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Herein, we describe a novel reaction between C-2-substituted indoles and 2-nitroacetophenones leading to a variety of indole-containing heterocyclic scaffolds. At 60 °C in AcOH with H 2 SO 4 as catalyst, C-2 aryl indoles give 3-(2-nitrovinyl)-indoles with high Z or E geometric selectivity depending on the type of substrate utilized. These compounds undergo an electrocyclization process in a sealed vial in a microwave apparatus in DMF at 250 °C to give benzo[ a ]carbazoles and naphtho[2,1- a ]carbazoles depending on whether the C-2 aromatic moiety is phenyl or naphthyl. Utilization of 2-methylindoles in the reaction with 2-nitroacetophenones and performing the reaction in a sealed vial in a microwave apparatus in AcOH at 200 °C leads to 1-hydroxy-β-carbolines. Selected compounds from each scaffold were tested for antiproliferative activities against MDA-MB-231 triple-negative breast cancer cells under normoxic and hypoxic conditions, and three compounds belonging to the 3-(2-nitrovinyl)-indole and 1-hydroxy-β-carboline series were identified to have single-digit micromolar IC 50 values.

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.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets.

The β-carboline motif is common in drug discovery and among numerous biologically active natural products. However, its synthetic preparation relies on multistep sequences and heavily depends on the type of substitution required in the core of the desired β-carboline target. Herein, we demonstrate that this structural motif can be accessed with the microwave-assisted electrocyclic cyclization of heterotrienic aci (alkylideneazinic acid) forms of 3-nitrovinylindoles. The reaction can start with 3-nitrovinylindoles themselves under two sets of conditions. The first one involves microwave irradiation of butanolic solutions of 3-nitrovinylindoles, whereas the second one consists of prior Boc protection of indolic nitrogen, where the protecting group cleanly comes off during the course of the reaction. Alternatively, the reaction can start with 3-nitrovinylindoles prepared in situ using various processes. Finally, the reaction may utilize indoles with β-nitrostyrenes, likely involving the intermediacy of spirocyclic oxazolines, which rearrange to similar heterotrienic systems undergoing cyclization to β-carbolines. As part of this study, several natural products, namely, alkaloids norharmane, harmane, and eudistomin N, were synthesized.

The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained β-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of various 3,5-di-aryl/heteroaryl-4-benzyl substituted α,β-unsaturated γ-hydroxy butyrolactams, which are subjects of significant interest to synthetic organic and medicinal chemistry.

A highly diastereoselective tandem reaction of 2'-nitrochalcones is reported, involving Michael addition and a subsequent ipso -substitution of the nitro group to produce 1-tetralones with two contiguous chiral centers. A related annulation reaction of 2'-nitrochalcones with potassium cyanide affording 1-indanones with a C3-quaternary chiral center is also demonstrated.

A novel, low-cost method for the preparation of not easily accessible free 3-aminoindoles has been developed. This approach is based on a well-established reaction between indoles and nitrostyrene in the presence of phosphorous acid, which results in the formation of 4'-phenyl-4'H-spiro[indole-3,5'-isoxazoles]. The latter could be transformed to corresponding aminated indoles by reaction with hydrazine hydrate in good or excellent yields upon microwave-assisted heating.

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.

