Active Methylene Moiety Research Articles

An Efficient Approach for the Synthesis and Antitumor Evaluation of Novel Azo- and Anil-Linked with 3-Aminopyrazolo[3,4-b]pyridine.

In this project, an effective procedure for constructing a new combination of pyrazolo[3,4-b]pyridine was depicted through the coupling of diazonium salt 2 of heterocyclic amine 1 with active methylene, enamine, and amidine moieties such as 3, 5, 7, and 9 at 0-5 °C in pyridine to afford hydrazinylhydrazonoyl derivatives 4, and diazenylheterocyclic derivatives 6, 8, and 10, respectively. Also, aminopyrazolo[3,4-b]pyridine 1 condensed with different aryl or heteroaryl aldehydes in EtOH/AcOH gave the corresponding aldimine 14, 15, 16. Compound 15 was cyclized via refluxing in DMF for 6 h to afford 18, while the transformation of compound 16 with an alkyl halide afforded 19a, b. The synthesized compounds, explicated by spectral data and elemental analysis, were examined for their antitumor activities. The in vitro cytotoxic activity of new pyrazolo[3,4-b]pyridines against the A2780CP, MCF-7, and HepG-2 cell lines was evaluated using the reference doxorubicin. Compounds 15 and 19a exhibited high reactivity against the A2780CP cell lines, with IC50 values of 35 and 17.9 μM, respectively. Also, compound 28 had the cytotoxic potential for A2780CP and MCF-7 cell lines, with IC50 values of 14.5, and 27.8 μM, respectively.

Recent advances in the synthesis and applications of β-keto sulfones: new prospects for the synthesis of β-keto thiosulfones.

This review mainly focuses on recent developments in the preparation of β-keto sulfones and their extensive synthetic applications. New prospects for the synthesis of β-keto thiosulfones have also been highlighted. Over the last decade, there has been exponential growth in the direct construction of β-keto sulfones using a wide variety of keto and sulfonyl precursors. Of note, the most promising photoredox transformations and electrochemical synthesis methods of β-keto sulfones are also presented. Moreover, β-keto sulfones are versatile building blocks in organic synthesis due to their three essential functional groups: sulfonyl, carbonyl, and active methylene moieties. The convenientpreparation of β-keto sulfones allows the synthesis of many valuable carbocyclic and heterocyclic compounds, and the effortless removal of the sulfonyl moiety via transformations is supported. The chemistry of β-keto sulfones (2013 to present) can be divided into several sections based on the sulfonyl surrogates, and ubiquitous synthetic strategies were systematically outlined.

Unique features of the ketosynthase domain in a nonribosomal peptide synthetase–polyketide synthase hybrid enzyme, tenuazonic acid synthetase 1

Many microbial secondary metabolites are produced by multienzyme complexes comprising nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). The ketosynthase (KS) domains of polyketide synthase normally catalyze the decarboxylative Claisen condensation of acyl and malonyl blocks to extend the polyketide chain. However, the terminal KS domain in tenuazonic acid synthetase 1 (TAS1) from the fungus Pyricularia oryzae conducts substrate cyclization. Here, we report on the unique features of the KS domain in TAS1. We observed that this domain is monomeric, not dimeric as is typical for KSs. Analysis of a 1.68-Å resolution crystal structure suggests that the substrate cyclization is triggered via proton abstraction from the active methylene moiety in the substrate by a catalytic His-322 residue. Additionally, we show that TAS1 KS promiscuously accepts aminoacyl substrates and that this promiscuity can be increased by a single amino acid substitution in the substrate-binding pocket of the enzyme. These findings provide insight into a KS domain that accepts the amino acid-containing substrate in an NRPS-PKS hybrid enzyme and provide hints to the substrate cyclization mechanism performed by the KS domain in the biosynthesis of the mycotoxin tenuazonic acid.

