Reaction of Pyrrolobenzothiazines with Schiff Bases and Carbodiimides: Approach to Angular 6/5/5/5-Tetracyclic Spiroheterocycles.

1H-Pyrrole-2,3-diones, fused at [e]-side with a heterocycle, are suitable platforms for the synthesis of various angular polycyclic alkaloid-like spiroheterocycles. Recently discovered sulfur-containing [e]-fused 1H-pyrrole-2,3-diones (aroylpyrrolobenzothiazinetriones) tend to exhibit unusual reactivity. Based on these peculiar representatives of [e]-fused 1H-pyrrole-2,3-diones, we have developed an approach to an unprecedented 6/5/5/5-tetracyclic alkaloid-like spiroheterocyclic system of benzo[d]pyrrolo[3',4':2,3]pyrrolo[2,1-b]thiazole via their reaction with Schiff bases and carbodiimides. The experimental results have been supplemented with DFT computational studies. The synthesized alkaloid-like 6/5/5/5-tetracyclic compounds have been tested for their biotechnological potential as growth stimulants in the green algae Chlorella vulgaris.

Approach to Pyrido[2,1-b][1,3]benzothiazol-1-ones via In Situ Generation of Acyl(1,3-benzothiazol-2-yl)ketenes by Thermolysis of Pyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones.

Acyl(imidoyl)ketenes are highly reactive heterocumulenes that enable diversity-oriented synthesis of various drug-like heterocycles. Such ketenes, bearing heterocyclic substituents, afford angularly fused pyridin-2(1H)-ones in their [4+2]-cyclodimerization reactions. We have utilized this property for the development of a new synthetic approach to pharmaceutically interesting pyrido[2,1-b][1,3]benzothiazol-1-ones via the [4+2]-cyclodimerization of acyl(1,3-benzothiazol-2-yl)ketenes generated in situ. The thermal behaviors of 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones and 3-benzoylpyrrolo[2,1-b][1,3]benzothiazole-1,2-dione (two new types of [e]-fused 1H-pyrrole-2,3-diones reported by us recently) have been studied by thermal analysis and HPLC to elucidate their capability to be a source of acyl(1,3-benzothiazol-2-yl)ketenes. As a result, we have found that only 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones are suitable for this. The experimental results are supplemented with computational studies that demonstrate that thermolysis of 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones proceeds through an unprecedented cascade of two thermal decarbonylations. Based on these studies, we discovered a novel mode of thermal transformation of [e]-fused 1H-pyrrole-2,3-diones and developed a new pot, atom, and step economic synthetic approach to pyrido[2,1-b][1,3]benzothiazol-1-ones. The synthesized drug-like pyrido[2,1-b][1,3]benzothiazol-1-ones are of interest to pharmaceutics, since their close analogs show significant antiviral activity.

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles.

Pyrrolo[2,1-b][1,3]benzothiazoles are an important class of fused sulfur and nitrogen-containing heterocycles intensively studied in medicinal chemistry and pharmacology. In the present paper, a new synthetic approach to pyrrolobenzothiazoles is developed based on 1,4-thiazine ring contraction in 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones under the action of nucleophiles. The proposed approach works well with alkanols, benzylamine, and arylamines. The scope and limitations of the developed approach are studied. The synthesized pyrrolobenzothiazole derivatives represent an interest to pharmaceutics, since their close analogs show CENP-E inhibitory activity, interesting for the targeted cancer therapy development.

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles.

There has been developed an easy synthetic approach to spiro[dihydrofuran-2,3'-oxindoles] via a highly diastereoselective formal [4 + 1] cycloaddition reaction of [e]-fused 1H-pyrrole-2,3-diones with diazooxindoles. The described novel heterocyclic systems are heteroanalogues of antimicrobial and antibiofilm fungal metabolites. The developed reaction represents the first example of involving 1H-pyrrole-2,3-diones fused at the [e]-side in a [4 + 1] annulation reaction.

Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines.

4-Acyl-1H-pyrrole-2,3-diones fused at [e]-side with a heterocyclic moiety are suitable platforms for the development of a hetero-Diels-Alder-reaction-based, diversity-oriented approaches to series of skeletally diverse heterocycles. These platforms are known to react as oxa-dienes with dienophiles to form angular 6/6/5/6-tetracyclic alkaloid-like heterocycles and are also prone to decarbonylation at high temperatures resulting in generation of acyl(imidoyl)ketenes, bidentate aza- and oxa-dienes, which can react with dienophiles to form skeletally diverse products (angular tricyclic products or heterocyclic ensembles). Based on these features, we have developed an approach to two series of skeletally diverse 4H-1,3-oxazines (tetracyclic alkaloid-like 4H-1,3-oxazines and 5-heteryl-4H-1,3-oxazines) via a hetero-Diels-Alder reaction of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side with cyanamides. The products of these transformations are of interest for drug discovery, since compounds bearing 4H-1,3-oxazine moiety are extensively studied for inhibitory activities against anticancer targets.

Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones.

The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides.

Novel Approach to the Synthesis of 3-amino-4-arylpyridin-2(1H)-one Derivatives.

The reaction of 4-arylidene-2-phenyloxazol-5(4H)-ones with enamines of ethyl acetoacetate gave 4-aryl-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylic acid esters, which, when heated with phosphorus oxychloride, were converted into esters of 7-aryl-5-methyl-2-phenyloxazolo[5,4-b]pyridine-6-carboxylic acids. Alkaline hydrolysis of these compounds gave 4-aryl-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,6-dihydropyridine-3-carboxylic acid esters. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10593-021-02980-w.

Synthesis, in vitro antibacterial activity against Mycobacterium tuberculosis, and reverse docking-based target fishing of 1,4-benzoxazin-2-one derivatives.

Seventeen 1,4-benzoxazin-2-ones bearing the enaminone moiety and three of their analogs were tested for the antibacterial activity against Mycobacterium tuberculosis (H37Rv). Minimal bactericidal concentrations (MBCs) were determined after 41 days of incubation by BACTEC. 1,4-Benzoxazin-2-ones bearing the unsubstituted benzo moiety showed the most promising activities (MBC = 5.00 µg/ml). For most active compounds, antibacterial activities were determined daily during the 41 days. The most promising compound showed a bacteriostatic effect at a concentration of 0.31 µg/ml on Day 4 of incubation, 0.62 µg/ml on Day 6, 2.50 µg/ml on Day 9, and 5.00 µg/ml on Day 41. All studied compounds, along with some of their reported analogs, were docked to 35 proteins of M. tuberculosis to find their potent targets in these organisms. As a result of reverse docking, aspartate 1-decarboxylase, panD, was selected as the most appropriate target. Docking of the most active compounds to mutant panD from pyrazinamide-resistant strains of M. tuberculosis implies that they would not be active against these strains. Considering that most of pyrazinamide clinical resistance cases are due to loss-of-function mutations in pyrazinamidase, pncA, compounds from this study could be useful drugs for the treatment of some cases of pyrazinamide-resistant tuberculosis.

Cycloaddition of Huisgen 1,4-dipoles: synthesis and rapid epimerization of functionalized spiropyrido[2,1-b][1,3]oxazine-pyrroles and related products.

1,4-Dipolar cycloaddition has emerged as a powerful tool for the synthesis of various cyclic compounds. In the present work, 1H-pyrrole-2,3-diones are proposed as new dipolarophiles for 1,4-dipolar cycloaddition. Their [4 + 2] cycloaddition with dipoles generated from dimethyl acetylenedicarboxylate and pyridine was found to proceed regioselectively affording spiro[pyrido[2,1-b][1,3]oxazine-2,3'-pyrroles] as diastereomeric mixtures which exist in rapid equilibrium in solution. It was established that this phenomenon of rapid epimerization is a characteristic of other similar spiropyrido[2,1-b][1,3]oxazines and even related spiroquinolizines, which was demonstrated by the investigation of related products of previously reported, and reproduced in this work, 1,4-dipolar cycloaddition reactions.

Synthesis of 1,4-benzothiazinones from acylpyruvic acids or furan-2,3-diones and o-aminothiophenol.

Two synthetic approaches to enaminones fused to 1,4-benzothiazin-2-one moiety, which can be interesting in studies on biological activity, chemosensors, and fluorescence, were developed via the reaction of furan-2,3-diones or acylpyruvic acids in the presence of carbodiimides with o-aminothiophenols. The target enaminones were formed together with pharmaceutically interesting 2-hydroxy-2H-1,4-benzothiazin-3(4H)-ones. A selective synthetic approach to 2-hydroxy-2H-1,4-benzothiazin-3(4H)-ones was developed via the solvent-switchable reaction of furan-2,3-diones with o-aminothiophenol. Preliminary biological assays (antimicrobial, acute toxicity) of the new compounds were carried out.

Crystal structures, packing features, Hirshfeld surface analyses and DFT calculations of hydrogen-bond energy of two homologous 8a-aryl-2,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidin-6(1H)-ones.

