Synthesis Of Indoles Research Articles

Activity and Biocatalytic Potential of an Indolylamide Generating Thioesterase.

The chemical synthesis of N-acyl indoles is hindered by the poor nucleophilicity of indolic nitrogen, necessitating the use of strongly basic reaction conditions that encumber elaboration of highly functionalized scaffolds. Herein, we describe the total chemoenzymatic synthesis of the bulbiferamide natural products by the biochemical activity reconstitution of a nonribosomal peptide synthetase assembly line-derived (NRPS-derived) thioesterase that neatly installs the macrocyclizing indolylamide. The enzyme represents a starting point for biocatalytic access to macrocyclic indolylamide peptides and natural products.

Indole Synthesis through Intramolecular Heck Reaction with in situ Generated Pd Nanoparticles in PEG

Indole Synthesis through Intramolecular Heck Reaction with in situ Generated Pd Nanoparticles in PEG

Rhodium Catalysts Based on Phenyl Substituted Cp Ligands for Indole Synthesis via Oxidative Coupling of Acetanilides and Alkynes

AbstractRhodium‐catalyzed oxidative coupling of acetanilides and alkynes via C−H activation is the most powerful synthetic tool for producing the indole motif from commercially available precursors. However, this reaction usually requires large catalyst loadings (5 mol% of rhodium). In this study, a 1,2‐diphenylcyclopentadienyl ligand‐based catalyst was developed that works well at 1 mol% loading of rhodium. DFT calculations of the C−H activation step provided insight into its high catalytic activity. The catalyst efficiency was also demonstrated in the synthesis of naturally occurring isocoumarins, such as polygonolide, tubakialactone B and penicimarine F. The developed catalytic protocols tolerate a wide range of functional groups, for example, halide, nitro, hydroxy, and alkoxy.

Novel Organosulfur Building Blocks for Heterocycle Synthesis

AbstractThe present article provides a personalized account of our recent work on the synthesis of substituted and fused five-membered heterocycles using various organosulfur building blocks, derived primarily through base-mediated condensation of active methylene compounds with (het)aryl/alkyl dithioesters, which have not been previously explored. We initially describe the ring-opening transformations of 4-[(methylthio)-(het)aryl-methylene]-2-phenyl-5-oxazolones, leading to the synthesis of functionalized oxazoles, thiazoles, and bisoxazoles. We then go on to focus on the synthesis of substituted benzothiophenes, indoles, and benzofurans, as well as their hetero-fused analogs. These compounds are synthesized via transition-metal-catalyzed intramolecular C–heteroatom (C–S, C–N, C–O) bond formation (via cross-coupling or C–H bond functionalization) of various reactive organosulfur intermediates, derived from base-mediated condensation of 2-bromo(het)arylacetonitriles, acetates, or desoxybenzoins or the corresponding 2-unsubstituted precursors. Finally, we highlight the synthetic applications of a new class of previously unexplored organosulfur building blocks, namely, unsymmetrically substituted 1,3-bis(het)aryl-1,3-monothioketones, derived via base-mediated condensation of ketones with (het)aryl/alkyl dithioesters, for the regioselective synthesis of substituted pyrazoles, isoxazoles, thiophenes, imidazoles, and benzothiophenes.1 Introduction2 4-[(Methylthio)-het(aryl)-methylene]-2-phenyl/2-(2-thienyl)-5-oxazolones: Versatile Templates for the Synthesis of Oxazoles, Thiazoles, and Bisoxazoles3 Synthesis of Benzothiophenes, Indoles, and Benzofurans via Transition-Metal-Catalyzed Intramolecular C–Heteroatom Bond Formation4 1,3-Bis(het)arylmonothio-1,3-diketones and 1,3-Bis(Het)aryl-3-(methylthio)-2-propenones: Versatile Intermediates for the Regioselective Synthesis of Five-Membered Heterocycles5 Conclusion

