Aza Heterocycles Research Articles

Synthesis and Antimalarial Evaluation of New 1,3,5-tris[(4-(Substituted-aminomethyl)phenyl)methyl]benzene Derivatives: A Novel Alternative Antiparasitic Scaffold

A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay.

Iodine-Promoted Oxidative Cyclization of Acylated and Alkylated Derivatives from Epoxides toward the Synthesis of Aza Heterocycles.

A new method for directly synthesizing acylated and alkylated quinazoline derivatives by the epoxide ring-opening reaction in the presence of I2/DMSO with 2-aminobenzamide is described herein. The developed mild protocol is efficient and displays a wide variety of functional group tolerance and substrate-controlled high selectivity, and the application of a continuous flow technique allows for faster reaction time and higher yields. Moreover, the robustness of the method is applicable in gram-scale synthesis.

Visible light mediated organocatalytic dehydrogenative aza-coupling of 1,3-diones using aryldiazonium salts.

An efficient protocol for diazenylation of 1,3-diones under photoredox conditions is presented herein. C-N bond forming Csp3 -H functionalization of cyclic and alkyl diones by unstable aryl diazenyl radicals is achieved through reaction with aryldiazonium tetrafluoroborates by organocatalysts under visible light irradiation. The reaction has wide substrate scope, gives excellent yields, and is also efficient in water as a green solvent. This method provides an easy access to aryldiazenyl derivatives that are useful key starting materials for the synthesis of aza heterocycles as well as potential pharmacophores.

A Direct and Divergent Entrance to Aza Heterocycles On 3‐Amino Carbazole

AbstractThe product‐switchable reagent‐controlled construction of 1,4‐Dihydropyridines and stereo‐structured amino dienes decorated with carbazole moieties have been realized via coupling of 3‐amino‐9‐ethylcarbazole with benzaldehyde and methyl propiolate. Highly functionalized pyrido[3,2‐b]carbazoles have been concisely synthesized in good yields via Et3N promoted single‐pot assembly of 3‐amino‐9‐ethylcarbazole with aryl/heteroaryl aldehydes and α‐aryl‐3‐oxopropanenitrile. The structures of the synthesized products were confirmed by spectral data and elemental analysis.

A ring expansion strategy towards diverse azaheterocycles.

The development of innovative strategies for the synthesis of N-heterocyclic compounds is an important topic in organic synthesis. Ring expansion methods to form large N-heterocycles often involve the cycloaddition of strained aza rings with π bonds. However, in some cases such strategies suffer from some limitations owing to the difficulties in controlling the regioselectivity and the accessibility of specific π-bond synthons. Here, we report the development of a general ring expansion strategy that involves a formal cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring ketones through synergistic bimetallic catalysis. These formal cross-dimerizations of two different strained rings are efficient and scalable, and provide a straightforward and broadly applicable means of assembling diverse N-heterocycles, such as 3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active compounds. Preliminary mechanistic studies revealed that the C-C bond of strained ring ketones is first cleaved by the Pd0 species during the reaction.

Recent approaches in the organocatalytic synthesis of pyrroles.

Organocatalysis has emerged as one of the most important tools for the synthesis of diverse structural scaffolds, and has become one of the most important hot topics of current research. Construction of the pyrrole ring has gained much attention from the last few decades due to its remarkable biological activities, pharmaceutical application, intermediate in the synthesis of many natural products, and material science application. With access to these 5-membered aza heterocycles, organocatalytic approaches have provided a new alternative from the perspective of synthetic efficiency, as well as from the green chemistry point of view, and a vast array of synthetic procedures has been developed. Enlightened by the significance of this growing research area, we aim to describe the recent organocatalytic approaches developed for the construction of pyrroles, and organized them based on substrates employed.

Iron-Catalyzed Hydrogen Transfer Reduction of Nitroarenes with Alcohols: Synthesis of Imines and Aza Heterocycles.

A straightforward and selective reduction of nitroarenes with various alcohols was efficiently developed using an iron catalyst via a hydrogen transfer methodology. This protocol led specifically to imines in 30-91% yields, with a good functional group tolerance. Noticeably, starting from o-nitroaniline derivatives, in the presence of alcohols, benzimidazoles can be obtained in 64-72% yields when the reaction was performed with an additional oxidant, DDQ, and quinoxalines were prepared from 1,2-diols in 28-96% yields. This methodology, unprecedented at iron for imines, also provides a sustainable alternative for the preparation of quinoxalines and benzimidazoles.

Vinyl sulfone-modified carbohydrates: Michael acceptors and 2π partners for the synthesis of functionalized sugars and enantiomerically pure carbocycles and heterocycles.

Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since CS bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.

Crystal, Hirshfeld, ADMET, drug-like and anticancer study of some newly synthesized imidazopyridine containing pyrazoline derivatives

To steer the selection of a potent drug, computer models have been fostered as a valid alternative to reduce pharmacokinetics related failure. The present study mainly focuses on the relationship between molecular properties and anticancerous activity of some newly synthesized aza heterocycles. Twelve new imidazo[1,2-a]pyridine incorporated pyrazoline derivatives were synthesized and were well characterized by 1HNMR, 13CNMR, LC-MS analysis. X-ray study resolved the structure of 4g, 4i and 4j as monoclinic crystal system. To quantify the electrostatic potential distribution and percentage intermolecular contacts in crystal packing, Hirshfeld surface study was performed. Moreover, virtual screening focused on ADMET and drug-like attributes to identify a promising derivative among the series. The anticancerous activity of the compounds was evaluated against A549 cell line. The study was further validated by subjecting best active compounds to induced hemolysis, which finally confirmed 4j as a potent molecule both in computational and in vitro study.

