Nucleophilic Substitution Of Bromine Research Articles

Design and Synthesis of Novel 6,7‐Dihydrobenzo[d]isoxazol‐4(5H)‐one Derivatives Bearing 1,2,3‐Triazole Moiety as Potential Hsp90 Inhibitors and their Evaluation as Antiproliferative Agents

AbstractAn effective approach to 5‐triazolyl‐substituted 6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐ones and 4,5,6,7‐tetrahydrobenzo[d]isoxazoles was developed. The approach included α‐keto bromination of 6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐one followed by nucleophilic substitution of bromine with the azide group. For the preparation of 5‐azido‐6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐one, the carbonyl group at position 4 was reduced to a methylene group under ionic hydrogenation conditions using triethylsilane as a reducing agent. Cu(I)‐catalyzed [2+3] cycloaddition of terminal alkynes to both obtained azides was used for the synthesis of two series of triazolyl derivatives. Compounds, which contain in their structures common for some Hsp90 inhibitors 2,4‐dihydroxy‐5‐isopropylphenyl fragment, were evaluated as antiproliferative agents against two breast cancer cell lines: hormone‐dependent MCF7 and HER2‐positive HCC1954. The lead compound showed half‐maximal inhibitory concentration (IC50) values below 5 μM and induced significant changes in the Hsp90 signaling pathways in HER2‐positive HCC1954 cells. It increased the expression of Hsp70 (used as a pharmacodynamic marker of Hsp90 inhibition) and inhibited the expression of HER2, p‐c‐Met, c‐Met, and p‐AKT. The combination of the selected isoxazole‐triazole hybrid molecule and the earlier described apoptosis inducer LCTA‐3344 demonstrated a significant antiproliferative effect against HCC1954 cells. The lead compound was revealed to be a promising candidate for future anticancer drug design, particularly against aggressive breast cancer positive for HER2.

Development of Self-Assembling bis-1,4-Dihydropyridines: Detailed Studies of Bromination of Four Methyl Groups and Bromine Nucleophilic Substitution.

One of the most important steps in the synthesis of 1,4-dihydropyridine (1,4-DHP) amphiphiles is the bromination of methyl groups in positions 2 and 6 of the entire ring. However, up to now, only N-bromosuccinimide was mainly used for bromination 1,4-DHPs. In this work, the synthesis of bis-1,4-DHP derivatives with ethyl and dodecyl ester groups attached to 1,4-DHP ring at positions 3 and 5 was performed by Hantzsch synthesis. The experimental studies were carried out to find out the best conditions and the agent for the tetra bromination of bis-1,4-DHP methyl groups at positions 2 and 6. Four different brominating agents were screened. The use of pyridinium bromide-perbromide in ethyl acetate was found to be optimal for the bromination of methyl groups. The bromination reaction was followed by the synthesis of cationic pyridine moiety containing amphiphilic bis-1,4-DHP derivatives. By nucleophilic substitution of bromine with various substituted pyridines, 12 new amphiphilic bis-1,4-DHP derivatives were obtained. Evaluation of self-assembling properties of tetracationic bis-1,4-dihydropyridine derivatives by dynamic light scattering (DLS) measurements was also performed.

Positively Charged Polyamine Nanofiltration Membrane for Precise Ion-Ion Separation.

Positively charged nanofiltration (NF) membranes offer enormous potential for lithium-magnesium separation, hard water softening, and heavy metal removal. However, fundamental performance limitations for these applications exist in conventional polyamide-based NF membranes due to the negatively charged surface and low ion-ion selectivity. We hereby innovatively develop an advanced positively charged polyamine-based NF membrane built by the nucleophilic substitution of bromine and amine groups for precise ion-ion separation. Specifically, polyethylenimine (PEI) and 1,3,5-tris(bromomethyl)benzene (TBB) are interfacially polymerized to generate an amine-linked PEI-TBB selective layer with an ultrathin thickness of ∼95 nm, an effective pore size of 6.5 Å, and a strong positively charged surface with a zeta potential of +20.9 mV at pH 7. The PEI-TBB composite membrane achieves a water permeance of 4.2 L·m-2·h-1·bar-1, various divalent salt rejections above 90%, and separation factors above 15 for NaCl/MgCl2 and LiCl/MgCl2 mixed solutions. A three-stage NF process is implemented to achieve a Mg2+/Li+ mass ratio sharply decreasing from 50 to 0.11 with a total separation factor (SLi,Mg) of 455. Furthermore, the polyamine-based NF membrane exhibits excellent operational stability under continuous filtration and high operational pressure, demonstrating great application potential for precise ion-ion separation.

