Polycyclic Indole Research Articles

Hyperconjugation-Driven Isodesmic Reaction of Indoles and Anilines: Reaction Discovery, Mechanism Study, and Antitumor Application.

Isodesmic reactions, in which chemical bonds are redistributed between substrates and products, provide a general and powerful strategy for both biological and chemical synthesis. However, most isodesmic reactions involve either metathesis or functional-group transfer. Here, we serendipitously discovered a novel isodesmic reaction of indoles and anilines that proceeds intramolecularly under weakly acidic conditions. In this process, the five-membered ring of the indole motif is broken and a new indole motif is constructed on the aniline side, accompanied by the formation of a new aniline motif. Mechanistic studies revealed the pivotal role of σ→π* hyperconjugation on the nitrogen atom of the indole motif in driving this unusual isodesmic reaction. Furthermore, we successfully synthesized a diverse series of polycyclic indole derivatives; among quinolines, potential antitumor agents were identified using cellular and in vivo experiments, thereby demonstrating the synthetic utility of the developed methodology.

Hyperconjugation‐Driven Isodesmic Reaction of Indoles and Anilines: Reaction Discovery, Mechanism Study, and Antitumor Application

AbstractIsodesmic reactions, in which chemical bonds are redistributed between substrates and products, provide a general and powerful strategy for both biological and chemical synthesis. However, most isodesmic reactions involve either metathesis or functional‐group transfer. Here, we serendipitously discovered a novel isodesmic reaction of indoles and anilines that proceeds intramolecularly under weakly acidic conditions. In this process, the five‐membered ring of the indole motif is broken and a new indole motif is constructed on the aniline side, accompanied by the formation of a new aniline motif. Mechanistic studies revealed the pivotal role of σ→π* hyperconjugation on the nitrogen atom of the indole motif in driving this unusual isodesmic reaction. Furthermore, we successfully synthesized a diverse series of polycyclic indole derivatives; among quinolines, potential antitumor agents were identified using cellular and in vivo experiments, thereby demonstrating the synthetic utility of the developed methodology.

Copper-Catalyzed [3 + 2] Annulation of O-Acyl Oximes with p-Hydroquinones for the Synthesis of 5-Hydroxyindoles.

A copper-catalyzed [3 + 2] annulation of O-acyl oximes with 2-electron-withdrawing group substituted p-hydroquinones for the efficient synthesis of polysubstituted 5-hydroxyindoles is developed. Further intramolecular cyclization leads to the concise and rapid construction of several kinds of 3,4- and 4,5-fused polycyclic indoles.

Synthesis of Chiral Polycyclic Indoles via Pd(II)-Catalyzed Sequential Cyclization and Carbonylation

Synthesis of Chiral Polycyclic Indoles via Pd(II)-Catalyzed Sequential Cyclization and Carbonylation

Efficient assembly and anti-tumor evaluation of novel polycyclic [1,2-a]-fused indoles

Structurally diverse cyclopenta[4,5]pyrrolo[1,2-a]indoles heterocycles were smoothly constructed in good to excellent yields (up to 99 %) with excellent diastereoselectivities (>19:1 dr) through a novel and facile strategy based on BF3-catalyzed Friedel-Crafts alkylation/Aldol/Dehydrative cyclization cascade reaction. The anti-proliferative activity of these newly synthesized polycyclic indoles was screened, and all the functionalized reductive derivatives exhibited favorable anti-tumor activity. Notably, compound 4ae displayed the remarkable inhibitory activity against MCF-7 and HeLa cells with IC50 values of 4.62 μM and 7.71 μM, respectively. Mechanistically, the representative compound 4ae could effectively induce apoptosis of MCF-7 cells in crediting to up-regulate the relative expression of apoptotic protein BAX/Bcl-2, subsequently activate Pro-caspase 9 and cleave PARP, simultaneously block the cell cycle through down- and up-regulate the expression of cyclin B1 and p53, respectively. Moreover, compound 4ae also exhibited promising antineoplastic efficacy in subcutaneous MCF-7 xenograft mice which manifest significant shrunken tumors conspicuous nuclear apoptotic signal and minimal systemic toxicity. This strategy not only established a novel and efficient method for the assembly of structurally complex indole heterocycles, but also provided a series of compounds possessing attractive anti-cancer activity, which holds immense potential for future biomedical applications.

