Electrophilic Substitution Reaction Of Indoles Research Articles

Synthesis of 3, 3′- bis (indolyl) methanes using Bio-Waste metal free super acid as efficient with recyclable catalysts

A bio-waste metal free sulfonated carbonaceous super acid catalyst (BWC) is generated from sodium lignosulphonate, which is obtained from bio-waste sulphite pulping process of paper making industries. Here, we report a highly efficient catalytic a sulphonated carbon material catalyzed electrophilic substitution reactions of indoles with aromatic aldehydes to afford 3,3′-bisindolylmethane (BIM) derivatives. The synthesized BIM compounds were characterized by modern analytical techniques like NMR, MS, FT-IR, CHNS analysis. The BWC green catalyst was characterized by FT-IR, thermal gravimetric analysis (TGA) scanning electron microscopy (SEM), thermal electronic microscopy (TEM) with elemental analysis. The significant features of this catalysis are easy catalyst preparation, high product yields, environmental benignity, short reaction time, broad substrate scope, with use of non-toxic solvents. The catalysts could be recycled with reused three times without decrease in the catalytic activity significantly.

ProHSO4: An efficient catalyst for solvent-free synthesis of bis(indolyl)methanes and their in silico screening for potential biological activity

A simple, mild, and efficient protocol has been developed for the synthesis of 3,3′-bis(indolyl)methanes (BIMs) using prolinium hydrogen sulfate (ProHSO4) as a catalyst under solvent-free and support-free conditions. This mechanochemical method undergoes electrophilic substitution reaction of indole with diverse aldehydes to afford the desired BIMs in high yields at room temperature. Due to diverse pharmacological utility, the synthesized BIMs were subjected to in silico studies. The structure activity analysis of BIMs revealed their ability to bind Eg5 kinesin, Human p38 α MAP Kinase, and Human 3 alpha HSD type 3 as a potential protein target for anticancer activity. The compounds exhibited higher binding affinities with Eg5 kinesin having hydrophobic interactions with α2, α3 helices and loop5 amino acid residues. Moreover, molecular docking with Human p38 α MAP Kinase protein depicted compounds as ATP-competitive molecules interacting with hydrophobic region I, II and allosteric DFG motif. A total of 13 derivatives were synthesized and subjected for in silico screening for predicting potential biological activity. Among them,3b, 3d, 3f, 3 g, 3i, 3j, and 3 k compoundswere identified as potential inhibitors of Eg5 kinesin, Human p38 α MAP Kinase, and Human 3 alpha HSD type 3, and their evaluation in the biological experimental system is warranted.

Effective Synthesis and Biological Evaluation of Natural and Designed Bis(indolyl)methanes via Taurine-Catalyzed Green Approach.

An ecofriendly, inexpensive, and efficient route for synthesizing 3,3′-bis(indolyl)methanes (BIMs) and their derivatives was carried out by an electrophilic substitution reaction of indole with structurally divergent aldehydes and ketones using taurine and water as a green catalyst and solvent, respectively, under sonication conditions. Using water as the only solvent, the catalytic process demonstrated outstanding activity, productivity, and broad functional group tolerance, affording the required BIM natural products and derivatives in excellent yields (59–90%). Furthermore, in silico based structure activity analysis of the synthesized BIM derivatives divulges their potential ability to bind antineoplastic drug target and spindle motor protein kinesin Eg5. The precise binding mode of BIM derivatives with the ATPase motor domain of Eg5 is structurally reminiscent with previously reported allosteric inhibitor Arry520, which is under phase III clinical trials. Nevertheless, detailed analysis of the binding poses indicates that BIM derivatives bind the allosteric pocket of the Eg5 motor domain more robustly than Arry520; moreover, unlike Arry520, BIM binding is found to be resistant to drug-resistant mutations of Eg5. Accordingly, a structure-guided mechanism of Eg5 inhibition by synthesized BIM derivatives is proposed.

Synthesis of silica chemisorbed bis(hydrogensulphato)benzene (SiO2–BHSB) as a new hybrid material and it's utility as an efficient, recyclable catalyst for the green synthesis of bis(indolyl)methanes

Synthesis of silica chemisorbed bis(hydrogensulphato)benzene (SiO2-BHSB) was achieved as a new hybrid catalytic material, its structure, stoichiometry and stability was established using modern analytical techniques such as CP-MAS 13C NMR, CP-MAS 29Si NMR, EDX, FT-IR, TGA and DTG. The synthesised material SiO2–BHSB was observed as an environmentally benign, recyclable catalyst for the synthesis of bis(indolyl)methanes (BIMs) via an electrophilic substitution reaction of indoles by aldehydes or ketones under solvent free grinding condition. A range of structurally diverse aldehydes, ketones and indoles were smoothly undergone the developed catalytic protocol to offer good to excellent yields of corresponding bis(indolyl)methane derivatives in shorter reaction times. The synthesised material SiO2–BHSB showed a sustained catalytic activity up to five cycles of its reuse for the synthesis of BIMs. The catalytic protocol offered a chemo-selective route for the synthesis of BIMs, in which aldehydes are pushed exclusively in presence of ketones to undergo the reaction. Simple working procedure, ease of isolation of the catalyst, environmentally compatible energy conditions and no side products are the additional salient features of this protocol.