Superbase‐Mediated Indirect Friedländer Reaction: A Transition Metal‐Free Oxidative Annulation toward Functionalized Quinolines

A superbase mediated indirect Friedländer reaction towards functionalized quinolines has been realized. The reaction was performed with o‐aminobenzyl alcohol and ketones having an active methylene moiety in the presence of KOH and in DMSO. The reaction proceeds predominantly via initial formation of an imine intermediate and subsequent oxidation of the benzyl alcohol functionality and condensation to afford substituted quinolines. We could also demonstrate that a minor fraction of the reaction proceeds via a chalcone intermediate. The transition metal‐free oxidative annulation was found to be general affording 2‐substituted, 2,3‐disubstituted/fused or multi‐substituted quinolines. The reaction was extended towards the functionalization of natural products and the applicability of the reaction for gram‐scale synthesis of quinolines was also demonstrated.

Synthesis of Polyfunctionalized Fused Pyrazolo‐Pyridines: Characterization, Anticancer Activity, Protein Binding and Molecular Docking Studies

AbstractThe reaction of a multi‐substituted pyrazole 1 with aryl or heteroaryl aldehydes and active methylene compounds afford unexpected pyrazolo[1,5‐a]pyridine derivatives 4(a‐k). Mechanism for this unexpected reaction involving reactivity of the active methylene moiety with a neighboring endocyclic NH group is proposed and structure has been established by the NMR and single crystal X‐ray diffraction studies. Moreover, all the newly synthesized compounds were tested for their anticancer activity against sixty human cell lines at NCI. Among all the compounds, three scaffolds 4d, 4 h and 4k showed enhancement in anticancer activity in comparison with remaining synthesized compounds. Interestingly compound 4k was found to highly active even at a five dose concentration. The IC50 values were determined against two cell lines MCF‐7 and HepG2, the results obtained have shown promising effects against cancer cell lines. Further, the molecular docking studies revealed that substituted pyrazolo[1,5‐a]pyridine derivatives are good candidates in the medicinal field.

Novel low-molecular weight styryl dyes based on 2-chloroimidazo[1,2-a]pyridine-3-carbaldehyde – Synthesis and fluorescent molecular rotor studies

A library of fluorescent molecular rotors (FMRs) were synthesized by condensation of 2-chloroimidazo[1,2-a]pyridine-3-carbaldehyde with various active methylene moieties and their viscosity sensing properties were studied. The substituted 2-chloroimidazo[1,2-a]pyridine-3-carbaldehydes were prepared by a multistep reaction starting from 2-aminopyridine or 5-methyl-2-aminopyridine. Substitution of styryl group at the third position of imidazo[1,2-a]pyridine ring, the lone pair of bridging nitrogen as well as hyperconjugated methyl group are in proper resonance within the molecule and sustain aromaticity in ring leading to the red shifted absorption. Large red shifted absorptions were observed after substituting electron withdrawing group at the third position as compared to the known 7-[(E)-2-(phenyl)vinyl]-2-phenylimidazo[1,2-a]pyridine analogues where the styryl groups are at the second position of imidazo[1,2-a]pyridines ring. These donor- π-acceptor extended styryl FMRs were investigated for their viscosity sensitivity and found to show values between 0.2135 and 0.5356 in glycerol-methanol system using fluorescence emission spectra. These low molecular weight FMRs are found to show up to 31 fold enhancement in emission intensity in viscous environment. Oscillator strengths (f) and transition dipole moments (µeg) have been studied to understand charge transfer within the molecules. The structures are confirmed by 1H NMR, 13C NMR, Mass and elemental analysis.

Novel NLOphoric 2-methoxy carbazole-based push pull chromophores: Synthesis, photophysical properties and TD-DFT Study

Abstract Photophysical properties of novel carbazole containing “push–pull” dyes obtained by the condensation of 2-methoxy-9-methyl-9 H -carbazole-3-carbaldehyde 3 with different active methylene moieties are studied. These dyes were well characterized by 1 H NMR, 13 C NMR and HRMS spectra. The UV–vis absorption and fluorescence emission spectra of the dyes were studied in solvents of varying polarities. DFT and TD-DFT computation were performed to study structural, molecular, electronic and photophysical parameters of the dyes. The four dyes are showing red shifted solid sate emission in the range of 487–593 nm. The ratio of ground to excited state dipole moment of the synthesized dyes were calculated using solvent polarity correlations and DFT method. The absorption wavelength and emission wavelength values are found to be in good agreement with the experimental results. Non-linear optical properties were investigated by using solvatochromic shift method and theoretical methods.

