activity with muscle-type and neuronal α3β4 and α4β2 receptors, benzylidene anabaseine (BA) derivatives have high selectivity for the α7 receptor subtype. Two BA compounds with substituents at the 2 and 4 positions of the benzylidene ring, GTS-21 and 4OH-GTS-21, may have therapeutic potential for treating neuropathological disorders such as Alzheimer’s disease due to their α7 selectivity. In this study, we specifically investigated the influence of the benzylidene attachment to anabaseine on α7 nicotinic receptor selectivity, as well as the effects of specific substituents at the 4- position of the benzylidene moiety. We demonstrate that benzylidene-attachment alone is sufficient to confer α7 selectivity to anabaseine. Increased potency and receptor binding affinity was obtained with a 4-hydroxyl substitution. Two other 4-substituted benzylidene anabaseines, 3-(4′-methylthiobenzylidene)anabaseine (4-MeS-BA) and 3-(4-trifluoromethylbenzylidene) anabaseine (4-CF 3-BA), offered very little agonist activity for any nicotinic receptors and instead were antagonists for both α7 and neuronal α3β4 and α4β2 receptors. Since the relative amounts of agonist and antagonist activities for specific BA compounds vary with the specific drug/receptor combinations, benzylidene anabaseines provide valuable tools for nAChR drug-receptor structure–function relationships.

Hydroxy Metabolites of the Alzheimer's Drug Candidate 3-[(2,4-Dimethoxy)Benzylidene]-Anabaseine Dihydrochloride (GTS-21): Their Molecular Properties, Interactions with Brain Nicotinic Receptors, and Brain Penetration

3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; GTS-21), an Alzheimer's drug candidate, selectively stimulates alpha7 nicotinic acetylcholine receptors. It rapidly enters the brain after oral administration and enhances cognitive behavior. Less than 1% of orally administered DMXBA is recovered in the urine. We report the identification and characterization of the major phase I metabolites of this drug candidate. Three hydroxy metabolites were generated in vitro by hepatic microsomal O-dealkylation of the two methoxy substituents on the benzylidene ring. They were also found in plasma of rats after oral administration, but at significantly lower concentrations relative to the parent compound. The metabolites displayed similar binding affinities and partial agonist potencies at rat brain alpha7 receptors. However, each displayed a higher efficacy than DMXBA for stimulating rat and human alpha7 receptors. Like DMXBA, the metabolites were weak antagonists at alpha4beta2 receptors. The predicted conformations of the metabolites were nearly identical with that of DMXBA. Ionization of the tetrahydropyridyl nitrogen was essential for high-affinity binding of DMXBA to the alpha7 receptor. The hydroxy metabolites were much more polar than DMXBA, derived from their experimentally estimated octanol/water partition coefficients, and they entered the brain much less readily than DMXBA. Their contributions to the behavioral effects of orally administered DMXBA, if any, would probably be very small during short-term administration. Benzylidene anabaseines pharmacologically similar to the hydroxy metabolites, but which enter the brain more readily, may provide greater stimulation of alpha7 receptors in the whole organism.

Hydrogen bonding interactions of benzylidene type Schiff bases studied by vibrational spectroscopic and computational methods

The structural features of four benzylidene type Schiff bases [(E)-benzaldehyde-N-phenyl imine, (A) (E)-2-hydroxybenzaldehyde-N-phenyl imine (B) (E)-benzaldehyde-N-2-hydroxyphenyl imine (C) (E)-2-hydroxybenzaldehyde-N-2-hydroxyphenyl imine (D)] were studied by FT-IR spectroscopy in solution, photoacoustic and Raman spectroscopies in the solid state and quantum chemical calculations. It was found that molecule D dimerised in the solid state with concomitant loss of aromaticity in the benzylidene ring. Beside the intermolecular CO⋯HO hydrogen bonds, intramolecular N–H⋯CO hydrogen bonds could be found experimentally as well as computationally. Spectra taken in solution and ab initio quantum chemical calculation helped to identify hydrogen bonding interactions occurring for compounds B and C. Intramolecular OH⋯N hydrogen bond predominated in molecule B, while this interaction, although it existed, was weaker.