1,1′-{[3,5-Bis((dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis[4-(anthracen-9-yl)pyridin-1-ium] Dibromide

A synthesis of a cationic moiety and fluorescent moieties containing amphiphilic 1,4-dihydropyridine (1,4-DHP) derivatives was performed starting with the Hantzsch-type cyclization of dodecyl acetoacetate, phenylaldehyde and ammonium acetate. Bromination of the 2,6-dimethyl groups of a parent 1,4-DHP compound, followed by nucleophilic substitution of bromine with 4-(anthracen-9-yl)pyridine, produced the desired 1,1′-{[3,5-bis((dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis[4-(anthracen-9-yl)pyridin-1-ium] dibromide. The obtained target compound was fully characterized by the IR, 1H NMR, 13C NMR and HRMS data. Studies of the self-assembling properties and characterization of the nanoparticles obtained by the ethanol injection method were performed using dynamic light scattering (DLS) measurements. DLS measurement data showed that 1,1′-{[3,5-bis((dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis[4-(anthracen-9-yl)pyridin-1-ium] dibromide produced liposomes that had average diameters of 200 nm when the samples were freshly prepared, and 140 nm after 7 days or 1 month storage. The PDI values of the samples were approximately 0.50 and their zeta-potential values were approximately 41 mV when the samples were freshly prepared, and 33 mV after storage. The obtained nanoparticles were stored at room temperature for one month and remained stable during that period. The mean molecular area of the cationic 1,4-DHP-anthracene hybrid 4 was 118 Å2, while the mean molecular area of the cationic 1,4-DHP 5 without anthracene substituents was only 83 Å2. The photoluminescence quantum yield (PLQY) value for the EtOH solution of the 1,4-DHP derivative 4 was 10.8%, but for the 1,4-DHP derivative 5 it was only 1.8%. These types of compounds could be used as synthetic lipids in the further development of prospective theranostic delivery systems.

2-Bromomethyl-1,3-thiaselenole in click chemistry: Synthesis of 1-(2,3-dihydro-1,4-thiaselenin-2-yl)-1H-1,2,3-triazoles via copper-catalyzed and thermal 1,3-dipolar cycloaddition with alkynes

Nucleophilic substitution of bromine in 2-bromomethyl 1,3-thiaselenole with sodium azide occurs at room temperature via an intermediate seleniranium cation with the ring expansion rearrangement to six-membered 2-azido-2,3-dihydro-1,4-thiaselenine in 95% yield. The cycloaddition click reaction of the latter with various terminal acetylenes catalyzed with Cu(OAc)2 in the presence of sodium ascorbate (CuAAC) proceeds regioselectively with the formation of only 1-(2,3-dihydro-1,4-thiaselenin-2-yl)-4-organyl-1H-1,2,3-triazoles in up to 97% yields. In the case of dipropargyl sulfide, the click cycloaddition with both triple bonds is realized at room temperature affording the corresponding bis-adduct in 73% yield. The reaction of 2-azido-2,3-dihydro-1,4-thiaselenine with dimethyl and diethyl acetylenedicarboxylates gives, via the 1,3-dipolar Huisgen cycloaddition, the corresponding 1,4,5-trisubstituted 1,2,3-triazoles, functionalized with the 2,3-dihydro-1,4-thiaselenine ring, in high yields. The obtained products are potentially bioactive compounds and first representatives of 1,2,3-triazoles combined with selenium/sulfur-containing heterocycles.

