Polyheterocyclic Compounds Research Articles

Синтез 5-амино-3-арил-1H-пиразол-4-карбонитрилов на основе гидразинов или бензгидразидов в условиях ультразвуковой активации

Pyrazoles containing amino and carbonitrile groups have a wide range of biological activities, including antimicrobial, antiinflammatory, antitumor, antioxidant, and are used to create pesticides and dyes. Also, these compounds are synthons for the preparation of various polyheterocyclic compounds. New potentially biologically active 5-amino-3-aryl-1H-pyrazole-4-carbonitriles containing pharmacophoric substituents have been obtained via three-component condensation reactions of malonic dinitrile with substituted aromatic aldehydes and benzhydrazides or hydrazines. This work considers the limits of applicability of hydrazines and hydrazides as weak nucleophiles in similar processes. The described target compounds have been synthesized using the «green chemistry» approach under ultrasonic activation in water or a mixture of water and isopropyl alcohol in the presence of triethylamine as base catalyst. The applicability of this environmentally friendly, economical and efficient approach for the synthesis of nitrogen-unsubstituted (7, 8) and N-aryl- (4, 6) or N-aroyl-substituted (1–3) pyrazole-4-carbonitriles has been demonstrated. The target pyrazole-4-carbonitrile (2) is formed and Schiff base (2’) is released as a by-product in the reaction of the weak binucleophile 3-nitrobenzhydrazide with 4-benzyloxy-3-methoxybenzaldehyde and malonic dinitrile. Step-by-step syntheses have shown that the initial reaction of a three-component interaction can be either croton condensation or the formation of a Schiff base. In any case, during subsequent heterocyclization, unstable substituted pyrazolines are formed, which aromatize to the target pyrazoles in the presence of atmospheric oxygen under synthesis conditions. The composition and structure of the products have been confirmed by elemental analysis, NMR 1H, 13C spectroscopy, HSQC, and HMBC heteronuclear correlations.

Mapping of Some Further Alkylation-Initiated Pathways to Polyheterocyclic Compounds from Indigo and Indirubin.

The reaction of indigo with two equivalents of the electrophile ethyl bromoacetate with caesium carbonate as a base result in the formation of structurally complex polyheterocyclics, including a fused spiroimidazole and a spiro[1,3]oxazino derivative, together with a biindigoid-type derivative, through a convenient one-pot reaction. Further assessment of the reaction using five equivalents of the electrophile gave rise to other molecules incorporating the 2-(7,13,14-trioxo-6,7,13,14-tetrahydropyrazino[1,2-a:4,3-a']diindol-6-yl) scaffold. The reaction of ethyl bromoacetate with the less reactive indirubin resulted in the synthesis of three derivatives of a new class of polyheterocyclic system via a cascade process, although yields were low. These compounds were derived from the parent indolo[1,2-b]pyrrolo[4,3,2-de]isoquinoline skeleton. Despite the modest yields of the reactions, they represent quick cascade routes to a variety of heterocycles from cheap starting materials, with these structures otherwise being difficult to synthesise in a traditional stepwise manner. These outcomes also contribute significantly to the detailed understanding of the indigo/indirubin cascade reaction pathways initiated by base-catalysed N-alkylation.

Ir-Catalyzed Asymmetric Hydrogenation of N-Fused Heteroarenes with High Nitrogen Density: An Access to Chiral 2,5-Disubstituted 5,6-Dihydropyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazines.

A highly enantioselective Ir-catalyzed asymmetric hydrogenation of 2,5-disubstituted pyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazines containing four nitrogen atoms has been first realized. Under additive-free conditions, a variety of chiral 2,5-disubstituted 5,6-dihydropyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazines can be afforded in high yields (86-98%) with excellent enantioselectivities of up to 99% ee. This method provides a straightforward strategy for the efficient synthesis of chiral multinitrogen polyheterocyclic compounds.

Multicomponent synthesis and photophysical properties of meso-thienyl BODIPY-pyrrolo[3,4-b]pyridin-5-ones. An experimental and theoretical study

Seven new pyrrolo[3,4-b]pyridin-5-ones linked to a meso-thienyl BODIPY moiety by an ethynylbenzene π-conjugated system were synthesized in one-pot manner via an Ugi-Zhu reaction coupled to a cascade process [aza Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration]. The photophysical properties of the polyheterocyclic compounds were evaluated by UV–Vis and fluorescence spectroscopy in five solvents of different polarities. All synthesized products showed two distinct absorption/emission bands, corresponding to both fluorophores separately. The fluorescence intensity of the pyrrolo[3,4-b]pyridin-5-one was the highest in toluene, and it decreased with increasing solvent polarity. On the other hand, the fluorescence intensity of the meso-thienyl BODIPY fragment was insensitive to solvent polarity. The effect of different substituents bonded to the pyrrole ring was evaluated, finding that strong electron-donating groups influence the fluorescence intensity and decay rate of the compounds, even with the presence of a methylene spacer. Moreover, the electronic structure was assessed by DFT and TD-DFT calculations, which reproduced the experimental results reasonably well, showing that the HOMO is located on the pyrrolo[3,4-b]pyridin-5-one core, while the LUMO is on the BODIPY fragment.