Study on second harmonic generation of 9-benzylidene-substituted-10-methyl-9,10-dihydroacridines

Eight 9-benzylidene-substituted-10-methyl-9,10-dihydroacridine derivatives were synthesized from acridine as starting material and were characterized by 1H-NMR, 13C-NMR, Ms and elemental analysis. The second harmonic generation (SHG) values of these compounds were determined in powder using Nd:YAG as a laser source, as compared with urea powder, and the values of second-order polarizabilities ( β xxx), the values of the composite magnitude ( β CTμg) of molecular hypersusceptibilities and their moment of these compounds were obtained by the solvatochromic method under ground state for everyone. The results showed that SHG value of 10 is higher than that of urea; the β CTμg of 5 (107.8×10 −30 esu) is lower than that of 4-nitro- N, N-dimethylaniline (30×10 −30 esu); the β CTμg of 7 (350.8×10 −30 esu) and 10 (244.6×10 −30 esu) are higher than that of 4-nitro- N, N-dimethylaniline; the β CTμg of 8 (3553×10 −30 esu), 11 (1187×10 −30 esu) and 12 (1163×10 −30 esu) are much more higher than that of 4-nitro- N, N-dimethylaniline. The results demonstrated that this series of compounds possesses good second-order nonlinear optical (NLO) property. The regular relationship could not be obtained between electronegativity of substituents ( R) attached to benzylidene ring and SHG values or β CTμg values although the Rs are different in electronegativity and should make an effect on the extent of intramolecular electron-transfer and would consequently influence SHG or β CTμg. The electron-withdrawing ability of R from benzylidene ring played an important role on λ max of these compounds.

Prearranged glycosides, 2. Intramolecular glycosylation of prearranged saccharides as a novel strategy for the construction of β‐L‐rhamnosidic linkages

AbstractDisaccharides containing a β‐L‐rhamnosyl residue were prepared by a novel intramolecular glycosylation strategy. Thus, suitably benzyl‐protected L‐rhamnosyl donors (ethyl and phenyl 1‐thiorhamnoside 7, 18) were prearranged in positions 2 and 3 with benzyl 2‐O‐benzoyl‐4,6‐O‐benzylidene‐α‐D‐glucopyranoside 8 in position 3 by a malonyl, succinyl and phthaloyl bridge, respectively, to give the corresponding connected saccharides 9, 12, 16 and 20. After regioselective opening of the benzylidene ring of the glucoside residue to give compounds 10, 13, 17 and 21, the latter afforded the 3,2′‐ and 3,3′‐bridged disaccharides 22–25 upon intramolecular glycosylation with a thiophilic reagent. The anomeric selectivity of this intramolecular glycosylation is strongly influenced by the nature of the alkanoyl and aroyl bridge, its position at the rhamnosyl residue and the solvent used for the coupling. Best results were obtained in acetonitrile with the succinyl „spacer”︁ attached to position 2 of the phenyl 1‐thiorhamnoside and position 3 of the glucoside that afforded the corresponding β‐(1→4)‐linked disaccharide 22β in 76% yield.

Glycosyl Imidates, 65. Efficient synthesis of the Lewis antigen X (Lex) family

Abstracttert‐Butyldimethylsilyl 2‐azido‐4,6‐O‐benzylideneglucopyranoside 5 proved to be a versatile starting material for the synthesis of the Lex antigen family. 3‐O‐Fucosylation of 5, ensuing reductive benzylidene ring cleavage, and then 4‐O‐galactosylation afforded Lex trisaccharide building block 12 which was readily converted into trisaccharide donor 14α,β and into trisaccharide 3c‐O‐acceptor 16. Their reaction in acetonitrile as solvent at low temperatures (nitrile effect) afforded exclusively the β‐connected hexasaccharide 17, which was transformed via the same steps into hexasaccharide donor 20α,β and acceptor 22. The use of these building blocks and known lactose derivative 23b, and 3‐O‐benzoylprotected azidosphingosine 32 as acceptors led to ready formation of the target molecules. Thus, from 20α, β and 23b octasaccharide 24b was obtained which was converted via 25b and 26b into O‐unprotected octasaccharide 27; the derived O‐acyl‐protected donor 29bα was linked to 32, thus providing by application of the “azidosphingosine glycosylation procedure” dimeric Lex 1B. From 20α, β and 16 nonasaccharide 35a was obtained; its transformation via 36a and 37a into donor 38aα,β gave by reaction with 23b undecasaccharide 39a; the derived donor 43aα furnished by treatment with 32 trimeric Lex 1C. Similarly, from 20α, β and 22 dodecasaccharide 35b was generated which gave via 36b, 37b, and donor 38bα, β by reaction with 23b as acceptor tetradecasaccharide 39b; 39b, after transformation into the corresponding donor 43bα, β gave by treatment with 32 as acceptor tetrameric Lex 1D. Additionally, octasaccharide donor 29bα, β was attached to spacer 30, thus yielding spacer‐connected dimeric Lex antigen 2. magnified image

