Indole 3-position Research Articles

Preparation of Indolin-3-one-Containing 1,4-Naphthoquinone Derivatives via Organocatalytic Asymmetric Michael Addition Reaction.

This article explores the asymmetric Michael addition reaction of 2-hydroxy-1,4-naphthoquinone and indole-3-ones catalyzed by cinchona alkaloids. This strategy utilizes 2-hydroxy-1,4-naphthoquinone and easily prepared indole-3-one as substrates, resulting in the synthesis of 23 unprecedented indolin-3-ones bearing a 1,4-naphthoquinone unit at the C2 position of indole under simple and mild reaction conditions, with up to 88% yield, 98% ee, and >20:1 dr.

Palladium-Catalyzed C3-Carbaldehyde Directed Regioselective C2-Thioarylation of Indoles.

Palladium-catalyzed thioarylation of indoles by diaryl disulfides in the presence of phenyliododiacetate is reported. The directing potential of weakly coordinating aldehyde group present at 3-position of indole was exploited for regioselective C2-H thioarylation over the possible C4-H functionalization. Mechanistic studies reveal that the process involves initial generation of thioaryl radical followed by sequential C-H activation, thiolate transfer, and reductive elimination.

K2CO3-catalyzed highly efficient O and N-acylation under mild conditions

An eco-friendly, mild and efficient acylation of various nucleophiles with alkenyl carboxylates via inorganic base catalysis is described. Among five inorganic base species examined, K2CO3 was proved to be the most efficient catalyst for the acylation. A broad variety of acylated products were achieved within 15 min at room temperature in high yields. In addition, we found that the 3-position of indoles should have a suitable substituent group under this procedure.

Photoredox C(2)-Arylation of Indole- and Tryptophan-Containing Biomolecules.

We introduce a novel and straightforward methodology for photoredox arylation of an indole scaffold using aryldiazonium salts under mild and metal-free conditions. Our approach enables the regioselective and chemoselective introduction of several aryl groups to the C(2) position of indoles and tryptophan, even in competition with other amino acids. This approach extends to the late-stage functionalization of peptides and lysozyme, heralding the unprecedented arylation of tryptophan residues in wild-type proteins and offering broad utility in chemical biology.

Rapid access to diverse indoles by addition/SNAr with Grignard reagents and 2-fluorophenyl acetonitriles

Indoles are essential heterocycles in natural products, biological chemistry, and medicinal chemistry. Efficient approaches to their synthesis, therefore, remain in demand. Herein is reported a novel and scalable method to produce a wide variety of indoles by combining Grignard reagents and 2-fluorobenzyl cyanides (59 examples, 45%–95% yields). The Grignard reagent adds to the nitrile to give a metalated imine that undergoes SNAr with unactivated C–F bonds. This strategy installs the R group of RMgX at the indole 2-position, and it is noteworthy that a diverse array of Grignard reagents (aryl, alkyl, vinyl, and cyclopropyl) provide the desired heterocyclic products. The resulting N-magnesiated indole can be in situ functionalized at the 3-position with alkyl halides or functionalized on the nitrogen with silyl chlorides. This method enables the synthesis of indoles with functional groups at each position of the indole backbone (C4–C7), providing handles for further functionalization.

Cu(II)-Catalyzed H/D exchange of indole derivatives

Cu(OTf)2 was explored as an efficient catalyst for hydrogen deuterium (H/D) exchange of indole derivatives. The advantage of this reaction is that deuteration selectivity can be adjusted by changing reaction parameters. When the reaction was performed with 10 mol% of Cu(OTf)2 as a catalyst in dioxane at 80 °C, deuteration preferentially occurred at C3 position of indole with high atom% deuterium incorporation. Furthermore, per-deuterated indole derivatives could be achieved by performing the reaction with higher catalyst loading in toluene at 120 °C. Performing the reaction on a continuous flow reactor facilitates the scale-up process, affording deuterated products with a throughput of 3.9 g/h.

One-Flow Synthesis of Substituted Indoles via Sequential 1,2-Addition/Nucleophilic Substitution of Indolyl-3-Carbaldehydes.

Substituted indoles are important as drugs. A number of valuable indoles have been synthesized via nucleophilic substitution at the 3'-position of indoles. However, the preparation of an indolylmethyl electrophile containing a tertiary carbon at the 3'-position and its subsequent nucleophilic substitution are challenging owing to the instability of the electrophile. Herein, we demonstrated the rapid one-flow synthesis of indoles via sequential 1,2-addition/nucleophilic substitution of indolyl-3-carbaldehydes. The use of a microflow technology helped in suppressing the undesired reactions caused by the unstable intermediates, resulting in significantly higher yields and reproducibility compared to those under batch conditions. A crown ether was effective when 1-alkylindole-3-carboxaldehyde was used as a substrate. However, the crown ether exerted a detrimental effect when 1H-indole-3-carboxaldehyde was used. A total of 15 structurally diverse indole derivatives were obtained in generally acceptable to good yields.

Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes.

Substituted arenes are ubiquitous in molecules with medicinal functions, making their synthesis a critical consideration when designing synthetic routes. Regioselective C-H functionalization reactions are attractive for preparing alkylated arenes; however, the selectivity of existing methods is modest and primarily governed by the substrate's electronic properties. Here, we demonstrate a biocatalyst-controlled method for the regioselective alkylation of electron-rich and electron-deficient heteroarenes. Starting from an unselective "ene"-reductase (ERED) (GluER-T36A), we evolved a variant that selectively alkylates the C4 position of indole, an elusive position using prior technologies. Mechanistic studies across the evolutionary series indicate that changes to the protein active site alter the electronic character of the charge transfer (CT) complex responsible for radical formation. This resulted in a variant with a significant degree of ground-state CT in the CT complex. Mechanistic studies on a C2-selective ERED suggest that the evolution of GluER-T36A helps disfavor a competing mechanistic pathway. Additional protein engineering campaigns were carried out for a C8-selective quinoline alkylation. This study highlights the opportunity to use enzymes for regioselective radical reactions, where small molecule catalysts struggle to alter selectivity.

Enantioselective Synthesis of an All-Carbon Quaternary Stereocenter by Chiral Brønsted Acid-Catalyzed Friedel-Crafts-Type Reaction between Pyrroles and 3-Indolylmethanols.

We have developed a chiral phosphoric acid-catalyzed enantioselective Friedel-Crafts alkylation reaction between pyrroles and indolylmethanols. Wide substrate scope was observed, and a chiral all-carbon quaternary center was constructed at the 3 position of indoles in high yields with high to excellent enantioselectivities (up to 99% ee).

Mechanistic duality of indolyl 1,3-heteroatom transposition.

A novel mechanistic duality has been revealed from the indolyl 1,3-heteroatom transposition (IHT) of N-hydroxyindole derivatives. A series of in-depth mechanistic investigations suggests that two separate mechanisms are operating simultaneously. Moreover, the relative contribution of each mechanistic pathway, the energy barrier for each pathway, and the identity of the primary pathway were shown to be the functions of the electronic properties of the substrate system. Based on the mechanistic understanding obtained, a mechanism-driven strategy for the general and efficient introduction of a heteroatom at the 3-position of indole has been developed. The reaction developed exhibits a broad substrate scope to provide the products in various forms of the functionalised indole. Moreover, the method is applicable to the introduction of both oxygen- and nitrogen-based functional groups.

Synthesis of C2-Carbonyl Indoles via Visible Light-Induced Oxidative Cleavage of an Aminomethylene Group.

A strategy for photochemical oxidative cleavage of the aminomethylene group at the C2 position of indole was developed to synthesize C2-carbonyl indoles. The reaction was initiated by the photochemical oxidation of N1, followed by a water-assisted concerted H-shift by abstracting hydrogen from aminomethylene. Bromopyridine was discovered to play dual roles as an oxidant for the regeneration of photocatalysts and as an accelerant for the single-electron transfer process.

Palladium‐Catalyzed Regioselective C4 Functionalization of Indoles with Quinones

AbstractA synthetic strategy for the installation of diversely functionalized quinones at the C4 position of indoles is developed via palladium‐catalyzed C−H and double C−H functionalization. This synthetic protocol provides a rapid route to a variety of 4‐quinonylindoles via the direct coupling of 3‐formylindoles with quinones. Furthermore, this synthetic methodology also efficiently affords biologically interesting bis(indol‐4‐yl)quinones in good yields by direct one‐pot double C−H activation of 3‐formylindoles with the corresponding quinones.magnified image

Constructing multi-enzymatic cascade reactions for selective production of 6-bromoindirubin from tryptophan in Escherichia coli.

6-Bromoindirubin (6BrIR), found in Murex sea snails, is a precursor of indirubin-derivatives anticancer drugs. However, its synthesis remains limited due to uncharacterized biosynthetic pathways and difficulties in site-specific bromination and oxidation at the indole ring. Here, we present an efficient 6BrIR production strategy in Escherichiacoli by using four enzymes, that is, tryptophan 6-halogenase fused with flavin reductase Fre (Fre-L3-SttH), tryptophanase (TnaA), toluene 4-monooxygenase (PmT4MO), and flavin-containing monooxygenase (MaFMO). Although most indole oxygenases preferentially oxygenate the electronically active C3 position of indole, PmT4MO was newly characterized to perform C2 oxygenation of 6-bromoindole with 45% yield to produce 6-bromo-2-oxindole. In addition, 6BrIR was selectively generated without indigo and indirubin byproducts by controlling the reducing power of cysteine and oxygen supply during the MaFMO reaction. These approaches led to 34.1 mg/L 6BrIR productions, making it possible to produce the critical precursor of the anticancer drugs only from natural ingredients such as tryptophan, NaBr, and oxygen.