Sulfonic acid@pericarp-pomegranate: A natural supported catalyst for synthesis of bis(indolyl)alkanes

A heterogeneous solid acid catalyst, sulfonic acid supported on pericarp-pomegranate (sulfonic acid@PP) is prepared with green an eco-friendly approach. The prepared sulfonic acid@PP catalyst was extensively characterized by IR, FE-SEM, EDX and TGA techniques. The efficiency of the catalyst has been investigated for the synthesis of bis(indolyl)alkanes by electrophilic substitution reaction of indoles with carbonyl compounds in ethanol at 80 oC. Easy recovery by simple filtration and at least three times reusability without significant loss in the yield of the desired product are conspicuous features of the reported catalyst. In addition, the notable features of this protocol are high conversions, shorter reaction times, cleaner reaction profile, simple experimental and work-up procedure.

First, in situ generated Mannitol-Boron or Sorbitol-Boron chelate complex as a novel, recyclable catalyst for the highly efficient synthesis of bis(indolyl)methanes, tris(indolyl)methanes and diindolyl (carbazolyl)methanes.

Abstract The first report on in situ generated Mannitol-Boron or Sorbitol-boron chelate complex, as a novel, recyclable homogenous, eco-benign catalyst for the liquid phase electrophilic substitution reactions of indoles with aromatic aldehydes or indole aldehydes or carbazole aldehydes to afford the corresponding bis(indolyl)methanes or tris(indolyl)methanes or di(indolyl) carbazolyl methanes in ethanol or aqueous ethanol at ambient temperature in good to excellent yields. This methodology is mild, highly efficient using minor quantities of catalyst with no side products and a very simple work-up procedure. The effect of solvent, the effect of substituents and the influence of mole ratio are also investigated. The addition of mannitol or sorbital to boric acid in excess formed mainly a 2, 2-di-borate ester which can be effectively removed from reaction waste water (> 97%) by subjecting the reaction waste water to reverse osmosis.

Phospho Sulfonic Acid: A Highly Efficient and Novel Catalyst for Formation of Bis(Indolyl)Alkanes from Aldehydes and Indole under Aqueous Conditions

Bis(indolyl)alkanes are a class of alkaloids that possess significant biological activities. Every year, the varieties of bis(indolyl)alkanes isolated from natural sources are increasing. Nevertheless, the deficiency of natural products from natural sources led to a decrease in the exploration of natural products for biological investigations. Corresponding to this fact, there is a demand to develop efficient protocols for the construction of bis(indolyl)alkanes. In this regards, we have prepared phospho sulfonic acid (PSA), which is a non-corrosive, highly reactive, inexpensive and low toxic catalyst, and have applied to construct bis(indolyl)alkanes. The catalyst was prepared by reaction of diammonium hydrogen phosphate with chloro sulfuric acid and was fully characterized by FTIR spectrometry. PSA has been used as a solid acid catalyst to promote the electrophilic substitution reaction of indole with aldehydes under water to furnish a library of bis(indolyl)alkanes in excellent yields over short reaction times. The present method eliminates use of toxic catalyst and solvent, and tolerates a series of functional groups. The catalyst can be reused several times without any important activity loss. The methodology has several advantages, for example, simple experimental procedure, cost efficiency (use of inexpensive catalyst), ease of preparation and handling of the catalyst and no side reactions.

Chemoselective synthesis of bis(indolyl)methanes using sulfonic acid-functionalized chitosan

Herein, we describe the electrophilic substitution reaction of indole with aldehydes and ketone using sulphonic acid functional group containing chitosan for the synthesis of bis(indolyl)methanes. The reaction is chemoselective affording a product from aldehydes and indole. The catalyst can be reused up to three times without great loss in yields. Hence, chitosan–SO3H (CTSA) proved to be a heterogeneous, efficient, chemoselective, and reusable catalyst for the synthesis of bis(indolyl)methane derivatives.

Colorimetric Determination of (Aminoalkyl)indole-containing Synthetic Cannabimimetics.