Linear free energy relationships in the reduction of imines over a Pd/Sepiolite catalyst

In this work we synthesized a series of imines of formula RC6H4CHNC 6H 5 and C 6H 5CHNC 6H 4R (R  OH-, CH 3O-, CH 3-, HOOC-, CH 3-CO, and CH 3COO-) and subjected them to hydrogenation with Hz over a 3% Pd catalyst supported on sepiolite extracted from Vallecas (Madrid, Spain). From the relationships found between In A and E a we inferred the occurrence of a compensating effect in the process. We also determined the influence of substituents on the reduction rate from the σ contributions reported by Hammett. By taking N-benzylideneaniline as a reference, we found the presence of electron-withdrawing substituents in either aromatic ring increased the rate of reduction of the >CNbond, while that of electron-releasing groups had the opposite effect. Substituents on the benzylidene ring were found to have a more marked effect than those on the phenylimine ring. A general multi-step reduction pathway similar to that reported by Horiuti-Polanyi ( Trans. Faraday Soc. 30, 1164 (1934)) is proposed to account for the experimental results obtained.

A Vibrational and Theoretical Interpretation of the Conformation of Mono- and Disubstituted N-Benzylideneanilines

Abstract Infrared data for N-benzylideneanilines mono- and disubstituted predict, in agreement with CNDO molecular orbital calculations, that the internal energy transfer is induced mainly by a donor group in para position of the benzylidene ring; this effect confers to this molecular portion a prevalent planar structure. However, the charge transfer is restricted by a steric interaction between one of the ortho hydrogen atoms of the aniline ring and the azomethine hydrogen; this situation constraints this molecular portion to adopt a major non planar conformation.

A Theoretical Analysis of the Contributions to the Internal Rotation Barrier in N-Benzylideneanilines

Abstract An analysis, using CNDO wave functions, has been carried out on the different contributions to the internal rotation barrier in N-benzylideneaniline (1) and p-dimethylaminobenzylidene-p-nitro-aniline (2) in several conformations. The stability of the different structures has been expressed in terms of a partition of the total energy into electronic, net charges and steric hindrance contributions. Based on the shape of the total energy surface it appears that the barrier composition may be reasonably well described without approaching the absolute minimum. Rotation of the aniline group in both molecules is mainly governed by steric hindrance. Rotation of the benzylidene group shows a prevalent destabilizing electronic effect. The donor strength of the substituent in the benzylidene ring seems to play an important role in stabilizing a less nonplanar structure.

Vibrational spectra of trans-N-benzylideneaniline and its isotopomers

Abstract

On the reaction of 4,6-O-benzylidene-2-deoxypyranosides with sodium cyanoborohydride: formation of 1,5-anhydroalditols

Some methyl 4,6-O-benzylidene-2-deoxypyranosides were submitted to the action of sodium cyanoborohydride in acidic medium. Regiospecific cleavage of the benzylidene ring was observed, giving the expected 6-O-benzyl derivative. Depending upon the substitution at C-2 reductive cleavage of the aglycone was observed as a side-reaction or as a main reaction. This could provide a new entry to 1,5-anhydroalditols branched at C-2.

Oxidative Cleavage of 4,6-O-Benzylidene Ring with t-Butyl Hydroperoxide and Copper(II) Chloride. Preparation of Methyl 4-O- and 6-O-Benzoylhexopyranoside Derivatives

Abstract Copper(II) chloride and palladium(II) acetate were found to be highly effective catalysts for oxidative cleavage of O-benzylidene ring with t-butyl hydroperoxide. Using the former catalyst 4,6-O-benzylidenehexopyranoside derivatives were converted into the corresponding 4- and 6-benzoates in high yields. This reaction was also applicable for conversion of benzyl group into benzoyl one.