1,1′-{[3,5-Bis(dodecyloxycarbonyl)-4-(naphthalen-2-yl)-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis{4-[(E)-2-(naphthalen-2-yl)vinyl]pyridin-1-ium}dibromide

Synthesis of a double-charged cationic amphiphilic 1,4-dihydropyridine derivative with dodecyl ester groups at positions 3 and 5 of the 1,4-DHP ring was performed starting from Hantzsch type cyclization of dodecyl acetoacetate, 2-naphthaldehyde and ammonium acetate. Bromination of this compound followed by nucleophilic substitution of bromine with (E)-4-(2-(naphthalen-2-yl)vinyl)pyridine gave the desired cationic amphiphilic 1,1′-{[3,5-bis(dodecyloxycarbonyl)-4-(naphthalen-2-yl)-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis{4-[(E)-2-(naphthalen-2-yl)vinyl]pyridin-1-ium}dibromide. The obtained target compound was fully characterized by IR, UV, 1H-NMR, 13C-NMR, HRMS and microanalysis. The characterization of the cationic 1,4-DHP nanoparticles in an aqueous solution was performed by DLS measurements. The obtained results showed that the compound formed nanoparticles with an average diameter of around 300 nm, a PDI value of around 490 and a zeta-potential of around 20 mV for freshly prepared samples. However, after one week of storage at room temperature, an aggregation of nanoparticles was detected.

Synthesis and Characterisation of 1,1′-{[3,5-Bis(dodecyloxy-carbonyl)-4-(thiophen-3-yl)-1,4-dihydropyridine-2,6-diyl]bis-(methylene)}bis(pyridin-1-ium) Dibromide

In the present work, construction of double-charged cationic amphiphilic 1,1′-{[3,5-bis(dodecyl¬oxy-carbonyl)-4-(thiophen-3-yl)-1,4-dihydropyridine-2,6-diyl]bis-(methylene)}bis(pyridin-1-ium) dibromide (7) was performed in four steps. Dodecyl 3-oxobutanoate (1) was condensed with thiophene-3-carbaldehyde (2) which was necessary for Hantzsch cyclisation dodecyl (E/Z)-3-oxo-2-(thiophen-3-ylmethylene)butanoate (3). Two-component Hantzsch type cyclisation of dodecyl (E/Z)-3-aminobut-2-enoate (4) and dodecyl (E/Z)-3-oxo-2-(thiophen-3-ylmethylene)butanoate (3) gave 3,5-bis(dodecyloxycarbonyl)-2,6-dimethyl-4-(thiophen-3-yl)-1,4-dihydropyridine (5). Bromination of compound 5 followed by nucleophilic substitution of bromine with pyridine gave the desired cationic amphiphilic 1,4-dihydropyridine 7. The obtained target compound 7 and new intermediates 3, 5 and 6 were fully characterised by IR, UV, 1H NMR, 13C NMR, HRMS or microanalysis. Characterisation of nanoparticles formed by the cationic 1,4-dihydropyridine 7 in an aqueous solution was performed by DLS measurements.

Synthesis and In Silico Study of 4-Substituted 1-Aminoanthraquinones

Eight new 4-substituted 1-amino-9,10-anthraquinones containing a primary amino group were syn­the­sized by nucleophilic substitution of bromine in 1-amino-4-bromo-9,10-anthraquinones. 1-Amino-4-[2-(hy­droxy­ethyl)amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid containing a biogenic amine fragment (2-aminoethanol) was converted into the corresponding 1-triazenyl derivatives. The structure of the synthesized compounds was determined on the basis of the LC/MS and 13C and 1H NMR data, and their drug likeness was estimated in silico. Compounds with a good drug likeness score were analyzed by DIGEP-Pred, their possible interactions with proteins were simulated using STRING, and their biological activity was interpreted using the Kyoto Encyclopedia of Genes and Genomes.

Synthesis and Study of Psychotropic Activity of 1-Substituted 4-Amino-5-oxoprolines

1-Substituted (2S,4S)-4-amino-5-oxoprolines have been obtained by nucleophilic substitution of bromine in dimethyl (2S,4RS)-4-bromo-N-phthaloylglutamate followed by isolation of the predominant (2S,4S)-diastereomer and removal of protecting groups. The psychotropic activity of the obtained compounds has been studied after a single administration in experimental animals. 4-Amino-1-(4-bromophenyl)-5-oxoproline and especially 4-amino-1-(4-aminophenyl)-5-oxoproline showed pronounced anxiolytic activity in the Elevated plus maze test. (2S,4S)-4-Amino-5-oxoprolines containing 4-methylphenyl, 4-bromophenyl, 4‑aminophenyl, and 2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl substituents at the 1-position exhibited nootropic activity: they improved the formation and retention of the memory trace in the Passive avoidance test and the Active avoidance test (Extrapolation escape test).