The purpose of this work was to prepare new isatin- and monothiomalondiamide-based indole derivatives, as well as to study the properties of the new compounds. The four-component reaction of 5-R-isatins (R = H, CH 3 ), malononitrile, monothiomalonamide (3-amino-3-thioxo- propanamide) and triethylamine in hot EtOH yields a mixture of isomeric triethylammonium 6'-amino-3'-(aminocarbonyl)-5'-cyano-2-oxo-1,2-dihydro-1' H - and 6'-amino-3'-(aminocarbonyl)- 5'-cyano-2-oxo-1,2-dihydro-3' H -spiro[indole-3,4'-pyridine]-2'-thiolates. The reactivity and structure of the products was studied. We found that oxidation of spiro[indole-3,4'-pyridine]-2'-thiolates with DMSO-HCl system produced only acidification products, diastereomeric 6'-amino-5'-cyano-5-methyl-2-oxo-2'-thioxo-1,2,2',3'-tetrahydro-1'H-spiro-[indole-3,4'-pyridine]- 3'-carboxamides, instead of the expected isothiazolopyridines. The alkylation of the prepared spiro[indole-3,4'-pyridine]-2'-thiolates upon treatment with N-aryl α-chloroacetamides and α-bromoacetophenones proceeds in a regioselective way at the sulfur atom. In the case of α-bromoacetophenones, ring-chain tautomerism was observed for the S-alkylation products. According to NMR data, the compounds consist of a mixture of stereoisomers of 2'-amino-6'-[(2-aryl-2-oxoethyl)thio]-3'-cyano-2-oxo-1'H-spiro[indoline-3,4'-pyridine]-5'-carboxamides and 5'-amino-3'-aryl-6'-cyano-3'-hydroxy-2-oxo-2',3'-dihydrospiro[indoline-3,7'-thiazolo[3,2-a]pyridine]-8'-carboxamides in various ratios. The structure of the synthesized compounds was confirmed by IR spectroscopy, HRMS, 1 H and 13 C DEPTQ NMR studies and the results of 2D NMR experiments ( 1 H- 13 C HSQC, 1 H- 13 C HMBC). Molecular docking studies were performed to investigate suitable binding modes of some new compounds with respect to the transcriptional regulator protein PqsR of Pseudomonas aeruginosa . The docking studies revealed that the compounds have affinity for the bacterial regulator protein PqsR of Pseudomonas aeruginosa with a binding energy in the range of -5.8 to -8.2 kcal/mol. In addition, one of the new compounds, 2'-amino-3'-cyano-5-methyl-2-oxo-6'-{[2-oxo-2-(p-tolylamino)ethyl]thio}-1'H-spiro-[indoline-3,4'-pyridine]-5'-carboxamide, showed in vitro moderate antibacterial effect against Pseudomonas aeruginosa and good antioxidant properties in a test with 1,1-diphenyl-2-picrylhydrazyl radical. Finally, three of the new compounds were recognized as moderately active herbicide safeners with respect to herbicide 2,4-D in the laboratory experiments on sunflower seedlings.

A straightforward three-step procedure affording a wide range of novel 7-aryl substituted paullone derivatives was developed. This scaffold is structurally similar to 2-(1 H -indol-3-yl)acetamides-promising antitumor agents-hence, could be useful for the development of a new class of anticancer drugs.

The reaction between dithiomalondianilide (N,N'-diphenyldithiomalondiamide) and alkyl 3-aryl-2-cyanoacrylates in the presence of morpholine in the air atmosphere leads to the formation of alkyl 6-amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]- pyridine-5-carboxylates in 37-72% yields. The same compounds were prepared in 23-65% yields by ternary condensation of aromatic aldehydes, ethyl(methyl) cyanoacetate and dithiomalondianilide. The reaction mechanism is discussed. The structure of ethyl 6-amino-4-(4-methoxyphenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylate was confirmed by X-ray crystallography. Two of the prepared compounds showed a moderate growth-stimulating effect on sunflower seedlings. Three of the new compounds were recognized as strong herbicide safeners with respect to herbicide 2,4-D in the laboratory and field experiments on sunflower.

The Michael addition reaction between dithiomalondianilide (N,N'-diphenyldithiomalondiamide) and arylmethylidene Meldrum's acids, accompanied by subsequent heterocyclization, was investigated along with factors affecting the mixture composition of the obtained products. The plausible mechanism includes the formation of stable Michael adducts which, under the studied conditions, undergo further transformations to yield corresponding N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthio-carbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolates and their oxidation derivatives, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones. The structure of one such product, N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate, was confirmed via X-ray crystallography.

Unusual cascade transformation involving ring opening and 1,2-alkyl shift was observed upon the reduction of 4' H -spiro[indole-3,5'-isoxazoles] or 2-(3-oxoindolin-2-yl)acetonitriles with sodium borohydride. This reaction allowed for expeditious and highly efficient preparation of 2-(1 H -Indol-3-yl)acetamides with antiproliferative properties.