A Mechanochemical Approach for the Construction of Carbon–Carbon Double Bonds: Efficient Syntheses of Aryl/Heteroaryl/Aliphatic Acrylates and Nitriles

An efficient method for the construction of carbon–carbon double bond has been developed from aromatic aldehydes and compounds with active methylene moieties in the presence of catalytic amount of solid sodium ethoxide via mechanochemical approach. This capable process provides a diverse range of homoaryl/heteroaryl/aliphatic acrylates and nitriles in good to excellent yields at short reaction period.

Synthesis and characterization of a group of new medium responsive non-symmetric viologens. Chromotropism and structural effects

A group of new non-symmetric viologens was synthesized and characterized spectrally using various techniques. These viologens contain active methylene moieties being capable to act as hydrogen bond donors (HBD) and interact in solution with various solvents, the latter acting as hydrogen bond acceptors (HBA). These specific solute-solvent interactions result in intense coloration of the resulting solutions. The chromotropic behavior of these compounds is triggered by basic solvents, and no significant change in color is observed in poorer HBA-solvents, such as several alcohols. The dependence of the color of the solutions on the polarity parameters of solvents (solvatochromism) was investigated. Solvent polarity parameters expressing both dipolarity/polarizability and basicity of solvents have been used. Finally the correlation of the chromotropic behavior of these compounds with their structure is examined, using both experimental data and Hammett equation.

ChemInform Abstract: Rhenium‐Catalyzed Regioselective Synthesis of Phenol Derivatives from 1,3‐Diesters and Terminal Alkynes.

AbstractReaction of malonates lacking a substituent at the active methylene moiety with terminal aromatic alkynes gives salicylates (III) regioselectively.

ChemInform Abstract: Intramolecular Polar Addition Reactions of Active Methylene Moieties to Aryl‐Substituted Alkenes via Photoinduced Electron Transfer.

AbstractA novel construction of five‐ to seven‐membered cycloalkane derivatives can be achieved.

Comparison of Cytotoxic and Antiproliferative Effects of Benzylidenecyclopentanone Analogues of Curcumin on RBL-2H3 Cells

Curcumin is a natural yellow pigment isolated from the rhizomes of Curcuma longa L. (turmeric), and has several pharmacological effects and no toxicity in both in animal and human clinical study. However, the problem of curcumin is its stability because of its active methylene moiety. Modification of this moiety to cyclopentanone is expected to increase the stability. Previous study reported that benzylidenecyclopentanone analogues of curcumin showed inhibitory effect on histamine release from RBL-2H3 (rat basophilic leukemia) cells, a tumor analog of mast cells. One of them, the hydroxy-methoxy analog (PGV-0), showed more potent effect than that of curcumin. In the present study, some benzylidenecyclopentanone analogues of curcumin were evaluated for their effects on the viability and proliferation of RBL-2H3 cells. Viable cells were counted under a light microscope with a cells-counting chamber or using the cell viability reagent WST-1. The results showed that mast cell viability and histamine content were not affected by curcumin and benzylidene cyclopentanone for 30 min incubation, however, impaired for overnight incubation. The hydroxy-dimethyl benzylidene analog (PGV-1) strongly decreased the mast cells viability for overnight incubation, and its effect was highest among the other analogues. In the proliferation study, this compound also strongly inhibited the proliferation of mast cells, whereas curcumin and hydroxy-methoxy benzylidene analog inhibited the proliferation slightly. There were no inhibitory effects on mast cells proliferation treated by dibenzylidene; dihydroxybenzylidene; and hydroxy-diethylbenzylidene cyclopentanone. Keywords : viability, proliferation, curcumin, benzylidene cyclopentanone, RBL-2H3 cells

Intramolecular polar addition reactions of active methylene moieties to aryl-substituted alkenes via photoinduced electron transfer

The synthesis of cycloalkane derivatives with ring sizes of 5–7 was achieved in moderate yields by photoirradiation of aqueous acetonitrile solutions, containing compounds that consist of active methylene moieties tethered to aryl-substituted alkenes along with sodium hydroxide and 9-cyanophenanthrene. When the substrate contains ethyl cyanoacetate as an asymmetric active methylene moiety, the reaction proceeds in a highly diastereoselective manner.