Design and Synthesis of Polyheterocyclic Compounds Containing Pyrazolopyridopyrimidine Nucleus with Antimicrobial Activities.

This study reports the design, synthesis, and antibacterial evaluation of a library of novel polyheterocyclic derivatives featuring a unique fused pyrimidopyridopyrazole moiety. A cyclocondensation reaction between an amino-pyrazolopyridopyrimidine precursor and malonates afforded a series of pyrimidopyridopyrazolopyrimidine derivatives. Further diversification was achieved through nucleophilic cyclocondensation, yielding a collection of complex polyheterocyclic systems encompassing various ring structures. All synthesized compounds were rigorously characterized using spectroscopic techniques and elemental analysis. The antibacterial activity of the newly synthesized compounds was assessed against a panel of Gram-positive and Gram-negative bacteria. Notably, several compounds exhibited promising antibacterial activity, highlighting their potential as leads for the development of novel antibiotics.

Thiol-Triggered Tandem Dearomative Michael Addition/Intramolecular Henry Reaction of 2-Nitrobenzofurans: Access to Sulfur-Containing Polyheterocyclic Compounds.

An efficient dearomative cyclization of 2-nitrobenzofurans via a thiol-triggered tandem Michael addition/intramolecular Henry reaction has been developed. A range of thiochromeno[3,2-b]benzofuran-11-ols and tetrahydrothieno[3,2-b]benzofuran-3-ols could be obtained in up to 99% yield and up to >20:1 dr. The valuable thiochromone fused benzofurans could be prepared with the reaction of 2-nitrobenzofurans and 2-mercaptobenzaldehyde via the tandem dearomative Michael addition/intramolecular Henry reaction/rearomatization/oxidative dehydrogenation process in a one-pot two-step operation. A mechanism for the reaction was tentatively proposed.

PTSA‐Catalyzed [3+2] Cycloaddition of in Situ Generated 3‐Ylidene Oxindoles with Coumarin‐Based N‐Phenyl Enamine Derivatives

AbstractBrønsted acid mediated [3+2] cycloaddition of coumarin‐based enamines with 3‐ylidene oxindoles generated in situ from 3‐hydroxy‐3‐aroylmethyl oxindoles enabled the synthesis of polyheterocyclic compounds with a pyrrolocoumarin core structure in a highly regioselective manner. The synthetic procedure is highly efficient and metal‐free, and no chromatographic purification of the products is required. The chromenopyrrole derivatives bearing an oxindole moiety formed as rapidly interconverting rotamers.

Advancements in Green Chemistry: Microwave-Assisted Synthesis of Poly-Heterocyclic Compounds in Aqueous Media

Advancements in Green Chemistry: Microwave-Assisted Synthesis of Poly-Heterocyclic Compounds in Aqueous Media

Ru(II) Catalyzed Oxidative Dehydrogenative Annulation and Spirocyclization of Isoquinolones with N‐Substituted Maleimides

AbstractA Ruthenium(II) catalyzed additive‐free oxidative, dehydrogenative annulation of different malemides on 3,4‐disubstituted isoquinolone to afford fused and spiro‐cyclized isoquinolo‐isoquinolone and isoindolo‐isoquinolone derivatives is reported here. By simply changing solvent and oxidizing agents, under two different conditions, this methodology produced two different poly‐N‐heterocyclized products. Isoquinolone‐NH was strategically used as the internal directing group in the ortho C−H activation using Ru(II) catalyst. Mechanistically dehydrogenative, oxidative C−C followed by C−N cross‐coupling and aza‐michael reaction pathway led to the corresponding fused and spiro‐products respectively. A diversified library of eighty‐one (81) such two products were synthesized by employing this methodology. The fused and the spirocyclized polyheterocyclic compounds absorbed at λmax 240–270 nm range, however only spiro‐compounds produced blue fluorescence at λem 391–450 nm range.