Cannabis is an important industrial plant, in addition to its illicit drug use. Compound Δ9-THC (Δ9-tetrahydrocannabinol) is mainly responsible for the hallucinogenic effect on humans. The aminoalkylindole group cannabimimetics targets at the same physiological receptors to mimic the analgesic effects of Δ9-THC. Since there is no reliable colorimetric test to detect these synthetic cannabimimetics on site, a simple colorimetric assay for (aminoalkyl)indole group-containing drugs was developed, based on the silica/sulfuric acid-catalyzed Ehrlich reaction of (aminoalkyl)indoles with p-dimethylaminobenzaldehyde. The electrophilic substitution reaction of indoles with carbonyl compounds resulting in the formation of bis(indolyl)alkanes in an acid-catalyzed reaction has been used for the first time for their spectrophotometric determination by color change from yellow to purple/blue. The method was statistically validated against liquid chromatography tandem mass spectrometry, and applied to certain (aminoalkyl)indole derivatives, with 0.5 - 2.5 μg mL-1 detection limits for AM-2201, JWH-081, MAM-2201, JWH-018, JWH-210, JWH-122, 5F-PB-22 and XLR-11.

Synthesis of Bis(indolyl)methanes Using Hyper-Cross-Linked Polyaromatic Spheres Decorated with Bromomethyl Groups as Efficient and Recyclable Catalysts

Highly uniform and hyper-cross-linked polyphenanthrene and polypyrene microspheres were synthesized by Friedel–Crafts bromomethylation of phenanthrene (Phn) and pyrene (Py) in the presence of zinc bromide as a catalyst, followed by self-polymerization of bromomethylated Phn and Py. The resultant 3-D carbon microspheres consisting of micro-, meso-, and macropores bear peripheral unreacted bromomethyl groups, which are directly utilized as catalysts to efficiently promote the electrophilic substitution reaction of indoles with aldehydes to yield a variety of bis(indolyl)methanes. The important features of this catalysis are easy catalyst synthesis, high product yields, environmental benignity, short reaction time, broad substrate scope, use of nontoxic solvents, and recyclability.

Fe3O4@SiO2@KIT-6 as an Efficient and Reusable Catalyst for the Synthesis of Novel Derivatives of 3,3'-((Aryl-1-phenyl-1H-pyrazol-4- yl)methylene)bis (1H-indole).

Korea advanced institute of science and technology cubic ordered mesoporous silica (KIT-6 mesoporous) silica coated magnetite nanoparticles, is an effective, ecobenign and recyclable catalyst for the electrophilic substitution reactions of indoles with various synthetized aldehydes to afford the corresponding novel diindolylmethanes in high yields and short reaction times. The catalyst can be recovered and reused without loss of activity. The work-up of the reaction consists of a simple separation, followed by concentration of the crude product and purification. The present methodology offers several advantages such as aqueous media, excellent yields, simple procedure, mild conditions and reduced environmental consequences. All of synthesized compounds are new and were characterized by IR, NMR and elemental analyses. A mixture of synthetized pyrazolecarbaldehydes [24] (2.0mmol), indole (4.0mmol) and Fe3O4@SiO2@KIT-6 (0.04mmol) and H2O (10mL) were stirred at room temperature for the required reaction time according to Table 2. After completion of the reaction, the product was solved in CHCl3 (3×10 mL) and insoluble catalyst was removed by filtration in the presence of an efficient magnetic bar. The organic phase including the product and CHCl3 was evaporated under vacuum. The resulting crude material was purified by recrystallization from EtOH to afford pure products. As part of our on interest for the development of efficient and environmentally friendly procedures for the synthesis of heterocyclic and pharmaceutical compounds, an efficient, facile and aqueous media was introduced for the synthesis of novel derivatives of diindolylmethanes containing pyrazole moiety. A variety of synthetized aldehyde compounds reacted smoothly with indoles to produce diindolylmethanes under these reaction conditions. The electron deficiency and the nature of the substituents on the aromatic ring show some effects on this conversion. All the reactions were run with catalytic amounts of catalysts. The best results gained with 0.04mmol of Fe3O4@SiO2@KIT-6 as a strong Lewis acid at room temperature in aqueous media. In conclusion, we have investigated the synthesized KIT-6 mesoporous silica coated magnetite nanoparticles (MMNPs) as a mild and efficient catalyst for the synthesis of novel diindolylmethanes coupled with pyrazole moiety in aqua media. The simplicity, easy workup together with the use of inexpensive, environmentally friendly and reusable catalyst, is the notable features of this catalytic procedure. To the best of our knowledge, this is the first report for the synthesis of a new library of diindolylmethane compound bearing pyrazole moiety that enhance the biological and pharmacological activity.

Catalytic properties of a cobalt metal-organic framework with a zwitterionic ligand synthesized in situ.