Microwave-assisted reaction between 2-(3-oxoindolin-2-yl)-2-phenylacetonitriles andbenzene-1,2-diamines leads to the high-yielding formation of the corresponding quinoxalines as sole, easily isolaable products. The featured transformation involves unusual extrusion of phenylacetonitrile molecule and could be performed in a short sequence starting from commonly available indoles and nitroolefins.

A highly efficient and expeditious one-pot approach towards 2-(3-oxoindolin-2-yl)acetonitriles was designed, which involves a base-assisted aldol reaction of ortho -nitroacetophenones, followed by hydrocyanation, triggering an unusual reductive cyclization reaction.

A facile and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)acetonitriles from 4-(2-aminophenyl)-4-oxo-2-phenylbutanenitriles is described. The featured transformation operates via nucleophilic intramolecular cyclization and involves oxidation of the aniline moiety. Overall, this modification allowed for the improvement of yields and expansion of the reaction scope., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

3-(1 H -Indol-3-yl)benzofuran-2(3 H )-ones were efficiently accessed via polyphosphoric acid-mediated condensation of 3-(2-nitrovinyl)-1 H -indoles with phenols.

Base-assisted transformations of 2-(3-oxoindolin-2-yl)acetonitriles were investigated. Unexpectedly, attempted reactions of substrates possessing nonprotected nitrogen atoms were accompanied by unusual extrusions of 2-arylacetonitriles, followed by a 1,2-aryl shift to afford 3-hydroxyindolin-2-ones. On the other hand, the reactions for N -alkyl derivatives of oxoindolines took the expected route by only providing 1,2,3,3a,4,8b-hexahydropyrrolo[3,2- b ]indoles.

trans -2-Amino-4-aryl-5-benzoyl-4,5-dihydrothiophene-3-carbonitriles were prepared either by the reaction of 3-aryl-2-cyanothioacrylamides with α-thiocyanatoacetophenone or by the Michael-type addition of cyanothioacetamide to α-bromochalcones followed by intramolecular cyclization. The mechanism of the first reaction was studied using high-level quantum chemical calculations. Density functional theory (DFT) studies were carried out to determine the mechanism of the first reaction. A new approach toward the construction of the thieno[2,3-d]pyrimidine core system was demonstrated by the reaction of the prepared dihydrothiophenes with HCHO and RNH 2 under noncatalyzed Mannich conditions., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

The mechanistic rationale involving activation of nitroalkanes towards interaction with nucleophilic reagents in the presence of polyphosphoric acid (PPA) was re-evaluated. Could nitrile oxide moieties be formed during this process? This experiment demonstrates that at least in some cases this could happen, as generated nitrile oxides were successfully intercepted as adducts of [3 + 2] cycloadditions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The recently discovered [4+1]-spirocyclization of nitroalkenes to indoles provided a convenient new approach to 2-(1 H -indol-2-yl)acetonitriles. However, this reaction was complicated by the formation of inert 3-(2-nitroethyl)-1 H -indole byproducts. Herein, we offer a workaround this problem that allows for effective transformation of the unwanted byproducts into acetonitrile target molecules.

Nitroalkanes activated with polyphosphoric acid could serve as efficient electrophiles in reactions with amines and hydrazines, enabling various cascade transformations toward heterocyclic systems. This strategy was developed for an innovative synthetic protocol employing simultaneous or sequential annulation of two different heterocyclic cores, affording [1,2,4]triazolo[4,3- a ]quinolines with 1,3,4-oxadiazole substituents.

Nitroalkanes activated with polyphosphoric acid serve as efficient electrophiles in reactions with various nucleophilic amines. Strategically placed second functionality allows for the design of annulation reactions enabling preparation of various heterocycles. This strategy was employed to develop an innovative synthetic approach towards 3,4-dihydroquinazolines from readily available 2-(aminomethyl)anilines.