Rhenium-catalyzed Regioselective Synthesis of Phenol Derivatives from 1,3-Diesters and Terminal Alkynes

Abstract Treatment of malonates without a substituent at the active methylene moiety with terminal alkynes gave salicylates regioselectively. In contrast, when malonates bearing a substituent at the active methylene moiety were used, cyclic β-keto esters were generated regioselectively. Treatment of the formed cyclic β-keto esters with In(OTf)3 gave phenol derivatives via decarboxylation.

Rhenium- and Manganese-Catalyzed Synthesis of Aromatic Compounds from 1,3-Dicarbonyl Compounds and Alkynes

We have succeeded in the development of three approaches to the synthesis of aromatic compounds from 1,3-dicarbonyl compounds and alkynes. The first approach is a manganese-catalyzed [2+2+2] cycloaddition between 1,3-dicarbonyl compounds, which have no substituents at the active methylene moiety, and terminal alkynes. This reaction proceeds with high regioselectivity when aryl acetylenes are employed as the alkyne component. The second approach is a rhenium- or manganese-catalyzed formal [2+1+2+1] cycloaddition between beta-keto esters and two kinds of alkynes. In this reaction, the aromatic compounds are obtained by the following reaction sequence: (1) insertion of the first alkyne into a carbon-carbon single bond of a beta-keto ester, (2) formation of 2-pyranones via intramolecular cyclization with the elimination of ethanol, and (3) Diels-Alder reaction between the formed 2-pyranone and the second alkyne. This reaction provides multisubstituted aromatic compounds in a regioselective manner. The third approach is a rhenium-catalyzed formal [2+2+1+1] cycloaddition reaction from two 1,3-diketones and one alkyne. In this reaction, the aromatic skeleton is constructed from three carbons of the first 1,3-diketone, two carbons of the alkyne, and one carbon of the second 1,3-diketone.

Rhenium-Catalyzed Addition of β-Enamino Esters to Allenes

Treatment of β-enamino esters with terminal allenes in the presence of a catalytic amount of a rhenium complex, [ReBr(CO) 3 (thf)] 2 , gave α-alkenylated β-imino or β-enamino esters. In this reaction, a new carbon―carbon bond is formed between the active methylene moiety of the β-enamino esters and the β-carbon of the terminal allenes.

The Reaction of Organozinc Reagents with Trifluoroacylated Phosphonates: Synthesis of Trifluoromethylated α,β‐Unsaturated Esters with an Active Methylene Moiety.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The reaction of organozinc reagents with trifluoroacylated phosphonates: Synthesis of trifluoromethylated α, β‐unsaturated esters with an active methylene moiety

AbstractThe consecutive reaction of phosphonates 1 with n‐butyllithium, trifluoroacetic anhydride, and organozinc compounds gives trifluoromethylated α,β‐unsaturated esters with an active methylene moiety and predominant Z‐selectivity in 54–78% (3 steps) yields. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:289–292, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20018

Unexpected switch in regioselectivity of tether-directed Bingel-type biscyclopropanations depending on the leaving groups at tethered active ethylene moieties.

The regioselectivity of tether-directed Bingel-type biscyclopropanations of [60]fullerene was switched depending on the leaving groups at tethered active methylene moieties; the reactions of [60]fullerene with unhalogenated tethered bis(active methylene) derivatives/I2 and with brominated derivatives in the presence of 1,7-diazabicyclo[5.4.0]undec-7-ene gave trans-4-adducts predominantly, while the reactions with chlorinated derivatives afforded equatorial-adducts almost exclusively.

Carbon-carbon bond formation via the Mitsunobu reaction on solid supports

The feasibility of C-C bond formation via the Mitsunobu reaction on solid supports has been investigated. Alkylation of a polymer supported alcohol with various compounds having an active methylene moiety in the presence of TMAD and Bu 3P gave the desired monoalkylated product, as well as an unexpected bis-alkylated product in ratios depending on the substrate loading. A rationalization for the latter is also presented.