Synthesis, characterization, computational studies and anti-inflammatory activity evaluation of some new indole substituted aryl ethers

A number of anti-inflammatory drugs with an aryl-ether part, such as Nimesulide and Rofecoxibs, have been shown to damage cells and kill liver cells. Keeping in view this rationale, the present work was aimed at synthesising new indole-substituted aryl ethers and evaluating their anti-inflammatory effects, which have minimal side effects. New indole substituted aryl ethers were synthesised. Spectral characterisation of these newly synthesised compounds was done using infrared (IR), proton nuclear magnetic resonance (1H NMR), and carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy techniques. Further, In-silico studies were performed with an aim to evaluate the suitability of synthesised compounds as potential bioactive candidates for anti-inflammatory activity. The synthesised compounds were subjected to anti-inflammatory activity evaluation using the carrageenan-induced rat paw edema model. Primarily, the chemical reaction completion was ensured using TLC and M.P. Further, the structures of all synthesised compounds were confirmed by the results of spectra characterization. Results of in-silico study exhibited the docking of compounds on target proteins. On the basis of experimental findings, it was concluded that compound AG-1 (N-(1H-indol-3yl) methylene)-4-phenoxyaniline) is the most potent anti-inflammatory compound amongst all the newly synthesised compounds. Findings of the present study concluded that AG-1 could be used as a viable new lead bioactive compound to serve as a potent candidate for a new anti-inflammatory drug. The novelty of the present work resides in the simplest way of synthesis, a good docking score, and excellent anti-inflammatory potential when evaluated in vivo.

Rhodium(III)-Catalyzed Atroposelective Indolization to Access Planar-Chiral Macrocycles.

Macrocycles incorporating conformationally defined indoles are widely found in bioactive natural products. However, the catalytic enantioselective synthesis of planar-chiral indoles via indolization involving macrocyclization remains elusive. Herein, we present the first rhodium(III)-catalyzed atroposelective macrocyclization, which involves the C-H activation of aniline, and a subsequent oxidation [3 + 2] annulation reaction with an intramolecular alkyne. This protocol achieves the construction of indoles, macrocyclization, and planar chirality control in a single step. Importantly, this strategy produces macrocyclic atropisomers bearing full-carbon ansa chains, which represent challenging targets in organic synthesis. Thermodynamic experiments revealed that the rotational barrier of the full-carbon ansa chain-linked macrocyclic atropisomer was lower than that of the atropisomer bearing an oxa-ansa chain. The reaction mechanism was elucidated by computational studies, which revealed that the C-H activation and intramolecular alkyne insertion steps collectively determined the enantioselectivity.

Ligand-Controlled Selective Synthesis of Indoles and Benzofurans from Secondary Anilines.

A ligand-controlled method for the selective synthesis of indoles and benzofurans from secondary anilines has been discovered. A six-ring palladacycle intermediate may be involved in this process by olefins as a transient directing mediator to give indoles. The indole/benzofuran ratio can be easily tuned by the MPAA ligand. Various substituted secondary anilines were well-tolerated, affording the corresponding products in moderate to good yields. Indole-derived drugs such as JWH-081, BB-22, and ML-098 could be obtained using our new method to achieve their precursors. Preliminary mechanistic studies indicated that BQ is the key factor in avoiding the β-H elimination of insertion species.

Synthesis and pharmacological study of novel indole based derivates as potential anti-cancer agents

Synthetic chemistry is an important tool for the development of the potent molecules against various ailments. Indole moiety plays a very crucial in the heterocyclic medicinal chemistry, especially in the treatment of the cancer. Vincristine and Vinblastine are two important naturally occurring molecules already used for the treatment of the cancer. In the current study, we first initially synthesised the 11 indole-based derivatives and then further put under the in-vitro cancer cell lines. From all the synthesised compounds, the molecule SS-1H emerged out as the most potent molecule especially against the mouse fibrosarcoma cell lines. This compound can further be modified for the development of a molecule.