Design, synthesis, theoretical studies, and biological activity evaluation of new nitrogen-containing poly heterocyclic compounds as promising antimicrobial agents

The increasing threat of antibiotic resistance has led to a pressing need for the development of new antimicrobial agents. Nitrogen-containing heterocycles are widely used in the development of drugs due to their broad spectrum of pharmacological activities, including antimicrobial properties. In this study, a series of 13 hybrid molecules containing two to four nitrogen heterocycles were designed using the molecular hybridization approach. The synthesized compounds were characterized and their antimicrobial properties were examined against two bacterial strains and a Candida strain. The most promising compounds were found to be those bearing the quinoline unit, exhibiting a MIC of less than 31.25 μg/mL against S. typhimurium and Bacillus subtilis. Molecular docking studies revealed that these compounds have excellent affinity with the DNA gyrase enzyme, making them potential candidates for further development as antimicrobial agents.

Access to Polyheterocyclic Compounds through Iron(II)-Mediated Radical Cascade Cyclization Utilizing 2-Ethynylbenzaldehydes and Aryl Isonitriles.

An oxidative radical cascade addition cyclization approach for the synthesis of quinoline-based π-extended polyheterocyclic compounds is reported. Eco-friendly iron catalysis and inexpensive tert-butylhydroperoxide (TBHP) as the oxidant have been utilized in the transformation of various readily available ortho-alkynylated aromatic aldehydes as radical precursors with aryl isonitriles as radical acceptors. Indole and thiophene-based carbaldehydes allow the preparation of quinolines that are π-conjugated with an additional heteroarene moiety in a single sequence by applying the introduced method.

Cyclization of 2-Aminopyridines as Binucleophile and Mucobromic Acid as C3 Synthon: A New Access to Imidazo[1,2-a]Pyridines

Abstract: For the first time, we have developed a strategy that provides an access to imidazo[ 1,2-a] pyridines via the cyclization of 2-aminopyridine with mucobromic acid as C3 synthon. In the combination with theoretical calculation, the reaction mechanism is proposed. Background: 2-Aminopyridines are the typical pyridine α-site derivatives, which have received growing interest in using as a kind of synthons in organic synthesis and drug synthesis because of their special binucleophilic framework. Methods: All these obtained compounds were characterized by NMR. Among them, 3a was characterized by single-crystal X-ray analysis. All the theoretical calculation works were performed by Gaussian software. Results: A series of the desired compounds can be synthesized at room temperature via a mild procedure under the promotion of simple inorganic base K2CO3. Conclusion: This mild strategy fits the concept of green chemistry, providing a novel idea for the construction of nitrogen-containing polyheterocyclic compounds.

Construction of Polyheterocyclic Compounds by Lewis Acid Mediated Intramolecular [3+2] Cycloaddition Reaction

AbstractAn efficient domino approach has been developed for the synthesis of polyheterocyclic derivatives constituting pyrrole moiety. Lewis acid catalyzed reaction of 2‐substituted‐2‐hydroxy‐indane‐1,3‐diones and 1,4‐benzoxazinone derivatives resulted in the formation of polyheterocyclic compounds under metal‐free and mild conditions in good to excellent yield. The reaction is highly regioselective for C−C and C−N bond construction proceeded via intramolecular [3+2] cycloaddition reaction. The protocol is highly efficient, obviates column chromatography and the products are obtained by simple filtration followed by washing with solvent.

New poly heterocyclic compounds based on pyrimidine-2-thiones: synthesis, evaluation of putative antiviral agents, DFT calculation, and molecular modeling

Owing to the enormous increase in viral infections in recent years, novel antiviral candidates are both eagerly awaited and unquestionably essential for the treatment of a variety of deadly and incapacitating viral disorders. As a part of our program in this area, a new series of thiazolopyrimidine, pyrimidothiazine, [1,2,4]triazolopyrimidine and N-substituted pyrimidinethione 6–17 have been synthesized in good yields (82–91%) through a facile method using new pyrimidinethione 4 as a building block and several reagents as halo acids/ketones or hydrazonyl halids in one framework. By using several spectroscopic methods, including IR, 1H NMR, 13C NMR, elemental analysis, and DFT calculations, the chemical structures of the novel derivatives were confirmed. The synthetic compounds' cytotoxicity and in vitro antiviral efficacy were examined against HSV-1. Results demonstrated that compounds 6, 7b, 14b,c, and 17 have been found to have significant antiviral activity against HSV-1. Additionally, after examining compounds (6 and 7b)' mechanisms of action, we discovered that compound 6 had a virucidal effect and a mild effect on replication at higher concentrations, whereas compound 7b had activity in all three modes of action, with the virucidal effect being the most potent, followed by the replication effect, and then adsorption. In order to comprehend these results, we investigated the thermal and electrical stability of the generated compounds, where their chemical and thermal properties, dipole moment, subtraction of the highest occupied molecular orbital from the lowest unoccupied molecular orbital (HOMO-LUMO gap), and molecular electrostatic potential were computed. We also, examined the binding mechanism, binding affinity, and non-bonding contacts of the generated derivatives using molecular docking against the Herpes simplex virus type-1 thymidine kinase (PDB ID: 2KI5). A hypothetical pharmacophore model was made using the Molecular Operating Environment (MOE) tool and 10 compounds with structural resemblances to those synthesized with known antiviral activity. The current work recommends compounds 6 and 7b as potential lead structures for future research and development of novel anti-HSV-1 medicines.

Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins.

[3 + 2] Cycloaddition reactions of heteroaromatic N-ylides with electron-deficient olefins have been developed. The heteroaromatic N-ylides, in situ generated from N-phenacylbenzothiazolium bromides, can smoothly react with maleimides under very mild conditions, affording fused polycyclic octahydropyrrolo[3,4-c]pyrroles in good-to-excellent isolated yields. This reaction concept could also be extended to 3-trifluoroethylidene oxindoles and benzylidenemalononitriles as electron-deficient olefins for accessing highly functionalized polyheterocyclic compounds. A gram-scale experiment was also carried out to verify the practicability of the methodology.

Synthesis of New Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via an Ugi-Zhu/Cascade/Click Strategy.

A diversity-oriented synthesis (DOS) of two new polyheterocyclic compounds was performed via an Ugi-Zhu/cascade (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration)/click strategy, both step-by-step to optimize all involved experimental stages, and in one pot manner to evaluate the scope and sustainability of this polyheterocyclic-focused synthetic strategy. In both ways, the yields were excellent, considering the high number of bonds formed with release of only one carbon dioxide and two molecules of water. The Ugi-Zhu reaction was carried out using the 4-formylbenzonitrile as orthogonal reagent, where the formyl group was first transformed into the pyrrolo[3,4-b]pyridin-5-one core, and then the remaining nitrile group was further converted into two different nitrogen-containing polyheterocycles, both via click-type cycloadditions. The first one used sodium azide to obtain the corresponding 5-substituted-1H-tetrazolyl-pyrrolo[3,4-b]pyridin-5-one, and the second one with dicyandiamide to synthesize the 2,4-diamino-1,3,5-triazine-pyrrolo[3,4-b]pyridin-5-one. Both synthesized compounds may be used for further in vitro and in silico studies because they contain more than two heterocyclic moieties of high interest in medicinal chemistry, as well as in optics due to their high π-conjugation.

Copper-Catalyzed Asymmetric Dearomative [3+2] Cycloaddition of Nitroheteroarenes with Azomethines.

Catalytic asymmetric dearomative [3+2] cycloaddition of α-imino γ-lactones with either 3-nitroindoles or 2-nitrobenzofurans by using a chiral copper complex as the catalyst was developed. A wide range of structurally diverse polyheterocyclic compounds containing spirocyclic-fused butyrolactone-pyrrolidine-indoline and butyrolactone-pyrrolidine-dihydrobenzofuran skeletons could be smoothly obtained with excellent results (>99:1 dr and 98% ee). The potential synthetic applications of this methodology were also demonstrated by the scale-up experiment and by the diverse transformations of one product. This method is characterized by high asymmetric induction, wide functional group tolerance and scalability, and attractive product diversification.

New applications of ninhydrin in the synthesis of polyheterocyclic compounds

The review demonstrates new areas of application of ninhydrin as a universal reagent in organic synthesis for the construction of a wide range of polycyclic compounds with benzofuran, pyrroline, pyrrole, imidazole, pyrimidine, propellanic and other fragments.

Synthesis of tetracyclic 4H-benzo[5,6]chromeno[3,4-d]oxazoles via palladium-catalyzed intramolecular direct heteroarylation.

We report a palladium-catalyzed intramolecular direct heteroarylation of oxazole tethered β-naphthols to access corresponding tetracyclic 4H-benzo[5,6]chromeno[3,4-d]oxazoles. Various functional groups are well tolerated and furnished the desired products in good to excellent yields under the present reaction conditions. The scale-up reaction and synthetic utility of the resulting molecules have been demonstrated. Moreover, UV/vis absorption and fluorescence emission properties have been evaluated for these polyheterocyclic compounds.

New Applications of Ninhydrin in the Synthesis of Polyheterocyclic Compounds

New Applications of Ninhydrin in the Synthesis of Polyheterocyclic Compounds