3-substituted Indoles Research Articles

Dearomative Alkylation-Based Two-Step cis-Diastereoselective Synthesis of Indoline-2,3-Fused Chromans and Tetrahydropyrans.

Herein, we describe a two-step, cis-diastereoselective synthesis of indoline-2,3-fused chromans from 3-substituted indoles. The method proceeds without intermediacy of ortho-quinone methides and leverages the dual function of TBS-protected 2-hydroxybenzyl iodides both as highly reactive alkylating agents in a t-BuONa/Et3B-promoted dearomative alkylation step and as a source of masked phenoxide nucleophiles in a subsequent TBAF-induced one-pot deprotection-cyclization step of the resulting indolenines. Importantly, this two-step protocol can also be extended to access indoline-2,3-fused tetrahydropyrans. These syntheses of indoline-2,3-fused chromans and tetrahydropyrans proceed with operational convenience, use easily accessible substrates and reagents, and feature broad substrate scope, high yields and complete diastereoselectivity. Furthermore, the synthesized products have the potential to undergo late-stage functionalization.

3-Acetyl Indole in the Synthesis of Natural Bioactive Compounds

Natural products, with their various sources from plants, marine organisms, and microorganisms, are considered a key source and inspiration for medicines and continue to be so. Indole alkaloids are a class of alkaloids and represent a large subunit of natural prod-ucts. Indole alkaloids of biological importance are numerous and cover a wide range of phar-maceutical applications, including anticancer, antiviral, antimicrobial, anti-inflammatory, and antioxidant. Obtaining natural, biologically active indole compounds involves isolating them from their natural sources or preparing them synthetically. 3-Substituted indoles repre-sent an emerging structural class of marine alkaloids based on their high degree of biological activity. 3-Acetyl indole is an important core used as a starting material for synthesizing many bioactive indole alkaloids. (5-Indole)oxazole alkaloids, β-carboline alkaloids, bis-in-dole alkaloids, chuangxinmycin, meridianine, and (±) indolemycin are the most important indole alkaloids that are prepared starting from 3-acety indole. The present review provides comprehensive information on the structures and the synthesis of bioactive indole alkaloids utilizing 3-acetyl indole and its derivatives as starting compounds. Additionally, it also spot-lights the diverse biological activities of these compounds.

Revolutionizing Indole Synthesis: A Microwave‐Powered Approach

AbstractTempted by the unique medicinal and biological potential of indole‐containing heterocycles, chemists, especially those specializing in heterocycle synthesis and drug discovery, are actively pursuing their efficient construction. This review spotlights the latest advancements in microwave‐assisted (M. W.) synthesis of diverse indole‐based heterocyclic compounds. We systematically categorize the reported methods based on the specific indole substitution patterns. This review concise the microwave assisted synthesis of indole based‐pyridine derivatives, indole based‐pyrimidine, indole based‐oxindole, spiro‐oxindole, Fischer indole Heck‐isomerization derivatives, functionalized indole, substituted indoles, indolyl quinoline, indole triazole and indolylnicotinonitriles derivatives. Ultimately, this review aims to provide organic and medicinal chemists with a concise yet informative guide to recent methodologies employing indole derivatives in the microwave‐powered synthesis of heterocycles.

Dual 5-HT6/SERT ligands for mitigating neuropsychiatric symptoms of dementia exerting neuroprotection against amyloid-β toxicity, memory preservation, and antidepressant-like properties

In light of the biological targets alterations in dementia patients suffering from neuropsychiatric symptoms, particularly in the 5-HT6 receptor and SERT transporters, this study aimed to develop dual-acting molecules targeting both these targets. By combining a 5-substituted indole with piperazine scaffolds, we synthesized molecules with nanomolar affinities for these sites, avoiding interaction with off-targets detrimental to dementia patients. Preliminary pharmacodynamic and ADMET assays let the identification of compound 15 as a lead molecule. In vitro studies showed that 15 provided neuroprotection against Aβ toxicity and reduced the levels of proapoptotic enzymes: caspase 3 and 7. In vivo, 15 reversed MK-801-induced memory deficits and exhibited antidepressant-like effects. Further studies showed that acute administration of compound 15 at a dose of 5 mg/kg increased BDNF levels, which are crucial for supporting neuronal survival and potentially slowing cognitive decline in dementia. These findings suggest 15's potential as a therapeutic for behavioral and psychological symptoms of dementia (BPSD), warranting further investigation.