Azide‐Induced Furan Ring Opening for the Synthesis of Functionalized Indoles

We explored the reactivity of various furans towards 2‐azidobenzaldehydes, heterocyclic azidoaldehydes, or substituted 2‐azidobenzyl alcohols to form 2‐(2‐azidobenzyl)furan derivatives, unveiling the remarkable compatibility of the azide group with conditions typical of Friedel‐Crafts reactions. Moreover, we demonstrated that compounds of this type can be successfully synthesized by diazotization/azidation sequence from 2‐(2‐aminobenzyl)furans bearing electron‐donating substituents, while effectively circumventing undesired side reactions. Additionally, we presented a synthetic methodology for the preparation of 2‐(2‐acylvinyl)indoles, that involves thermal generation of nitrenes to initiate furan ring opening. Remarkably, our approach entails a nonconjugated configuration of the azidoaryl group and the furan ring, setting it apart from classical indole syntheses. The broad applicability and high efficiency of our method, which utilizes readily available starting materials, underscore its versatility as a synthetic tool of significant promise.

Photocatalytic PPh3-Mediated Synthesis of C3-Functionalized Indoles via Radical Annulation of Nitroarenes and Alkenes.

Oxidatively generated phosphine radical cations are reactive intermediates that can be used for the generation of carbon and heteroatom centered radicals via deoxygenation processes. Such P-radical cations can readily be generated via single electron transfer oxidation using a redox catalyst. Cheap and commercially available nitroarenes are ideal nitrogen sources for the construction of organic amines and N-containing heterocycles. Activation of nitroarenes with phosphines has been achieved in the ionic mode, which requires specially designed P-nucleophiles and high temperatures. Herein, we report an alternative mode of nitro activation that proceeds via a radical process. The radical strategy leads to open shell intermediates that show interesting unexplored reactivity. This is documented by the development of an economic and highly efficient synthesis of valuable indole derivatives through photocatalytic PPh3-mediated annulation of nitroarenes with alkenes showing large functional group tolerance. The method allows room-temperature activation of nitroarenes and a double C-H bond functionalization of alkenes is achieved to provide rapid access to C3-functionalized indoles, which are key structural components of diverse natural and drug molecules. Experimental mechanistic studies that are further supported by DFT calculations indicate that a nitrosoarene radical cation plays a key role in the annulation process.

Computational Design, Chemical Synthesis, and Bioevaluation of Pyrimidinyl‐Indoles for Targeting Breast Cancer Cells

AbstractCancer is a global health challenge, despite significant advancements in research. Addressing this issue, we report the design, synthesis and biological evaluation of pyrimidinyl indoles as potential antineoplastic agents. Pyrimidinyl indoles interact with pyruvate kinase isoform M2 (PKM2), which is commonly overexpressed in oral, lung, breast and colorectal cancers. In silico studies indicated that these molecules are having affinity towards PKM2 and targeting key residues such as Phe26, Leu27, Tyr390, Gln393, Leu394 and Glu397 at the interfacial active site region between the two chains of PKM2. Thereafter compounds were designed, synthesized and characterized using nuclear magnetic resonance (NMR), infrared spectroscopy (IR) and mass spectrometry (MS). This was followed by in vitro screening using cell lines and enzyme‐coupled assays. One of the designed PKM2 inhibitor demonstrated potent anticancer activity against MCF‐7 (Breast Cancer) cells while sparing normal MCF‐10 A breast cells. Molecular dynamics (MD) simulation studies showed that the developed inhibitor stabilized the PKM2 active site over a 100 ns simulation.

Synthesis of Non-canonical Tryptophan Variants via Rh-catalyzed C-H Functionalization of Anilines.

Tryptophan and its non-canonical variants play critical roles in pharmaceutical molecules and enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long-standing challenge. Here, we report a regioselective synthesis of non-canonical tryptophans bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc)-protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc-directed C-H metalation and demetalation to afford a wide range of C2-unsubstituted indole products in a redox-neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non-canonical tryptophan residues in a highly regioselective manner.

