4-substituted Anilines Research Articles

Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors.

Mer and c-Met kinases, which are commonly overexpressed in various tumors, are ideal targets for the development of antitumor drugs. This study focuses on the design, synthesis, and evaluation of several 2-substituted aniline pyrimidine derivatives as highly potent dual inhibitors of Mer and c-Met kinases for effective tumor treatment. Compound 18c emerged as a standout candidate, demonstrating robust inhibitory activity against Mer and c-Met kinases, with IC50 values of 18.5 ± 2.3 nM and 33.6 ± 4.3 nM, respectively. Additionally, compound 18c displayed good antiproliferative activities on HepG2, MDA-MB-231, and HCT116 cancer cells, along with favorable safety profiles in hERG testing. Notably, it exhibited exceptional liver microsomal stability in vitro, with a half-life of 53.1 min in human liver microsome. Compound 18c also exhibited dose-dependent cytotoxicity and hindered migration of HCT116 cancer cells, as demonstrated in apoptosis and migration assays. These findings collectively suggest that compound 18c holds promise as a dual Mer/c-Met agent for cancer treatment.

Syntheses, crystal structures, DFT calculation and solid-state spectroscopic properties of new zincate(II) complexes with N-(4-substituted phenyl)-N'-(4-nitrophenyl)-oxamate

The electronic effects electron donating and withdrawing groups R on the properties of N-(4-R-phenyl)-N'-(4-nitrophenyl)oxamito zincate(II) complexes was investigated featuring R = Me (a), H (b), F (c), Cl (d) and Br (e). The N-(4-R-phenyl)-N'-(4-nitrophenyl)oxamide ligands 2 were synthesized by reacting ethyl 4-nitrooxanilate with the respective 4-substituted anilines. Subsequent treatment with [nBu4N]OH and [Zn(OAc)2(H2O)2] gave the respective zincate complexes [nBu4N]2[Zn(N-(4-nitrophenyl)-N'-(4-substituted phenyl)oxamides)2] (3). Spectroscopic methods were used to describe compounds 2a–e and 3a–e. Single crystal X-ray diffraction analysis confirmed the formation of 3a–c in the solid state. The tetrahedral coordination sphere of the zinc (II) ion features four amide nitrogen donor atoms based on two ethanediamide ligands. The UV–Vis spectra of Complexes 3a–e display a characteristic LLCT (π → π *) band, which was confirmed by TD-DFT calculations. DFT calculations show that the Zn(II) orbitals do not contribute to the HOMO or LUMO, with the latter being primarily found on the two 4-nitrophenyl rings for compounds 3a − e, while the HOMO-1 and HOMO are located on the 4-substituted phenyl rings. Notably, HOMO and LUMO energies and gabs do not differ significantly. Transitions from HOMO to LUMO + 1 are the most important for all ligands. The luminescence properties of solid compounds 3a − e were also investigated at 298 K. Solid state photoluminescence studies reveal that these complexes emit strong yellow-orange luminescence at 450–600 nm with a maximum at about ∼ 500 nm in the cyan region. Furthermore, the thermal stabilities of compounds 3a − e have been investigated.

An efficient synthesis of 4-Thiocyanato anilines using benzyltrimethylammonium dichloroiodate and ammonium thiocyanate in DMSO:H2O

Treatment of a variety of 2(3)- mono-substituted anilines with benzyltrimethylammonium dichloroiodate (1.2 equiv) and ammonium thiocyanate (1.2 equiv) in DMSO:H2O (9:1) at 70 °C gave the corresponding 4-thiocyanato-2(3)-substituted anilines in excellent isolated yields (60–99%; ave. yield for all anilines = 90%). The reaction worked well for substrates with 2-halo, 2-alkoxy, 2-aryloxy, 2-alkyl, 2-dialkylamino, 2-N-sulfonylamino, 2-alkyn-1-yl, 2-cyano, 2-acyl, 2-sulfonyl, and 2-heteroaryl substitution. 3-Substituted, 3,5- or 2,6-disubstituted anilines and substituted phenols were also well tolerated. 4-Substituted anilines gave the corresponding 2-aminobenzothiazole products, whereas 4-, 5-, 6-, or 7-substituted indoles were not reactive. Regioselective thiocyanation of 2-quinoline, 3-amino-1-methylpyrazole, 2-amino-4-phenylthiazole, and 2-phenylimidazo[1,2-a] pyridine was achieved in 93–99% yield, thus demonstrating the broad-substrate scope for this thiocyanation reaction.