Synthesis of 2,4-Diamino-6-arylpyridine-3,5-dicarbonitriles and Study of Their Optical Properties

2,4-Diamino-6-arylpyridine-3,5-dicarbonitriles were synthesized by the nucleophilic substitution of bromine in 4-amino-2-bromo-6-arylpyridine-3,5-dicarbonitriles. The optical properties of the synthesized compounds were studied to show that they fluoresce in solution and in the solid state in the violet region of the spectrum.

Tetrasubstituted Phthalocyanines with Benzoic Acids Moieties

Phthalonitriles substituted with o-hydroxybenzoic, o-aminobenzoic, and o-mercaptobenzoic acids moieties were synthesized by nucleophilic substitution of bromine in 4-bromophthalonitrile and of nitro group in 4-nitrophthalonitrile. Template condensation of these phthalonitriles with metal acetates gave the corresponding phthalocyanines. Metal-free phthalocyanines were synthesized by dissociation of the magnesium complexes of the substituted phthalocyanines in a sulfuric acid medium. Treatment of the resultant phthalocyanines with sodium ethoxide in ethanol yielded sodium salts of the carboxylic acids. The spectral properties of the compounds synthesized were examined.

Synthesis and piezoelectric properties of N-phthaloylglutamic acid derivatives

The (S,S)- and (R,R)-enantiomers of dimethyl 2,4-diphthalimidoglutarate were synthesized by nucleophilic substitution of bromine in dimethyl (2S,4RS)-4-bromo-N-phthaloyl-glutamate upon treatment with potassium phthalimide, followed by separation. The crystal structure of the obtained compounds was studied by X-ray diffraction. Crystals of enantiomerically pure dimethyl 4-hydroxy- and 4-phthalimido-N-phthaloylglutamates were found to possess a noticeable piezoelectric activity.

Unsaturated derivatives of trifluoromethanesulfonimide

N-Allyl- and N-propargyltrifluoromethanesulfonimides were synthesized by reaction of trifluoromethanesulfonic anhydride with allylamine and propargylamine. Some reactions of the resulting unsaturated derivatives were studied, in particular bromination, dehydrobromination of the bromination product, and nucleophilic substitution of bromine.

Nucleophilic substitution of 4-bromo-5-nitrophthalodinitrile: XIII. Synthesis and properties of 4-(1-benzotriazolyl)-5-(4-tritylphenoxy)phthalonitrile and phthalocyanines based thereon

4-(1-Benzotriazolyl)-5-(4-tritylphenoxy)phthalonitrile was synthesized by nucleophilic substitution of bromine and nitro group of 4-bromo-5-nitrophthalonitrile, and on its basis the corresponding octa-substituted phthalocyanines were obtained. Spectral properties of the synthesized compounds were investigated.

Nucleophilic substitution in 4-bromo-5-nitrophthalodinitrile: XII. Synthesis and properties of 4-(1-benzotriazolyl)-, 4-nitro-5-(4-nonylphenoxy)phthalonitriles and the ligands based on them

4-Nitro- and 4-(1-benzotriazolyl)-5-(4-nonylphenoxy)phthalonitriles were prepared by nucleophilic substitution of bromine and nitro group in 4-bromo-5-nitrophthalonitrile. Based on the latter the corresponding octa-substituted phthalocyanines were synthesized. The spectral properties of the prepared compounds were investigated.