Synthesis of Tumor Selective Indole and 8-Hydroxyquinoline Skeleton Containing Di-, or Triarylmethanes with Improved Cytotoxic Activity.

The reaction between glycine-type aminonaphthol derivatives substituted with 2- or 1-naphthol and indole or 7-azaindole has been tested. Starting from 2-naphthol as a precursor, the reaction led to the formation of ring-closed products, while in the case of a 1-naphthol-type precursor, the desired biaryl ester was isolated. The synthesis of a bifunctional precursor starting from 5-chloro-8-hydroxyquinoline, morpholine, and ethyl glyoxylate via modified Mannich reaction is reported. The formed Mannich base 10 was subjected to give bioconjugates with indole and 7-azaindole. The effect of the aldehyde component and the amine part of the Mannich base on the synthetic pathway was also investigated. In favor of having a preliminary overview of the structure-activity relationships, the derivatives have been tested on cancer and normal cell lines. In the case of bioconjugate 16, as the most powerful scaffold in the series bearing indole and a 5-chloro-8-hydroxyquinoline skeleton, a potent toxic activity against the resistant Colo320 colon adenocarcinoma cell line was observed. Furthermore, this derivative was selective towards cancer cell lines showing no toxicity on non-tumor fibroblast cells.

Eco-friendly Synthesis of Indole Conjugated Chromeno[d]Pyrimidines as Anti-cancer Agents and their Molecular Modelling Studies

Introduction: Many medicinally active new chemical entities depend on indole conjugated chromeno[d]pyrimidine derivatives as a building block. The synthesis of 4-(1H-indol-3-yl)-3,4- dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione 4 were achieved in the current study by treating 4- hydroxy-2H-chromen-2-one 1, indole aldehydes 2, and urea/thiourea 3 in the presence of L-proline. Methods: By adopting the above protocol, we were able to synthesize eight compounds, i.e. 4-(1Hindol- 3-yl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-diones (4a-4h), in the presence of Lproline as a catalyst in ethanol as solvent for 2-3 hours at 70-75°C with decent yields of 80-85%, and their structures were ascertained by various spectral techniques. They were further screened for their potentiality to inhibit cancer growth in HepG2 and MDA-MD-231 cells. Results: The scope of the synthesis of biological relevant Indole conjugated Chromeno[ d]Pyrimidines by three-component reaction (MCRs) process was investigated. The most optimised conditions obtained were 0.3 eq of L-proline for 2 hours at 70-75°C which gave the best yield (85%). The few advantages of this newly developed method are excellent yields, no metal catalyst, less toxic solvents, simple workup no chromatographic column purifications. On further screening for their anticancer activities, out of all, the compound 4b displayed noteworthy cytotoxicity with IC50 values of 8.1 and 9.2 μM against HepG2 and MDA-MD-231, respectively. Additionally, in silico studies also supported that compound 4b had favourable binding energy (-7.8 kcal/mol) when compared to the co-crystal ligand (LS5) in inhibiting the human cyclin-dependent kinase 2 (CDK2) protein. Conclusion: In conclusion, we have developed a simple, convenient, and efficient method for the synthesis of structurally diverse indole conjugated chromeno[d]pyrimidine analogues in the presence of L-proline as catalyst in ethanol as solvent with good yields. Further, the in vitro cytotoxic studies against HepG2 and MDA-MD-231 cells demonstrated that the synthesized compounds had good to reasonable activity, except for compound 4d.

Transition metal-free efficient synthesis of bis(indolyl)propynes (BIPs).