The crystal structures and packing features of two homologous Meyer's bicyclic lactams with fused pyrrolidone and medium-sized perhydropyrimidine rings, namely, 8a-phenyl-2,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidin-6(1H)-one, C13H16N2O (1), and 8a-(4-methylphenyl)-2,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidin-6(1H)-one, C14H18N2O (2), were elucidated, and Hirshfeld surface plots were calculated and drawn for visualization and a deeper analysis of the intermolecular noncovalent interactions. Molecules of 1 and 2 are weakly linked by intermolecular C=O...H-N hydrogen bonds into chains, which are in turn weakly linked by other C=O...H-Car interactions. The steric volume of the substituent significantly affects the crystal packing pattern.

Dipyrazolodioxadiazocines as shelf-stable "ready-to-use" precursors for an in situ generation of enolate-iminium 1,4-dipoles: a straightforward atom-economical approach to pyrazolo[5,1-d][1,3,5]dioxazines.

An original, facile and highly efficient method for the in situ generation of cyclic enolate-iminium 1,4-dipoles via unique thermal decomposition of easily available dipyrazolodioxadiazocines has been developed. Various substituted pyrazolo[5,1-d][1,3,5]dioxazines have been prepared in high yields via unusual cycloconversion of dipyrazolodioxadiazocines in the presence of ketones. Furthermore, the developed method is 100% atom economical and proceeds under metal-, catalyst- and solvent-free conditions.

Facile regiodivergent synthesis of spiro pyrrole-substituted pseudothiohydantoins and thiohydantoins via reaction of [e]-fused 1H-pyrrole-2,3-diones with thiourea.

A highly divergent synthesis of regioisomeric thiohydantoins and pseudothiohydantoins spiro-fused to a pharmacologically valuable pyrrole-2-one fragment involving the reaction of [e]-fused 1H-pyrrole-2,3-diones with thioureas was developed. The obtained spiro pseudothiohydantoin derivatives were found to undergo a pseudothiohydantoin-thiohydantoin rearrangement. The reactions were shown to proceed under catalyst-free conditions in good yields, and the products were isolated without applying preparative chromatography methods.

Synthesis of meta-substituted anilines via a three-component reaction of acetone, amines, and 1,3-diketones.

A facile method for the synthesis of meta-substituted arylamines from acyclic precursors was developed. This method is based on three-component cyclo-condensation/aromatization of in situ generated imines of acetone with 1,3-diketones either under conventional heating or under microwave irradiation. The utility of this methodology is illustrated by the possibility of a gram scale synthesis of various anilines from readily available reagents.

Annulation of 1H-pyrrole-2,3-diones by thioacetamide: an approach to 5-azaisatins.

A novel approach to 1H-pyrrolo[3,2-c]pyridine-2,3-diones (5-azaisatins) has been developed via an unprecedented annulation of pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones by thioacetamide. A new way of C-H functionalization of thioacetamide has been discovered. The reaction proceeds under green catalyst-free conditions.

Synthesis, modification, and cytotoxic evaluation of 2,3-secotriterpenic ß-ketoesters.

A set of ß-ketoesters was synthesized from 2,3-seco-18αH-oleanane and 2,3-secolupane bromomethyl ketones. Additionally, hydroxy derivatives with the A-seco- or five-membered A ring were obtained as a result of the reduction or of alkaline hydrolysis of acetic acid ß-ketoesters 4, 9. Cytotoxic screening revealed the compound 4 with marked activity (IC50 3.07-3.61 µM) against the HCT 116, MS, RD TE32 cancer cells. The studies of the cytotoxic mechanism enabled elucidating the fact that treatment of the HCT 116 cells with compound 4 for 18 h leads to induction of apoptosis in a dose-dependent manner. This observation was confirmed by registration of chromatin condensation, by the fluorescence increased during Annexin V-FITC staining, and by appearance of a sub-G0 peak in the cell cycle analysis with DAPI. Compound 4 also inhibited migration of cancer cells in the wound healing assay.

Synthesis of pyrimido[1,6-a]quinoxalines via intermolecular trapping of thermally generated acyl(quinoxalin-2-yl)ketenes by Schiff bases.

Acyl(quinoxalin-2-yl)ketenes generated by thermal decarbonylation of 3-acylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones react regioselectively with Schiff bases under solvent-free conditions to form pyrimido[1,6-a]quinoxaline derivatives in good yields.

Regiodivergent condensation of 5-alkoxycarbonyl-1H-pyrrol-2,3-diones with cyclic ketazinones en route to spirocyclic scaffolds.

The condensation of 5-alkoxycarbonyl-1H-pyrrolediones with cyclic ketazinones was systematically investigated. It was discovered that the regioselectivity of this reaction can be easily swapped between two alternative directions affording derivatives of partially hydrogenated indole or benzofurane. The control of this regioselectivity is efficiently governed by steric effects at the hydrazone moiety of the ketazinone reagent.