An imidazolium-functionalized isobutylene polymer having improved mechanical and barrier properties: Synthesis and characterization

Brominated poly(isobutylene-co-p-methylstyrene) (BIMS) is of great use to industries because of its extremely good permeability properties. However, it lacks strength and adhesion necessary to make it amenable to various processing techniques. To overcome the limitations of BIMS, ionic modification via nucleophilic substitution of bromine by 1-methylimidazole through a facile synthetic route is presented. The modified ionic product was characterized by various techniques such as solubility, Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy (NMR), thermogravimetric analysis, and dynamic mechanical analysis. The FTIR spectrum of the obtained samples showed a distinct peak around 1261 cm−1 corresponding to CN stretching vibration and reduction in peak intensity around 695 cm−1 corresponding to CBr stretching vibration. NMR also clearly showed the occurrence of a singlet peak corresponding to the methyl protons of imidazole in the region of 4.1 ppm and a shift in the methylene protons adjacent to the benzene ring confirming the substitution of bromine atom by imidazole ring. The reaction at reflux temperature of 130°C for 48 h yielded the highest level (3.1 wt %, 1.18 mol %) of modification while optimizing the reaction parameters. The modified ionic polymers displayed greater thermal stability, greater flexibility, improved tensile strength, and higher barrier properties compared to the unmodified BIMS. A 1.8-fold increase of elongation at break was achieved with 1.18 mol % (3.1 wt %) of modification. The modified polymers also showed remarkable drop in oxygen transmission rate values from 10−16 to 10−18 m3 m/m2/s/Pa, which further highlights their improved properties. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

ChemInform Abstract: Synthesis and Methylation Products of 4(5)‐(2‐Furyl)imidazole.

Bromination of 2-acetylfuran with copper(II) bromide in a mixture of ethyl acetate and chloroform leads selectively to furacyl bromide, the nucleophilic substitution of bromine in which by OAc and subsequent use of the Weidenhagen reaction enabled the synthesis of 4(5)-(2-furyl)imidazole. On N-methylation of this imidazole in KOH-acetone 2 isomers are formed, the 1-methyl-4- and 1-methyl-5-(2-furyl)imidazoles. It was established that, unlike alkylation of 4(5)-phenylimidazole, the main product of the reaction is 1-methyl-5-(2-furyl)imidazole.

Use of pyridinium ionic liquids as catalysts for the synthesis of 3,5-bis(dodecyloxycarbonyl)-1,4-dihydropyridine derivative

Abstract The synthesis of cationic amphiphilic 1,4-dihydropyridine derivative, potential gene delivery agent is achieved via an efficient multi-step sequence. The key step of this approach is a two-component Hantzsch type cyclisation of 3-oxo-2-[1-phenylmethylidene]-butyric acid dodecyl ester and 3-amino-but-2-enoic acid dodecyl ester utilising bis(2-hydroxyethyl)ether as a solvent and 1-butyl-4-methylpyridinium chloride as a catalyst. The 1,4-dihydropyridine derivative with long alkyl ester chains at positions 3 and 5 of the 1,4-DHP ring — 3,5-bis(dodecyloxycarbonyl)-2,6-dimethyl-4-phenyl-1,4-dihydropyridine was obtained in substantially higher yield with respect to classical Hantzsch synthesis. Bromination of this compound followed by nucleophilic substitution of bromine with pyridine gave the desired cationic amphiphilic 1,4-dihydropyridine.

Synthesis and methylation products of 4(5)-(2-furyl)imidazole

Bromination of 2-acetylfuran with copper(II) bromide in a mixture of ethyl acetate and chloroform leads selectively to furacyl bromide, the nucleophilic substitution of bromine in which by OAc and subsequent use of the Weidenhagen reaction enabled the synthesis of 4(5)-(2-furyl)imidazole. On N-methylation of this imidazole in KOH-acetone 2 isomers are formed, the 1-methyl-4- and 1-methyl-5-(2-furyl)imidazoles. It was established that, unlike alkylation of 4(5)-phenylimidazole, the main product of the reaction is 1-methyl-5-(2-furyl)imidazole.

Nucleophilic substitution in 4-bromo-5-nitrophthalodinitrile: X. Synthesis of 4-(1-benzotriazolyl)-5-(1(2)-naphthyloxy)-phthalodinitriles and related phthalocyanines

4-(1-Benzotriazolyl)-5-[1(2)-naphthyloxy]phthalodinitriles were obtained by nucleophilic substitution of bromine and nitro group in 4-bromo-5-nitrophthalodinitrile. These compounds were used for the synthesis of the corresponding octa-substituted phthalocyanines. Spectral data of the compounds obtained were examined.