Synthesis Of Indoles Research Articles

Evaluation of Antimicrobial, Anticholinesterase Potential of Indole Derivatives and Unexpectedly Synthesized Novel Benzodiazine: Characterization, DFT and Hirshfeld Charge Analysis

The pharmacological effectiveness of indoles, benzoxazepines and benzodiazepines initiated our synthesis of indole fused benoxazepine/benzodiazepine heterocycles, along with enhanced biological usefulness of the fused rings. Activated indoles 5, 6 and 7 were synthesized using modified Bischler indole synthesis rearrangement. Indole 5 was substituted with the trichloroacetyl group at the C7 position, yielding 8, exclusively due to the increased nucleophilic character of C7. When trichloroacylated indole 8 was treated with basified ethanol or excess amminia, indole acid 9 and amide 10 were yielded, respectively. Indole amide 10 was expected to give indole fused benoxazepine/benzodiazepine 11a/11b on treatment with alpha halo ester followed by a coupling agent, but when the reaction was tried, an unexpectedly rearranged novel product, 1,3-bezodiazine 12, was obtained. The synthetic compounds were screened for anticholinesterase and antibacterial potential; results showed all products to be very important candidates for both activities, and their potential can be explored further. In addition, 1,3-bezodiazine 12 was explored by DFT studies, Hirshfeld surface charge analysis and structural insight to obrain a good picture of the structure and reactivity of the products for the design of derivatised drugs from the novel compound.

Synthesis and Antidepressant activity of some N-substituted-2-phenyl indole derivatives

In this investigation, few 1-ethyl acetate-2-phenylindole derivatives were synthesized and the antidepressant activity of these molecules was assessed in forced swim test and tail suspension test. The synthesis of the target molecules required three steps leading to the formation of phenyl indole using Fisher indole synthesis followed by the substitution of ethylacetate to the ring nitrogen of indole. The IR spectra showed stretching and bending vibrations at 1300-1100 cm-1(C-N), 1500-1700 cm-1 (C=C), 3000-3200 cm-1 (C-C) and 2600-3000 cm-1 (CH). Similarly vibrations due to C-O (1000-1100 cm-1), OH (3200-3500 cm-1) and Nitro (1400-1500 cm-1) were displayed. The standard drug fluoxetine and the test compounds 3d and 3e were found to significantly reduce the immobility of mice TST and enhance the swimming frequency.

Pd(II)-Catalyzed Tandem Cycloannulative-Alkenylation of o-Alkynyl-Phenols/Anilines with (E)-β-Iodovinyl Sulfones: A Direct Strategy To Construct 3-(Vinyl sulfonyl)benzoheterole Derivatives.

Benzoheteroles and vinyl sulfones are the most promising pharmaceutical relevance motifs, yet the hybrid analogues of these scaffolds still need to be explored. We report herein a general and highly efficient Pd(OAc)2-catalyzed intramolecular cyclization and vinylation of o-alkynylphenols/o-alkynylanilines with (E)-β-iodovinyl sulfones under mild reaction conditions. A direct C(sp2)-C(sp2) cross-coupling is enabled for the diversity-oriented synthesis of vinyl sulfone-tethered benzofurans and indoles in good to high yields with excellent stereoselectivity. Notably, this tandem process was consistent at the gram scale, and in situ, generation of 2-(phenylethynyl)phenol has also been utilized in a scalable synthesis. Late-stage synthetic transformations were also further explored, including isomerization and desulfonylative-sulfenylation. Moreover, several control experiments were accomplished, and we proposed a plausible mechanism based on existing experimental results.

Rhodium-Catalyzed Synthesis of 2-Methylindoles via C-N Bond Cleavage of N-Allylbenzimidazole.