An Exceptional Valorization of CuO Nanoparticles in Ionic Liquids as an Efficient Medium for the Electrophilic Substitution of Indole Towards the Formation of Bis(indolyl)methanes

Aim: Ionic liquids are promising green solvents with simple but unique structure-related physical properties such as negligible vapour pressure, exceptional thermal conductivity, remarkable thermal stability and their suitability and inertness towards a broad range of catalytic applications. CuO NPs have been addressed as a cost-effective and a reagent of a choice that necessitates only mild reaction conditions to offer a high yield of the desired products with exceptional selectivity in a short duration of time. Therefore, in the present work, attempts have been made to explore the catalytic potentials of CuO NPs in an ionic liquid medium to synthesize biologically important bis(indolyl)methanes. Background: Catalytic explorations of metal oxide nanoparticles in ionic liquids offers a cooperative effect that has a significant impact on the kinetics as well as on the outcome of the reaction. Therefore, such catalytic systems in the present times have seized the scientific community's interest from the perspectives of sustainable development in synthetic organic chemistry. The combination of metal oxide nanoparticles with highly tunable ionic liquids is not only used to synthesize simple organic molecules but also explored in the synthesis of complex organic molecules of high commercial and biological relevance. Objectives: The current work offers a rapid and robust protocol for synthesizing bis(indolyl)methanes via electrophilic substitution reaction between indole and various aldehydes in the presence of a CuO nanoparticles-ionic liquid system. The discussion focuses on the high tolerance of different functionalities by the catalytic system leading to the synthesis of bis(indolyl)methanes. Methods: CuO NPs have been synthesized via the co-precipitation method using ionic liquid. The applicability of metal oxide nanoparticles-IL matrix was further investigated in synthesizing bis(indolyl)methanes. Results: The FT-IR absorption below 600 cm-1 and the XRD pattern showing all the peaks in the diffraction diagram revealed the formation of CuO NPs. FESEM images show the flake-shaped morphology of CuO NPs and are found to be separated from the agglomerated clusters Conclusion: Ionic liquid-CuO NPs matrix reveals good to exceptional catalytic properties, and their advancements as a catalytic system at room temperature open new avenues for synthetic organic chemists.

Dynamic Kinetic Resolution of Racemic 2-Substituted Indoles by Pd-Catalyzed Asymmetric Hydrogenation

Dynamic Kinetic Resolution of Racemic 2-Substituted Indoles by Pd-Catalyzed Asymmetric Hydrogenation

Synthesis of 2-Substituted Indoles via Migration Reaction of 3-Substituted Indoles with Triflic Acid.

This study showcases the 1,2-migration reactions of alkyl and aryl groups on the indole molecule. Trifluoromethanesulfonic acid effectively facilitates the migration of the substituent from C3- to C2-position of the indole structure. The resulting C2-substituted indoles offer a valuable pathway for the synthesis of natural products and medicinal compounds.

Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives.

Aberrantly elevated adenosine in the tumor microenvironment exerts its immunosuppressive functions through adenosine receptors A2AR and A2BR. Antagonism of A2AR and A2BR has the potential to suppress tumor growth. Herein, we report a systemic assessment of the effects of an indole modification at position 4, 5, 6, or 7 on both A2AR/A2BR activity and selectivity of novel 2-aminopyrimidine compounds. Substituting indole at the 4-/5-position produced potent A2AR/A2BR dual antagonism, whereas the 6-position of indole substitution gave highly selective A2BR antagonism. Molecular dynamics simulation showed that the 5-cyano compound 7ai had a lower binding free energy than the 6-cyano compound 7aj due to water-bridged hydrogen bond interactions with E169 or F168 in A2AR. Of note, dual A2AR/A2BR antagonism by compound 7ai can profoundly promote the activation and cytotoxic function of T cells. This work provided a strategy for obtaining novel dual A2AR/A2BR or A2BR antagonists by fine-tuning structural modification.

Cascade Electrochemical Aerobic Oxygenation of 2-Substituted Indoles and Electrochemical [5 + 3] Annulation with Amidines: Access to Eight-Membered Benzo[1,3,5]triazocin-6(5H)-ones.