Synthesis and DFT Investigation of New Low-Melting Supramolecular Schiff Base Ionic Liquid Crystals

Supramolecular, low-melting (near or below 0.0 °C) ionic liquid crystals with two rings of Schiff bases were prepared and studied. The Schiff bases were synthesized using 4-substituted aniline derivatives and 4-pyridine carbaldehyde and then mixed in equimolar amounts with linear 1-bromoalkanes of different chain lengths, namely C6, C8, and C14. The mesomorphic behavior and thermal properties of the compounds were determined by polarized optical microscopy (POM) and differential scanning calorimetry (DSC). Only the ionic liquids analogous with 1-bromotetradecane exhibit mesomorphic behavior. All, except the smectic A (SmA) monomorphic fluorine-substituted complex, show dimorphic enantiotropic mesophases, namely SmA followed by nematic (N) mesophases depending on the temperature rise. The DSC and POM results for the induced mesophases were then treated with density functional theory calculations (DFT). The results showed that both the polarity of the polar groups and the length of the alkyl groups strongly influence the mesomorphic properties of the ionic liquids.

Ferrate(VI) Oxidation Mechanism of Substituted Anilines: A Density Functional Theory Investigation.

Ferrate(VI) (Fe(VI)) is a promising oxidant coagulant and disinfectant for the degradation of organic micropollutants. However, it is hard to elucidate the detailed oxidation mechanism through the current experimental approaches. Substituted anilines (SANs) are important chemical compounds that are widely used in many industries. This paper presents the use of density functional theory (DFT) to understand the oxidation mechanism of SANs by Fe(VI) and the effect of substituents. The calculation results revealed that the primary oxidations of SANs follow the hydrogen atom transfer (HAT) mechanism. Interestingly, the hydroxyl oxygen of HFeO4– is more reactive than the carbonyl oxygen when reacting with SANs. The formation of the SAN radical is crucial, and all of the products are formed from it. Azobenzene is more favorable to generate the above products. In addition, the obtained results indicate that this kind of substituent has a much greater influence on the reaction rather than the position. Thus, the present study provides a valuable insight into the transformation pathways of SANs in the Fe(VI) oxidation process and the effects of the substituent on oxidation. These results will advance the understanding of Fe(VI) involved in wastewater treatment.

Half-sandwich ruthenium(II) complexes containing 4-substituted aniline derivatives: structural characterizations and catalytic properties in transfer hydrogenation of ketones

Four half-sandwich Ru(II) complexes (1)–(4) with the general formulae [Ru(η6-p-cymene)(L)Cl2] were synthesized by the reaction of one equivalent of the Ru(II) p-cymene dimer with two equivalents of a p-substituted aniline derivative L (where L is p-methyl, p-isopropyl, p-methoxy, or p-hydroxy aniline). The structures of complexes (2)–(4) were determined by single-crystal X-ray diffraction studies. The structural analysis revealed piano-stool geometry at the Ru(II) ions which are coordinated to the η6-p-cymene, two chloride anions and the amine group of the aniline ligand. In the structure of (2)–(4), the coordinated chloride ions make intermolecular hydrogen bonding with the –NH2 group of an adjacent molecules (NH–Cl) resulting in hydrogen bond networks. The catalytic activities of the complexes in transfer hydrogenation of acetophenone were studied. Complex [Ru(η6-p-cymene)(p-methylaniline)Cl2] (1) showed the best catalytic performance in the transfer hydrogenation of acetophenone. The presence and positions of methyl and bromide groups on the acetophenone have an impact on the catalytic activity in transfer hydrogenation properties of the complex (1). Moreover, catalytic activity of the complex (1) is significantly higher in the transfers hydrogenation of cyclohexanone than 2-hexanone.