A rhodium-catalyzed oxidative C-H/N-H dehydrogenative [3 + 2] annulation strategy has been reported between anilines and N-allylbenzimidazole for the synthesis of 2-methylindole scaffolds. An N-allylbenzimidazole has been used as a 2C synthon for the synthesis of indole, and more importantly, this transformation involves the cleavage of the thermodynamically stable C-N bond of allylamine. Detailed mechanistic studies have been performed and a key intermediate was detected in HRMS. This transformation proceeds through a cascade of C(sp2)-H allylation followed by intramolecular cyclization.

Synthesis, Structure and Biological Activity of Indole-Imidazole Complexes with ZnCl2: Can Coordination Enhance the Functionality of Bioactive Ligands?

The ability of the indole-imidazole hybrid ligands to coordinate with the Zn(II) ion and the resulting structures of this new class of coordination compounds were analyzed in order to determine their structural properties and biological functionalities. For this purpose, six novel Zn(II) complexes, [Zn(InIm)2Cl2] (1), [Zn(InMeIm)2Cl2] (2), [Zn(IniPrIm)2Cl2] (3), [Zn(InEtMeIm)2Cl2] (4), [Zn(InPhIm)2Cl2] (5) and [Zn2(InBzIm)2Cl2] (6) (where InIm is 3-((1H-imidazol-1-yl)methyl)-1H-indole), were synthesized by the reactions of ZnCl2 and the corresponding ligand in a 1:2 molar ratio in methanol solvent at an ambient temperature. The structural and spectral characterization of these complexes was performed using NMR, FT-IR and ESI-MS spectrometry and elemental analysis, and the crystal structures of 1-5 were determined using single-crystal X-ray diffraction. Complexes 1-5 form polar supramolecular aggregates by utilizing, for this purpose, the N-H(indole)∙∙∙Cl(chloride) intermolecular hydrogen bonds. The assemblies thus formed differ depending on the distinctive molecular shape, which can be either compact or extended. All complexes were screened for their hemolytic, cytoprotective, antifungal, and antibacterial activities. The results show that the cytoprotective activity of the indole/imidazole ligand significantly increases upon its complexation with ZnCl2 up to a value comparable with the standard antioxidant Trolox, while the response of its substituted analogues is diverse and less pronounced.

Iron-catalyzed intramolecular reductive cyclization of o-nitroarenes to indoles under visible light irradiation

An efficient, mild and environmentally benign methodology for the synthesis of indoles via air stable, inexpensive Knölker complex catalyzed intramolecular reductive cyclization of o-nitrostyrenes at room temperature under photoirradiation has been developed. The stated methodology was capable for a diverse range of o-nitrostyrenes, generates outstanding yields of the indoles.

Recent Advances in Indole Synthesis and the Related Alkylation

AbstractThe derivatives of indoles are very useful intermediates in pharmaceuticals and organic synthesis. The efficient synthesis of the indole blocks and related functionalizations, especially the alkylation of indoles are hot topics in recent years. This review will focus on the following two aspects: i) new developments for the synthesis of indoles which was catalyzed by transition metals, the alkylation of indoles, including the one on N1‐position, C2‐position, as well as C3‐position. 1. Introduction 2. Synthesis of indoles catalyzed by various metals 2.1. Synthesis of indoles by palladium catalysts 2.2. Synthesis of indoles by other metal catalysts 3. Alkylation of indoles 3.1. N1‐alkylation of indoles 3.2. C2‐alkylation of indoles 3.3. C3‐alkylation of indoles

A Metal‐Free C−H Amination‐Based Strategy for N‐Amino Indole Synthesis

AbstractAn oxidative cyclization of electron‐rich α‐arylhydrazones promoted by phenyliodine bis(trifluoroacetate) (PIFA) has been accomplished. This metal‐free, chemoselective transformation allows to obtain synthetically and medicinally important N‐amino‐1H‐indoles, obviating the need for pre‐functionalization of substrates.

Tunable Regio- and Stereoselective Synthesis of Z-Acrylonitrile Indoles and 3-Cyanoquinolines from 2-Alkynylanilines and Alkynylnitriles.