The cascade electrochemical C3-selective aerobic oxygenation of 2-substituted indoles and electrochemical [5 + 3] annulation with amidines through an undivided cell galvanostatic method employing molecular oxygen and "electricity" as green oxidants was developed. This protocol provides an efficient and direct approach to eight-membered benzo[1,3,5]triazocin-6(5H)-ones. Mechanistic studies suggested that two subsequent electrochemical processes both proceeded through radical pathways.

Water vs. Organic Solvents: Water-Controlled Divergent Reactivity of 2-Substituted Indoles.

Water is not a good solvent for most organic compounds, yet water can offer many benefits to some organic reactions, hence enriching organic chemistry. Herein, the unique divergent reactivity of 2-substituted indoles with ⋅NO sources is presented. The amount of water solvent was harnessed for a scalable, benign, and expedient synthesis of indolenine oximes, albeit with water's inability to dissolve the reactants. 2-Methoxyethyl nitrite, which has been tailored for reactions in water, empowered this protocol by enhancing the product selectivity. We further report on chemoselective transformations of the products that rely on their structural features. Our findings are expected to offer access to an underexplored chemical space. The platform is also applicable to oximinomalonate synthesis. Mechanistic studies revealed the important role of water in the reversal of stability between oxime and nitroso compounds, promoting the proton transfer.

Asymmetric Hydrogenation of Racemic 2-Substituted Indoles via Dynamic Kinetic Resolution: An Easy Access to Chiral Indolines Bearing Vicinal Stereogenic Centers.

The asymmetric hydrogenation (AH) of N-unprotected indoles is a straightforward, yet challenging method to access biologically interesting NH chiral indolines. This method has for years been limited to 2/3-monosubstituted or 2,3-disubstituted indoles, which produce chiral indolines bearing endocyclic chiral centers. Herein, we have reported an innovative Pd-catalyzed AH of racemic α-alkyl or aryl-substituted indole-2-acetates using an acid-assisted dynamic kinetic resolution (DKR) process, affording a range of structurally fascinating chiral indolines that contain exocyclic stereocenters with excellent yields, diastereoselectivities, and enantioselectivities. Mechanistic studies support that the DKR process relies on a rapid interconversion of each enantiomer of racemic substrates, leveraged by an acid-promoted isomerization between the aromatic indole and nonaromatic exocyclic enamine intermediate. The reaction can be performed on a gram scale, and the products can be derivatized into non-natural β-amino acids via facile debenzylation and amino alcohol upon reduction.

Synthesis of indolyl pyrroloindolines via a cascade arylation/cyclization of indole acetamides with 3-substituted indoles

A novel TEA-mediated cascade arylation/cyclization reaction between indole acetamides and 3-substituted indoles for the synthesis of various indolyl pyrroloindolines has been developed.

Study of the catalytic activity of methylene-bridged dicationic –SO3H-functionalized imidazolium phosphomolybdate hybrids for the one-pot sequential synthesis of 3-substituted indoles

Organic–inorganic dicationic imidazolium and phosphomolybdate based hybrids [DILPOM-1/2/3] developed for one pot synthesis of 3-substituted indoles in solvent free thermal methods.

Photocatalytic C2-trifluoroethylation and perfluoroalkylation of 3-substituted indoles using fluoroalkyl halides.

A photocatalytic reactivity platform for the C2-trifluoroethylation and perfluoroalkylation of 3-substituted indoles has been developed. A range of fluoroalkyl halides have been employed as radical precursors under mild, transition-metal-free conditions to access new (per)fluorinated chemical space featuring the indole substructure. This general protocol is also applicable to indole-containing peptides.

Cascade Reactions of Aryl-Substituted Terminal Alkynes Involving in Situ-Generated α-Imino Gold Carbenes.

An efficient, highly selective and divergent synthetic method to construct 2-substituted indoles and aryl-annulated carbazoles via the intermolecular generation of α-imino gold carbenes from terminal alkynes or diynes in combination with sulfilimines is disclosed. Importantly, the tandem reaction is proposed to proceed through an intermolecular gold carbene generation/C-H annulation followed by the activation of a second alkyne leading to 6-endo-dig cyclization, which is significantly different from previous dual activation or 1,6-carbene shift approaches for diyne systems. In the case of ortho-alkynylaniline as starting material, an unexpected regioselective formation of the indole moiety via the intermolecular path, instead of intramolecular hydroamination was discovered. This reactivity paved the way for a one-pot synthesis of the 11H-indolo [3,2-c] quinoline scaffold by exploiting the formed amino indole for a subsequent Pictet-Spengler reaction with aldehydes. The photophysical properties of the carbazoles indicated good violet-blue emission with quantum yields up to 40 %.