Noncatalyzed, regio- and stereoselective hypochlorite oxidation of 3-aminothieno[2,3- b ]pyridine-2-carboxamides is presented. Unexpectedly, the oxidation proceeded by different mechanistic pathways, and different products were formed, depending on the nature of solvents used. A possible mechanism, the structure of products, kinetics and dynamics of intramolecular processes, and biological activity of products are discussed., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

A convenient preparative method is developed allowing for expeditious assembly of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2 H -pyrrol-2-ones from routinely available inexpensive synthetic precursors. These compounds could not be prepared via the previously known protocols, as 2-aminofuran derivatives were produced instead., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Brønsted acid-assisted spirocyclization allowed for preparation of 4' H -spiro[indole-3,5'-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4'-alkylsubstituted derivatives hardly available by other means., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

An efficient and straightforward Brønsted-acid mediated cascade process was developed, involving cyclization of readily available β-ketonitriles into 2-aminofurans, and their subsequent recyclization into 2-(1 H -indol-2-yl)acetamides is developed. This synthetic route opens a new avenue for an expeditious assembly of various isotryptamine derivatives for medicinal chemistry.

An original, facile, and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)acetonitriles from ortho -nitrochalcones is described. The featured transformation is a triggered Michael addition of the cyanide anion to the chalcone followed by a cascade cyclization mechanistically related to the Baeyer-Drewson reaction., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Unusual reactivity of nitroalkanes, involving formation of aci-forms (nitronic acids or nitronates) and their subsequent interaction with carbon-based nucleophiles, is surveyed in this review., (Copyright © 2020 Aksenov, Aksenov, Ovcharov, Aksenov and Rubin.)

A novel synthetic methodology for the assembly of imidazolines via an unusual reaction between nitroalkanes and aliphatic 1,2-diamines in the presence of phosphorous acid is described. In contrast to the related highly efficient preparation of benzimidazoles from aromatic amines, this process represents a major synthetic challenge and for a long time was elusive. Analysis of the method limitations is provided., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Recently discovered reactivity of nitrostyrenes in phosphorous acid to facilitate the diastereoselective [4 + 1]-cycloaddition of indoles in combination with unusual oxazoline ring cleavage and subsequent 1,2-alkyl shift afforded stereochemically defined 2-(3-oxoindolin-2-yl)-2-arylacetonitriles as sole products.

An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4' H-spiro[indole-3,5'-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.

A novel methodology for general and chemoselective preparation of non-symmetric 1,3,4-oxadiazoles is developed. This unusual reaction proceeds via polyphosphoric acid-assisted activation of nitroalkanes towards nucleophilic attack with acylhydrazides., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A second generation polyphosphoric acid-mediated one-pot three-component synthesis of indoloquinoline scaffold is developed. This improved version of the process involves electrophilically activated nitroalkanes for the installation of strategic C-C and C-N bonds and ring C assembly. This modification allows the elimination of unnecessary solvent change operations and all steps are carried out in a true, uninterrupted one-pot manner. A further improvement involves the possibility to install an ortho -amino group in situ . A synthetic application of this method is showcased by the concise synthesis of an isocryptolepine alkaloid and its synthetic analogs with potent anticancer activities., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A strain-release-driven, cation-templated intramolecular nucleophilic addition of tethered alkoxides to prochiral cyclopropenes is described. Employment of chiral β- and γ-amino alkoxides allowed for highly diastereoselective assembly of a small series of enantiopure cyclopropane-fused oxazepanones. It was shown that the chiral center at C-4 plays a crucial role in controlling desymmetrization of the cyclopropenyl moiety, instigated by a profound potassium-templated effect. The preliminary biological activities of the new cyclopropane-fused medium heterocycles against Gram-positive bacteria, Gram-negative bacteria, mycobacteria, cancer cells, and fungus were evaluated.

Indolo[3,2-c]quinolones have been efficiently synthesized via an acid-mediated, one-pot, three-component condensation of arylhydrazines, o-aminoacetophenones, and triazines or nitriles. The synthetic application of this method is showcased by the concise synthesis of isocryptolepine alkaloid and a series of its synthetic analogues with demonstrated cancer cell antiproliferative activities.