The merger of two bifunctional moieties, 2-alkynylaniline and alkynylnitriles, in the presence of ZnBr2 offers the tunable synthesis of two biologically important motifs: acrylonitrile indoles and 3-cyanoquinolines. The group present on the terminal alkyne of 2-alkynylaniline regulates the reaction pathways, intra- versus intermolecular, which thereby adds stereoselectivity and regioselectivity in this protocol. The conversion of an acrylonitrile indole ring to quinoline is an intriguing synthetic utility of this methodology.

Lithium tert‐butoxide/DMSO‐mediated Rapid Synthesis of Naphthalenes, Benzofurans, and Indoles

AbstractHerein, an efficient lithium tert‐butoxide/DMSO‐mediated rapid synthesis of naphthalenes, benzofurans, and indoles is reported. The anticipated aromatics and heteroaromatics are obtained in high yields within a few minutes, even in a decagram‐scale reaction.

Direct C2-H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes.

A light-driven metal-free protocol for the synthesis of sulfone-containing indoles under mild conditions is reported. Specifically, the process is driven by the photochemical activity of halogen-bonded complexes formed upon complexation of a sacrificial donor, namely 1,4-diazabicyclo[2.2.2]octane (DABCO), with α-iodosulfones. The reaction provides a variety of densely functionalized products in good yields (up to 96% yield). Mechanistic investigations are reported. These studies provide convincing evidences for the photochemical formation of reactive open-shell species.

Ruthenium-Catalyzed Oxidative Synthesis of N-(2-triazine)indoles by C-H Activation.

1,3,5 triazines, especially indole functionalized triazine derivatives, exhibit excellent activities, such as anti-tumor, antibacterial, and anti-inflammatory activities. Traditional methods for the synthesis of N-(2-triazine) indoles suffer from unstable materials and tedious operations. Transition-metal-catalyzed C-C/C-N coupling provides a powerful protocol for the synthesis of indoles by the C-H activation strategy. Here, we report the efficient ruthenium-catalyzed oxidative synthesis of N-(2-triazine) indoles by C-H activation from alkynes and various substituted triazine derivatives in a moderate to good yield, and all of the N-(2-triazine) indoles were characterized by 1H NMR, 13C NMR, and HRMS. This protocol can apply to the gram-scale synthesis of the N-(2-triazine) indole in a moderate yield. Moreover, the reaction is proposed to be performed via a six-membered ruthenacycle (II) intermediate, which suggests that the triazine ring could offer chelation assistance for the formation of N-(2-triazine) indoles.

Design, synthesis, cytotoxic activity, and molecular docking studies of indol and indazole-based stilbenes.

To develop new highly effective anticancer agents derived from naturally occurring stilbene scaffold, in total of 25 indol and indazole-based stilbenes including 18 new compounds were designed according to molecular hybridization strategy and synthesized via Witting reaction. The synthesized derivatives were assayed for cytotoxic activities against human tumor cell lines (K562 cells and MDA-MB-231 cells) and normal cell line (L-02 cells). The biological screening results showed that indol and indazole-based stilbenes are of great interest for developing anticancer agents as eight derivatives possessed strong antiproliferative activities with IC50 values less than 10 µM. In particular, indol-based stilbene IS1l bearing piperidine exhibited the most potent cytotoxicity against both K562 and MDA-MB-231 cells with IC50 values 2.4 µM and 2.18 µM, respectively, along with a remarkable selectivity towards human normal L-02 cells. Moreover, molecular docking was exploited to elucidate the binding model of IS1l with biochemical target tryptophan 2,3-dioxygenase (TDO). Together, the results suggested that compound IS1l is a promising anticancer agent worthy of further investigation.