A Process for the Synthesis and Use of Highly Aromatic Organosilanes as Additives for Poly(Vinyl Chloride) Films

Three organosilanes were synthesized in good yields from the condensation of 4,4′,4″-((phenylsilanetriyl)tris(oxy))tribenzaldehyde and 4-substituted anilines under acidic conditions. The structure of the organosilanes was confirmed using a variety of techniques. Organosilanes were mixed with poly(vinyl chloride) (PVC) and homogenous films were produced. The effect of long-term irradiation on the films containing organosilanes was tested using various methods. Monitoring the infrared spectra of PVC films before, during and after irradiation processes showed the formation of side products comprising polyene, carbonyl and hydroxyl groups. The intensities of absorption bands due to these functional groups were much lower in the presence of organosilanes as compared to the blank film. Also, the decrease in the weight and molecular weight of PVC films after irradiation was lower in the presence of organosilanes. Additionally, there was a minimal surface change of irradiated PVC in the presence of organosilanes. Clearly, organosilanes act as inhibitors, particularly the one containing the hydroxyl group, for the photodegradation of PVC. Different mechanisms were proposed to speculate the role played by organosilanes in stabilizing PVC against long-term ultraviolet light exposure.

Density functional theory calculations on the grafting copolymerization of 2-substituted aniline onto chitosan

Chitosan is a biodegradable natural polymer which is safe and non-toxic and used in different applications. Grafting of chitosan with aniline derivatives is an important route to improve its properties. Chitosan has different active groups that can be blocked in the grafting process, which could be confirmed by calculation studies. The author thinks that the confirmation of chitosan active group included in the grafting by calculations is not given before. So authors give evidence to the direction of grafting and mechanism. Poly(2-methylaniline) (P2-MA), poly(2-hydroxyaniline) (P2-HA) and their copolymers are used in the present study. Quantum mechanics calculations using density functional theory were applied to study the grafting process. The obtained data reveal that grafting occurs at NH2 groups, which is less energetic (2.04). This conclusion confirms the experimental studies. Computational calculations show that the interaction between chitosan and both P2-MA and P2-HA takes place at the NH2 group of chitosan with high stabilization energy (− 1346.7746). A complete next-to-leading order (NLO) values show that the graft could be a better candidate for NLO application (42.25 kcal mol−1) global properties (hardness). Also, the grafting process gives high reactive products due to a decrease in band gap energy.

Synthesis of 5,12-Diazapentacenes and Their Properties.

An efficient synthesis via a precursor route to a new class of linear dialkyldiaminoazapentacenes is reported. The synthetic route involves the coupling of 4-substituted aniline derivatives to 2,5-dibromoterephthalonitrile via Buchwald-Hartwig amination followed by an acid-mediated cyclization to furnish the diazapentacenes. These reactions occur under short reaction times (<2 h), provide high yields (77-99%), and do not require column chromatography for purification. The electrochemical and optical properties of the diazapentacenes were evaluated, and the values indicate that these molecules are promising n-type materials for organic electronic devices. The photostability of these molecules was significantly greater than unsubstituted acenes. Their method of degradation via endoperoxide generation was confirmed by X-ray crystallography and mass spectrometry.

Synthesis, characterization, in vitro antimicrobial and QSAR studies of diorganotin(IV) complexes of Schiff bases derived from 2-(3-methylbutanoyl)-1H-indene-1,3(2H)-dione and 4-substituted anilines

A series of some new diorganotin(IV) complexes [R2SnLCl] was synthesized by the reaction of 2-(3-methylbutanoyl)-1H-indene-1,3(2H)-dione and 4-substituted anilines (p-OCH3, p-NO2, p-CH3, p-Cl) with R2SnCl2, (R=Me, Et, n-Bu, Ph) in 1:1 molar ratio. The structure of the Schiff bases and their complexes were characterized by IR, 13C, 1H, 119Sn NMR, and mass spectral techniques. The synthesized ligands and derived organotin complexes were evaluated in vitro against some bacterial strains, viz., Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus, Staphylococcus aureus and fungal strains, viz., Aspergillus flavus, Aspergillus niger, and Candida albicans by serial dilution method. The antimicrobial results revealed that organotin complexes showed a distinct escalation in biocidal activity. Phenyl and butyl complexes were found to be more intoxicating. Furthermore, we performed QSAR studies which explained the different factors affecting the enhancement in the bioactivity of the complexes.