Synthesis of N-fused polycyclic indoles via a Pd-catalyzed multicomponent cascade reaction consisting of an amide-directed [3+1+1] annulation reaction of 3-diazo oxindole and isocyanides

A palladium-catalyzed and amide-assisted multicomponent reaction of 3-diazo oxindole, isocyanide, and water to generate biologically important oxazole-fused indole scaffolds has been reported.

Synthesis of N-Fused Polycyclic Indole Derivatives via Ru(II)-Catalyzed C-H Bond Activation and Intramolecular Hydroarylation.

A new synthesis of N-fused tetracyclic indole derivatives and their related polycyclic analogues has been developed based on ruthenium(II)-catalyzed C-H activation and intramolecular hydroarylation. A series of polycyclic indoles with a 3-formyl group have been prepared in good to high yields. Various aliphatic and aromatic amines have been studied to form a transient directing group with the aldehyde for the catalytic process. A significant impact of the structures of the aromatic amines was identified, and 1-naphthylamine was shown to enable the catalytic process. DFT computations were performed to gain further insight into the role of the transient directing groups.

Photoredox‐Catalyzed Carbon Radical Generation from α‐Keto‐N,O‐acetals: Synthesis of Functionalized Azepino[1,2‐a]indoles and Azepino[1,2‐a]furo[3,2‐b]indoles

AbstractC10a‐Acetoxylated perhydroazepino[1,2‐a]‐indoles, accessible via visible light‐mediated sensitized photooxygenation of cyclo‐hepta[b]indoles, are precursors to structurally elaborate carbon‐centered radicals. Their photoredox‐catalyzed SET reduction by phenothiazine or phenoxazine photocatalysts, followed by fragmentation and C−O bond cleavage, liberates tricyclic α‐amino‐α‐carbonyl radicals that readily engage in radical addition reactions with silyl enol ethers and silyl ketene acetals. The C−C functionalized azepinoindole[1,2‐a]indoles are useful building blocks for the synthesis of polycyclic indole derivatives as shown by the controlled borohydride reduction of a C10a‐methylenecarboxylate derivative, which leads stereoselectively to tetracyclic azepino[1,2‐a]furo[3,2‐b]indoles. The photocatalytic method developed herein is also suitable for the radical functionalization of simple α‐acetoxy acetophenones.

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.

Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis.

Herein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially available Lewis acids. The reaction proceeded through a stepwise pathway involving a nucleophilic addition of indoles to BCBs followed by an intramolecular Mannich reaction to form rigid indoline-fused polycyclic structures, which resemble polycyclic indole alkaloids. This new reaction tolerated a wide range of indoles and BCBs, thereby allowing the one-step construction of various rigid indoline polycycles containing up to four contiguous quaternary carbon centers.

Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis

AbstractHerein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially available Lewis acids. The reaction proceeded through a stepwise pathway involving a nucleophilic addition of indoles to BCBs followed by an intramolecular Mannich reaction to form rigid indoline‐fused polycyclic structures, which resemble polycyclic indole alkaloids. This new reaction tolerated a wide range of indoles and BCBs, thereby allowing the one‐step construction of various rigid indoline polycycles containing up to four contiguous quaternary carbon centers.

Synthesis of Thienyl Polycyclic Fused Indoles Based on the Indium Catalyzed Prins/Friedel‐Crafts Tandem Reaction

AbstractAn indium catalyzed Prins/Friedel‐Crafts tandem cyclization reaction has been developed. This reaction provides an efficient and practical method to construct a variety of polycyclic indole frameworks with high diastereoselectivity and good functional group tolerance (30 examples, up to 98% yield with >95 : 5 dr). The resulting products are easily accessible for further chemical transformations.

Rh(III)-Catalyzed Successive C–H Activations of 2-Phenyl-3H-indoles and Cyclization Cascades to Construct Highly Fused Indole Heteropolycycles

Rh(III)-catalyzed successive C-H activations of 2-phenyl-3H-indoles and cyclization cascades with diazo compounds were developed to construct highly fused indole heteropolycycles with a broad range of substrates and good yields. In particular, this transformation included two successive C-H activations and unusual [3+3] and [4+2] sequential cyclization cascades, in which the diazo compound played a different role in the two cyclization processes, while simultaneously forming a highly fused polycyclic indole scaffold with a new quaternary carbon center.