The Fürstner Indole Synthesis: Titanium-Catalyzed Intramolecular McMurry-Type Carbonyl Coupling

Key words carbonyl coupling - indole synthesis - reductive cyclization - titanium catalysis

One-Pot Synthesis of N-Functionalized Indoles through a Three-Step Tandem Process

Key words isatins - imine formation - indoles - quaternary centers - tandem reaction

Enantioselective Copper-Catalyzed Fukuyama Indole Synthesis from 2-Vinylphenyl Isocyanides.

Enantioenriched chiral indoles are of high interest for the pharmaceutical and agrochemical industries. Herein, we present an asymmetric Fukuyama indole synthesis through a mild and efficient radical cascade reaction to access 2-fluoroalkylated 3-(α-cyanobenzylated) indoles by stereochemical control with a chiral copper-bisoxazoline complex using 2-vinylphenyl arylisocyanides as radical acceptors and fluoroalkyl iodides as C-radical precursors. Radical addition to the isonitrile moiety, 5-exo-trig cyclization, and Cu-catalyzed stereoselective cyanation provide the targeted indoles with excellent enantioselectivity and good yields. Due to the similar electronic and steric properties of the two aryl substituents to be differentiated, the enantioselective construction of the cyano diaryl methane stereocenter is highly challenging. Mechanistic studies reveal a negative nonlinear effect which allows proposing a model to explain the stereochemical outcome. Scalability and potential utility of the enantioenriched 3-(α-cyanobenzylated) indoles as hubs for chiral tryptamines, indole-3-acetic acid derivatives, and triarylmethanes are demonstrated, and a formal synthesis of a natural product analogue is disclosed.

One-Pot Synthesis of 3-Substiuted Indoles from 2-(2-Nitro-1-phenylethyl)cyclohexanone Derivatives

Herein, a one-pot synthesis of 3-substituted indoles from 2-(2-nitro-1-phenylethyl)cyclohexanone derivatives catalyzed by Pd/C is reported. The starting materials can be easily prepared by the reaction of substituted ketones and nitroalkenes. The facile experimental procedure comprises the treatment of 2-(2-nitro-1-phenylethyl)cyclohexanone derivatives with H2 as a hydrogen donor in the presence of 10 mol % Pd/C. Subsequently, the exchange of H2 with CH2═CH2 as a hydrogen acceptor affords a variety of 3-substituted indoles in high yields. The formation of intermediate nitrones is essential for a smooth reaction.

Highly Chemoselective Synthesis of Indole Derivatives.

A facile and efficient synthesis of polysubstituted indoles from α-arylamino-β-hydroxy-2-enamides, α-arylamino-β-oxo-amides, or their tautomeric mixture via electrophilic activation strategy is described. The salient feature of this methodology is the use of either combined Hendrickson reagent and triflic anhydride (Tf2O) or triflic acid (TfOH) to control the chemoselectivity in the intramolecular cyclodehydration to provide a predictable approach to these valuable indoles with flexible substituent patterns. Moreover, the mild reaction conditions, simple execution, high chemoselectivity, excellent yields, and wide range of synthetic potential of products make this protocol much attractive for academic research and practical applications.

Atroposelective Nenitzescu Indole Synthesis

Invited for the cover of this issue is the group of Frederic W. Patureau at the RWTH Aachen University. The image depicts atropoisomerism, in particular through the helix-shaped vines in the forefront focus. This metaphorically illustrates the importance of atroposelectivity in biologically active molecules, such as in the 5-hydroxyindoles that were accessed through the first enantioselective Nenitzescu indole synthesis. Read the full text of the article at 10.1002/chem.202300279.

Pyrroloiminoquinone Alkaloids: Total Synthesis of Makaluvamines Aand K.

Herein, an efficient, scalable, and concise approach to an advanced pyrroloiminoquinone synthetic intermediate (6b) by way of a Larock indole synthesis is reported. The synthetic utility of this intermediate is demonstrated by its ready conversion to makaluvamines A (1) and K (4).