MULTICOMPONENT ONE-POT SYNTHESIS OF NOVEL INDOLE ANALOGUES AS POTENT ANTIOXIDANT AGENTS

Objective: The purpose of this study was to design and synthesize innovative multicomponent one-pot indole analogues that would be effective antioxidants for the body. Methods: A novel series of indolyl-pyrimidine derivatives were synthesized and characterized by spectrum analysis, and their antioxidant activity and DPPH, total antioxidant capacity, ferric reducing antioxidant power methods, and DNA cleavage activity were examined. Results: Compound 6a displayed promising free radical scavenging and total antioxidant properties. Compound 6b has demonstrated excellent ferric reducing activity, which is due to the presence of a “CH3” substitution at five position of indole. When compared to a standard DNA marker, compound 6a demonstrated the highest DNA cleavage activity at desired concentrations. Conclusion: We have synthesized novel pyrimidine analogues containing an indole moiety to investigate drug-like molecules. We have devised that a method that is simple, multicomponent, has a short reaction time, and is ecologically benign.

Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators.

Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the N′-methylene position of indoles’ Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives 9a–9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N-dimethylformamide dimethylacetal. All compounds were characterized by 1H-NMR, 13C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h-induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.

Energy Transfer Photocatalytic Radical Rearrangement in N-Indolyl Carbonates.

A new type of sp3-like N-centered radical has been generated by selective energy transfer catalysis. Upon photoexcitation, homolytic N-O bond cleavage of N-indolyl carbonate in the presence of an Ir complex produced N- and O-centered radicals. The high spin density at the C3 position of indole led to radical recombination with the O-centered radical, affording valuable 3-oxyindole derivatives without decarboxylation. Transformations of the desired products into various molecules were also demonstrated.

A Useful Methods of Direct Sulfenylation at the 3-Position of Indoles Employing various Sulfenylating Agents

3-Sulfenylated indoles as a significant heterocyclic scaffold have garnered enormous interest and utility in the past several decades due to significant biological and pharmaceutical activities, including anti-HIV, anti-obesity and anti-cancer activity. To date, several methods have been developed for the synthesis of 3-sulfenylated indoles using distinct sulfenylating agents. In this review, the recent developments in the metal free synthesis of 3-sulfenylated indoles moieties are covered, which show insight into both the large distinct reactions condition as well as mechanism.

Metal-free synthesis of C2-quaternary indolinones by (NH4)2S2O8 mediated oxidative dearomatization of indoles.

An efficient metal-free, (NH4)2S2O8 mediated oxidative dearomatization of indoles for the construction of C2-quaternary indolinones was disclosed. A series of C2-quaternary indolinones derivatives with good functional group tolerance were obtained in moderate to excellent yields. This methodology provides an alternative approach for the direct generation of all-carbon quaternary centers at the C2 position of indoles. This catalytic approach represents a step-economic and convenient strategy for the oxidative dearomatization of indoles.

Heck Reaction Boosted Heterocycle Ring-Closing and Ring-Opening Rearrangement: A Strategy for the Synthesis of Indolyl-Type Ligands.

A novel method for P-involved heterocycle ring-closing-ring-opening rearrangement (HRR) via the Heck reaction is disclosed. The approach enables direct installation of a phosphorus-containing aryl group onto the C2 position of indole. This new rearrangement directly transforms easily prepared indole derivatives into indolyl-derived phosphonates and phosphinic acids with high yields, and many of the products are difficult to obtain by using established methods. This new HRR reaction provides an extremely simple and step-economic method to induce C-C bond formation and P-N bond cleavage for the synthesis of a variety of indolyl-type ligands.

Ethylene tri-/tetramerization catalysts supported by diphosphinoindole ligands

A new class of diphosphinoindole ligands have been developed. Upon activation with MMAO-3A, Cr catalysts supported by these bisphosphine ligands are active for ethylene tri-/tetramerization. The best result was achieved by using the bisphosphine ligand containing a phenyl group at C3 position of indole, giving a high activity of up to 364 kg/(g Cr/h) with a total selectivity of up to 72% toward 1-hexene (23.5%) and 1-octene (48.4%). A representative chromium tetracarbonyl complex was synthesized and structurally characterized by single-crystal X-ray diffraction.