Expression of the two-component regulator StyS/StyR enhanced transcription of the styrene monooxygenase gene styAB and indigo biosynthesis in Escherichia coli

Indigo, an economically important dye, could be biosynthesized from indole by catalysis of the styrene monooxygenase StyAB. To enhance indigo biosynthesis, the styAB gene and its transcription regulator gene styS/styR in styrene catabolism were cloned from Pseudomonas putida and coexpressed in Escherichia coli. The presence of the intact regulator gene styS/styR dramatically increased the transcriptional levels of styA and styB by approximately 120-fold in the recombinant strain SRAB2 with coexpression of styS/styR and styAB compared to the control strain ABST with solo expression of styAB. A yield of 67.6 mg/L indigo was detected in strain SRAB2 after 24 h of fermentation with 120 μg/mL indole, which was approximately 14-fold higher than that in the control strain ABST. The maximum yield of indigo was produced from 160 μg/mL indole in fermentation of strain SRAB2. However, the addition of styrene to the media significantly inhibited the transcription of styA and styB and consequent indigo biosynthesis in recombinant E. coli strains. Furthermore, the substitution of indole with tryptophan as the fermentation substrate remarkably boosted indigo production, and the maximal yield of 565.6 mg/L was detected in strain SRAB2 in fermentation with 1.2 mg/mL tryptophan. The results revealed that the regulation of styAB transcription by the two-component regulator StyS/StyR in styrene catabolism in P. putida was effective in E. coli, which provided a new strategy for the development of engineered E. coli strains with the capacity for highly efficient indigo production.

Montmorillonite K‐10 Clay Promoted Direct Dehydrative Nucleophilic Substitution of Pyrrole and Indole with 4‐Chromanols

AbstractA mild and inexpensive method of alkylation of pyrrole and indole with substituted 4chromanols and 3‐arylidene‐4‐chromanols mediated by montmorillonite K‐10 is reported. Indole and pyrrole upon treatment with 4‐chromanols in the presence of activated montmorillonite K‐10 undergo facile nucleophilic substitution under ambient condition to afford 2‐(chroman‐4‐yl)‐1H‐pyrrole and 3‐(chroman‐4‐yl)‐1H‐indole in moderate to good yields. In the case of 3‐arylidene‐4‐chromanols, this direct dehydrative substitution reaction is found to be highly regioselective affording only the respective C‐4 substituted (arylidene‐chroman‐4‐yl)‐ pyrrole/indole derivatives.

Biological evaluation of indolactams for in vitro bryostatin 1-like activity

Small molecule activators of protein kinase C (PKC) have traditionally been classified as either tumor promoters or suppressors. Although bryostatin 1 has well established anti-cancer activity, most natural products that target the PKC regulator domain exhibit tumor promotion properties. In this study, we examine a focused library of indolactam analogues in cell-based assays to establish the structural features of the scaffold that enhance bryostatin 1-like activity. These systematic biological assessments identified specific indole substitution patterns that impart diminished tumor promotion behavior in vitro for indolactam analogues, while still maintaining nanomolar potency for PKC.

Base-Promoted Tandem Synthesis of 2-Substituted Indoles and N-Fused Polycyclic Indoles.

Herein is developed a base-promoted approach for the synthesis of C2-substituted indoles and N-fused polycyclic indoles via 5-endo-dig cyclization of 2-alkynyl anilines, followed by a 1,3'-acyl migration or a dearomatizing Michael addition process. A range of N-H free indoles and 8,9-dihydropyrido[1,2-a]indol-6(7H)-one scaffolds were synthesized in good to excellent yields with broad scope.

Facile synthesis of α-tertiary alkyl/aryl amines via cu-catalyzed alkylation of indoles and anilines with tertiary alkyl bromides

Methods of copper-catalyzed alkylation of indoles and anilines with tertiary alkyl bromides were reported. These protocols provided various N-tert-alkyl 3-substituted indoles and electron-deficient N-tert-alkyl anilines in moderate to good yields via CN coupling.