2-Substituted Aniline as a Simple Scaffold for LuxR-Regulated QS Modulation.

The ability of the 2-substituted aniline motif to serve as a scaffold for designing potential LuxR-regulated quorum sensing (QS) modulators has been investigated, using docking experiments and biological evaluation of a series of 15 specially synthesized compounds. Aniline, 2-acetyl-aniline and 2-nitroaniline were considered, as well as their N-acylated derivatives. Docking experiments showed that the 2-substituted aniline motif fits within the LuxR binding site at the place of the lactone moiety of AHL, and the biological evaluation revealed QS antagonisitic activity for several compounds, validating the hypothesis that this scaffold acts on QS. Structure activity relationships are discussed regarding interactions with the key residues of the LuxR binding site, showing significant variations in the H-bonding pattern.

Studies on the activities of electrophilic sites on benzene ring of 4-substituted anilines and their acyl compounds with multiphilicity descriptor

In this paper, the activities of electrophilic sites on benzene ring of 4-substituted anilines and their acyl compounds were studied with the quantitative indicator of multiphilicity descriptor. Four substituents were synthesized with microwave irradiation in good yields to verify the quantitative analysis data. Friedel-Crafts acylation was carried out by the microwave method for the first time.

Synthesis and biological potency of anilino-triazine insecticides.

An insecticide screening effort identified N-(4-bromophenyl)-4,6-bis(2,2,2-trifluoroethoxy)-1,3,5-triazine-2-amine as having weak potency against two lepidopteran species, Helicoverpa zea and Spodoptera exigua. A structure-activity relationship study about the trifluoroethoxy substituents and the aniline of this compound was carried out in an effort to improve insecticidal potency. Initially, a series of analogs bearing various substituents on the aniline were prepared, and the insecticidal potency was evaluated against H. zea and S. exigua in greenhouse diet feeding assays. The results showed that electron-withdrawing substituents, such as Cl, Br and CF3 , were preferred over electron-donating substituents, such as methoxy, and that potency was significantly better when the substituent was in the para-position. Additional investigations showed that bis(anilino)trifluoroethoxytriazines were more potent. Replacement of the remaining trifluoroethyl group in the bis(anilino)triazine series with an alkyl amine lead to compounds of equal or superior efficacy. The work presented showed that electron-withdrawing substituents in the para-position of the aniline ring of the initial hit delivered the best levels of insecticidal potency against the two insect species tested. Further investigations showed that potency could be improved by replacing one of the two trifluoroethoxy groups with additional 4-substituted aniline. This level of potency was maintained or further improved when the remaining trifluoroethoxy was replaced with a substituted amine. © 2017 Society of Chemical Industry.

Synthesis, Characterization and Docking Studies of 4, 4’-Diaminotriphenylmethanes (DATPMs)

DATPMs were synthesized by the acid-catalysed Baeyer condensation of 4-substituted benzaldehydes and aniline in good yields. The materials were purified by column chromatography and characterized by FTIR, 1H-13CNMR and elemental analysis. The optimized ligands were docked with the IKKα, (PDB code: 3BRT) using the MOE-Dock module and are found to obey Lipinski’s Ro5 cut-off limits. The computational results revealed that the DATPMs, like other derivatives of TPM, could be potential anticancer drugs. Moderate protein kinase inhibitory activity was exhibited by samples 2 and 3 by displaying inhibition bald zone of 10 and 9 mm respectively against the Streptomyces 85E strain.

Optical Sensing Properties of Pyrene-Schiff Bases toward Different Acids.

A set of (4-substituted-phenyl)-pyren-1-ylmethylene-amine (PMA) was prepared by the reaction of pyrene-1-carboxaldehyde and the corresponding 4-substituted aniline. The structure of the PMA compounds were confirmed by spectroscopic data (IR, (1)HNMR, (13)CNMR, ISI-MS and elemental analysis. The structure of (4-bromo-phenyl)-pyren-1-ylmethylene-amine (BrPMA) was further confirmed by the single X-ray crystallography. The absorption and emission spectroscopic behaviors were investigated in variant acids. The compounds showed dramatic spectroscopic changes upon acidifying with strong acids and negligible effects when weak acids are used in the acidifications. Hence, the PMA compounds can be used as sensors to distinguish between weak and strong acids.