Development of Novel Substituted 1,2,3,4-tetrahydro Cyclohex-1,2,3-trihydro Cyclopenta [B] Indole Derivatives as Potential Therapeutic Agents

Abstract: The current study aims to synthesize, characterize, and evaluate a specific class of heterocyclic compounds called fused polycyclic indoles, in combination with carbazoles, carbolines, and their partially saturated counterparts. These compounds have been known to have potent biological activity. The study's procedures involve synthesizing these compounds and evaluating them for central nervous system activity. Results showed that all the compounds had CNS-depressing effects in mice. Some compounds, such as YA1 and YA5, were found to have a stronger CNS-depressing activity than others. All compounds tested, YA1 to YA7, caused more than 50% change in locomotor activity when compared to a standard drug. YA3 and YA5 were found to have the highest activity at 86.2% and 83.9% respectively after 120 minutes of administration at a dose of 100 mg/kg. In addition, the acute oral toxicity studies showed that YA3 was non-toxic and YA5 was found to be toxic. The findings of the study provide evidence that these title compounds have good CNS activity.

One-Pot Synthesis of Polynuclear Indole Derivatives by Friedel–Crafts Alkylation of γ-Hydroxybutyrolactams

The Friedel-Crafts reaction of novel 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones was used for low cost, one-pot preparation of polycyclic indole derivatives structurally similar to Ergot alkaloids.

Visible Light-Catalyzed Synthesis of Difluoroalkylated Polycyclic Indoles

Visible Light-Catalyzed Synthesis of Difluoroalkylated Polycyclic Indoles

Visible Light Promotes Cascade Trifluoromethylation/Cyclization, Leading to Trifluoromethylated Polycyclic Quinazolinones, Benzimidazoles and Indoles

Efficient visible-light-induced radical cascade trifluoromethylation/cyclization of inactivated alkenes with CF3Br, which is a nonhygroscopic, noncorrosive, cheap and industrially abundant chemical, was developed in this work, producing trifluoromethyl polycyclic quinazolinones, benzimidazoles and indoles under mild reaction conditions. The method features wide functional group compatibility and a broad substrate scope, offering a facile strategy to pharmaceutically produce valuable CF3-containing polycyclic aza-heterocycles.

Electrochemically time-dependent oxidative coupling/coupling-cyclization reaction between heterocycles: tunable synthesis of polycyclic indole derivatives with fluorescence properties

Electrochemically time-dependent oxidative coupling/coupling-cyclization reaction between heterocycles: tunable synthesis of polycyclic indole derivatives with fluorescence properties

Chiral-Phosphoric-Acid-Catalyzed C6-Selective Pictet-Spengler Reactions for Construction of Polycyclic Indoles Containing Spiro Quaternary Stereocenters.

Compared with the well-established asymmetric Pictet-Spengler reactions on the pyrrole ring of indoles, the catalytic asymmetric Pictet-Spengler reaction on the benzene ring of indoles has been rarely studied. Herein the C6-selective Pictet-Spengler reactions of indoles have been realized by employing 2-(1H-indol-7-yl)anilines and isatins in the presence of chiral phosphoric acid, affording novel polycyclic indole derivatives bearing spiro quaternary stereocenters in excellent yields with excellent enantioselectivities. This reaction could be conducted on the gram scale without any loss of activity or enantioselectivity.

Gold-Catalyzed Domino Cycloisomerization/Alkoxylation: An Entry to 3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole.

A novel and mild synthetic route for the preparation of functionalized polycyclic indole skeletons via a gold-mediated cycloisomerization/alkoxylation of 1,6-aldehyde-yne has been developed. This atom-economical catalytic process that associates IPrAu(MeCN)BF4 and an alcohol demonstrated remarkable selectivity in accessing functionalized 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole derivatives of high synthetic utility (21 examples, yields of ≤96%) and could be optimized under asymmetric conditions with an enantiomeric excess of ≤86%.