Herein we describe the high yield synthesis of a highly crystalline cobalt(ii) MOF with a novel zwitterionic ligand made up of 3,3',4,4'-BPTC and 1,4-cyclohexanediamine, obtained in situ during the hydrothermal synthesis. The compound with the molecular formula C46H38N4O14Co·2H2O has a molecular mass of 965.7783 g mol-1, a triclinic crystalline system (a = 5.86 Å, b = 9.28 Å, c = 19.92 Å, α = 83.93°, β = 88.01°, γ = 78.59), it is thermally stable up to 300 °C and presents structural stability before and after removing the solvent molecules from its pores. This novel material showed catalytic properties in an electrophilic substitution reaction of indoles and aldehydes allowing the syntheses of bis(indolyl)methanes in high yields under mild reaction conditions and can be reused at least once with the same catalytic activity.

Synthesis of bis(indolyl)methanes Catalyzed by Triethylborane

Triethylborane (TEB) was found to be a mild, efficient, and acid catalyst in electrophilic substitution reaction of indoles with aldehydes compounds to afford the corresponding bis(indolyl)methanes. Vibrindole A (5) and bis(indolyl)methanes derivatives 16 and 18 were synthesized using this methodology. Compound 16 is an intermediary in the synthesis of the natural bisindoles arsindoline B (2) and streptindole (6). The structure of vibrindole A (5) was unequivocally confirmed by a single crystal X-ray diffraction analysis.

Ag Nanoparticles: An Efficient and Versatile Reagent for Synthesis of Bis(indolyl)methanes

Ag nanoparticles are found to be an efficient catalyst for the electrophilic substitution reaction of indole with aldehydes to afford the corresponding bis(indolyl)methanes in good yields. The remarkable features of this new procedure are high conversions, shorter reaction times, cleaner reaction profiles, and simple experimental and work-up procedures.

An efficient synthesis of 3-indolyl-3-hydroxy oxindoles and 3,3-di(indolyl)indolin-2-ones catalyzed by sulfonated β-CD as a supramolecular catalyst in water

Sulfonated-β-cyclodextrin (β-CD-SO3H) promoted efficient and fast electrophilic substitution reaction of indoles with various isatins reflux in water is reported affording various 3-indolyl-3-hydroxy oxindoles and 3,3-di(indolyl)indolin-2-ones in good to excellent yields in short reaction time.

Efficient synthesis of 3,3-di(indolyl)oxindoles catalyzed by sulfonic acid-functionalized mesoporous silica nanoparticles (SAMSNs) in aqueous media

An efficient protocol has been developed for the aqueous-mediated synthesis of 3,3-di(indolyl)oxindole derivatives via the electrophilic substitution reaction of indoles with various isatins using sulfonic acid-functionalized mesoporous silica nanoparticles (SAMSNs) as a recoverable heterogeneous acid catalyst. This catalyst can be reused several times without significant loss of activity.

Synthesis of Pharmacologically Active Bis(indolyl) and Tris(indolyl) Derivatives Using Chlorotrimethylsilane

AbstractChlorotrimethylsilane is found to be a comparatively fast and efficient catalyst for carrying out electrophilic substitution reactions of indoles with various aldehydes/ketones/triethylorthoformate, yielding excellent amount of bis(indolyl)methanes/tris(indolyl)methanes. The merits of this protocol are avoidance of any external energy source, minimal reaction time, simple and easy procedure and high yield under solvent free room temperature condition. The versatility of this method has been tested with various aldehydes/ketones and received satisfactory results.

Synthesis of Bis(indolyl)methanes: A Natural Approach

An efficient and greener synthesis of bis(indoly)methanes was investigated via electrophilic substitution reaction of indole with carbonyl compounds in the presence of lemon juice as natural acid catalyst. The demonstrated environmentally benign protocol provided bis(indoly)methanes under mild reaction conditions, shorter reaction time and in excellent yield with simple work up procedure.

An Eco-Friendly Improved Protocol for the Synthesis of Bis(3-indolyl)methanes Using Poly(4-vinylpyridinium)hydrogen Sulfate as Efficient, Heterogeneous, and Recyclable Solid Acid Catalyst

Highly efficient and eco-friendly protocol for the synthesis of bis(3-indolyl)methanes by the electrophilic substitution reaction of indole with aldehydes catalyzed by poly(4-vinylpyridinium)hydrogen sulfate was described. Excellent yields, shorter reaction times, simple work-up procedure, avoiding hazardous organic solvents, and reusability of the catalyst are the most obvious advantages of this method.

Well-dispersed sulfated zirconia nanoparticles as high-efficiency catalysts for the synthesis of bis(indolyl)methanes and biodiesel

Well-dispersed sulfated zirconia nanoparticles were synthesized with poly(N-vinylpyrrolidone) as a surfactant. The resultant sulfated zirconia nanoparticles are characterized by SEM, XRD, FT-IR and XPS. These nanoparticles were directly used as catalysts for the synthesis of bis(indolyl)methanes and biodiesel via electrophilic substitution reaction of indole with various aldehydes and the esterification of long-chain free fatty acids and exhibited excellent catalytic activity. The mechanism of the formation of the synthesized zirconia nanoparticles was also proposed.