A transition metal-free approach has been devised for the synthesis of a variety of bis(indolyl)propyne (BIP) derivatives. The strategy involves an iodine-catalyzed cascade condensation of α,β-unsaturated acetylenic aldehydes with diversely substituted indoles. The strategy was applicable to gram scale synthesis and a library of 50 molecules, which were afforded in good to excellent yields (up to 96%), was developed. The salient features of the reaction involve the synthesis of indole based privileged scaffolds in a short reaction time under transition metal-free conditions, with a wide substrate scope and excellent yields under ambient conditions.

Genome-wide epigenetic dynamics of tea leaves under mechanical wounding stress during oolong tea postharvest processing

Understanding the epigenetic responses to mechanical wounding stress during the postharvest processing of oolong tea provides insight into the reprogramming of the tea genome and its impact on tea quality. Here, we characterized the 5mC DNA methylation and chromatin accessibility landscapes of tea leaves subjected to mechanical wounding stress during the postharvest processing of oolong tea. Analysis of the differentially methylated regions and preferentially accessible promoters revealed many overrepresented TF-binding motifs, highlighting sets of TFs that are likely important for the quality of oolong tea. Within these sets, we constructed a chromatin accessibility-mediated gene regulatory network specific to mechanical wounding stress. In combination with the results of the TF-centred yeast one-hybrid assay, we identified potential binding sites of CsMYC2 and constructed a gene regulatory network centred on CsMYC2, clarifying the potential regulatory role of CsMYC2 in the postharvest processing of oolong tea. Interestingly, highly accessible chromatin and hypomethylated cytosine were found to coexist in the promoter region of the indole biosynthesis gene (tryptophan synthase β-subunit, CsTSB) under wounding stress, which indicates that these two important epigenetic regulatory mechanisms are jointly involved in regulating the synthesis of indole during the postharvest processing of oolong tea. These findings improve our understanding of the epigenetic regulatory mechanisms involved in quality formation during the postharvest processing of oolong tea.

Metal-Free, PPA-Mediated Fisher Indole Synthesis via Tandem Hydroamination-Cyclization Reaction between Simple Alkynes and Arylhydrazines.

A new variant of Fisher indole synthesis involving Bronsted acid-catalyzed hydrohydrazination of unactivated terminal and internal acetylenes with arylhydrazines is reported. The use of polyphosphoric acid alone either as the reaction medium or in the presence of a co-solvent appears to provide the required balance for activating the C-C triple bond towards the nucleophilic attack of the hydrazine moiety without unrepairable reactivity loss of the latter due to competing amino group protonation. Additionally, the formal hydration of acetylenes to the corresponding ketones occurs under the same conditions, making it an alternative approach for generating carbonyl groups from alkynes.

Synthesis of 3‐CF3‐Indoles from HFO‐1234ze(E) via Cross‐Coupling and Intramolecular Cyclization

AbstractThe synthesis of indoles with a trifluoromethyl group has attracted a lot of attention because they are promising structural subunits for pharmaceuticals and agrochemicals. As part of our project aimed toward the upcycling of hydrofluoroolefins (HFOs), we developed a method to construct a CF3‐bearing indole ring system through the Suzuki–Miyaura cross‐coupling of a brominated HFO‐1234ze(E) (CF3CH=CHF) with N‐tosylated o‐borylanilines, followed by nucleophilic 5‐endo‐trig cyclization at the vinylic position of the generated fluorostyrenes. We found that the Pd2(dba)3/SPhos catalyst system in the presence of K2CO3 and water in toluene afforded the corresponding 3‐CF3‐indoles in high yields in a one‐pot operation.

Efficient one-pot synthesis of 3-arylmethyl indoles promoted by (Bu3Sn)2MoO4 as a reusable catalyst

Efficient one-pot synthesis of 3-arylmethyl indoles promoted by (Bu3Sn)2MoO4 as a reusable catalyst

A Cascade Synthesis of Indoles.

We report herein an expedient method for the regioselective synthesis of indoles from o-haloanilines and α-ketol-derived N-tosylhydrazones. This two-step, modular synthesis of N-H indoles can be carried out conveniently without purification of intermediates.