Synthesis and Antiproliferative Activity Studies on 2-Substitued Aniline Quinazoline Derivatives

A series of 2-substituted aniline quinazoline derivatives were prepared with the starting material of quinazoline-2,4(1H,3H)-dione, and then followed by the reaction of chlorination, Suzuki reaction and nucleophilic substitution. The structures of target compounds were identified by H NMR, C NMR and HRMS. The preliminary biological evaluations were performed using thiazolyl blue tetrazolium bromide (MTT) method to test their antiproliferative activities against some tumor cell lines. The results suggest that some compounds have the abilities to inhibit the growth of Hela tumor cell lines, and most potent compounds 4u and 4v also exhibit good antiproliferative activities against A549 and MCF-7 tumor cell lines.

Change of mechanism with a change of substituents for a Zincke reaction

The reaction between N-(2,4-dinitrophenyl)-4-(4-pyridyl)pyridinium chloride and 4-aminothiophenol led to an unexpected displacement of the 2,4-dinitrophenyl group, in contrast with the normal Zincke product formed with other nucleophilic 4-substituted anilines. Evidence for a SET process was obtained from EPR spectra of the reaction mixture.

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines

Small-molecule drug discovery requires reliable synthetic methods for attaching amino compounds to heterocyclic scaffolds. Trifluoroacetic acid-2,2,2-trifluoroethanol (TFA-TFE) is as an effective combination for achieving SN Ar reactions between anilines and heterocycles (e.g., purines and pyrimidines) substituted with a leaving group (fluoro-, chloro-, bromo- or alkylsulfonyl). This method provides a variety of compounds containing a "kinase-privileged fragment" associated with potent inhibition of kinases. TFE is an advantageous solvent because of its low nucleophilicity, ease of removal and ability to solubilise polar substrates. Furthermore, TFE may assist the breakdown of the Meisenheimer-Jackson intermediate by solvating the leaving group. TFA is a necessary and effective acidic catalyst, which activates the heterocycle by N-protonation without deactivating the aniline by conversion into an anilinium species. The TFA-TFE methodology is compatible with a variety of functional groups and complements organometallic alternatives, which are often disadvantageous because of the expense of reagents, the frequent need to explore diverse sets of reaction conditions, and problems with product purification. In contrast, product isolation from TFA-TFE reactions is straightforward: evaporation of the reaction mixture, basification and chromatography affords analytically pure material. A total of 45 examples are described with seven discrete heterocyclic scaffolds and 2-, 3- and 4-substituted anilines giving product yields that are normally in the range 50-90 %. Reactions can be performed with either conventional heating or microwave irradiation, with the latter often giving improved yields.

ChemInform Abstract: Rapid and Effective Synthesis of Diarylsulfur Diimides from Substituted Anilines and Sulfur Monochloride.

AbstractThe proposed intermediate (III) can be isolated at lower temperature and independently converted to sulfur diimides under similar conditions.

Substituent Effect on the Association Phenomenon of an Aqueous Solution of Benzylidene Substituted Aniline at Different Temperatures

Conductivity parameters of an aqueous solution of benzylidene substituted anilines (I-IV) have been determined at five different temperatures in the range of 283.15-318.15 ºK, through accurate conductance measurements. The obtained data were analyzed in accordance to Lee-Wheaton equation taking into account the activity of the electrolyte in the solution. The conductance measurement results were used to determine the association constants (KA) of ion-pairs, the mean distance between ions in solution, in addition to the molar conductance at infinite dilution (Λo¬) for the free ion in the solution. The dependence of (KA) values on the temperature has been examined by plotting Log KA against the reciprocal values of temperature (1/T), which showed linear relationship, where (KA) values decrease with increasing temperature. Moreover, the enthalpy (ΔH), Gibbs free energy (ΔG) and the entropy (ΔS) have been derived from this linear relationship.