Sulfur‐Catalyzed Oxidative Coupling of Dibenzyl Disulfides with Amines: Access to Thioamides and Aza Heterocycles

AbstractIn the presence of catalytic amounts of elemental sulfur, dibenzyl disulfide/DMSO was found to be an excellent thiobenzoylating agent of amines to provide a wide range of thioamides. The reaction becomes autocatalytic when anilines substituted by an o‐cyclizable group were used as nucleophile, leading to the corresponding 2‐aryl aza heterocycles.magnified image

Antimicrobial Evaluation of New Synthesized Aza Heterocycles

The Pd-precatalyst was found to exhibit high catalytic activity for C-C bond formation in Suzuki-Miyaura cross-coupling reactions of differentheteroaryl (5-bromo-2-bromoacetyl) thiophene,4- (5-bromothiophen-2-yl)-methyl-1,3-thiazole,isoquinolinium bromide salt) with either aryl or heteroarylboronic acids. All reactions in this study were conducted in water under thermal heating as well as microwave irradiation conditions. The antimicrobial activities of synthesized compounds were evaluated against eight different strains of microorganisms (four fungal strains, two Gram-positive bacteria and two Gram-negative bacteria) using a cup plate diffusion method. The results showed that, most of the 20 tested compounds exhibited varying degrees of antimicrobial activities. However, 6 compounds recorded high antifungal activity (? 20 mm zone of inhibition), 3 were antibacterial (against Gram-positive) and 4 showed high broad-spectrum antibacterial efficacy (against Gram-positive and Gram-negative). These bioactive compounds are recommended for further pharmacological and toxicological investigations for possible formulation as wide spectrum antibacterial and antifungal agents.

Synthesis of pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered to 1,2,3-triazoles and their evaluation as potential anticancer agents

A series of hybrid aza heterocycles containing pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered to 1,2,3-triazole scaffold were synthesized from 1,3-dipolar cycloaddition reaction of pyrazolopyrimidinone based alkyne with azides using Cu(II) catalyst in presence of sodium ascorbate and evaluated for their anticancer efficacy in vitro against C6 rat and U87 human glioma cell lines. These compounds induced a concentration dependent inhibition of C6 rat and U87 human glioma cell proliferation. Compound 5f arrested the cells at S-phase of the cell cycle and induced apoptosis in U87 GBM cell lines. Further, apoptosis was evidenced by the cleavage of Caspase-3, PARP and up regulation of p53. In silico docking studies reveal that the compounds 5a, 5f and 5l were more effective in binding with TGFBR2 than other compounds.

The new green procedure for pyrazolopyrimidinone based dihydropyrimidinones and their antibacterial screening

A series of novel hybrid aza heterocycles containing pyrazolopyrimidinone and dihydropyrimidinone scaffolds was developed using Cu(II) catalyzed Biginelli condensation as an efficient, new green synthetic method under mild and solvent free conditions. Pyrazolopyrimidinone based aldehydes, alkyl acetoacetates and urea/thiourea were used as the components in the reaction to afford hybrid aza heterocycles in high to excellent yields. The products were screened for in vitro antibacterial activity and all of those demonstrated high to excellent activity.

Design, Synthesis and Anticancer Activity of Aza Heterocycles Containing Gallate Moiety (Part III)

Our previously reported compound, 3-(2-hydroxy-3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (1), was allowed to react with acetophenone, ethyl cyanoacetate and/or malononitrile to give the corresponding compounds 2a, 2b and 2c, respectively. Treatment of compounds 2b and 2c with thiourea afforded thiopyrimidine derivatives 3a and 3b, respectively. The coupling of 3a and 3b with 2′,3′,4′,6′-tetra-O-acetyl-_-D-glucopyranosyl bromide (4) afforded compounds 5a and 5b, respectively. Reaction of compound 2c with acetophenone yielded pyridone derivative 6, which was fused in pyridine hydrochloride to give demethylated product 7. The coupling of compound 6 with some cyclic and acyclic halosugars afforded various N-glycoside derivatives (8, 9, 11, 13, and 14). New compounds were tested for their antitumor activity on MCF-7 human breast adenocarcinoma cell line and HepG2 liver carcinoma cell line. Almost all tested compounds exhibited antitumor activity, especially 4-(3-(2-hydroxy-3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-phenyl-1,2-dihydro-pyridine-3-carbonitrile (6) which displayed the most potent inhibitory activity with IC50 = 2.97 and 2.67 g/mL against MCF-7 and HepG2 cell lines, respectively. Compound 6 was tested for its acute toxicity (lethal dose) and found to have very low toxicity based on LD50 values (no label > 600 < 2000 mg/kg) as recommended by the Organization for Economic Co-operation and Development.

First synthesis of pyrrolylpyridines from alkynes and isothiocyanates

Pyrroles [1, 2], pyridines [3, 4], and their hydrogenated derivatives are fundamental life-sustaining aza heterocycles with broad spectra of biological activity and practical applications. This stimulates extensive studies in the field of chemistry of these compounds and increasing interest of not only synthetic chemists [5, 6] but also biologists, pharmacologists, medics [7–9], materials scientists, and other specialists [10–12]. Obviously, a combination of pyrrole and pyridine rings in a single molecule could enhance their intrinsic useful properties and give rise to new ones. As we showed previously [13–16], thermally induced 6π-electrocyclization of conjugated azatriene systems, in particular of 2-aza-1,3,5-trienes obtainable in one preparative step from lithiated allenes and aliphatic isothiocyanates, smoothly produces 6-(alkylsulfanyl)-2,3-dihydropyridines, some of which (depending on the nature and position of substituents in the dihydropyridine ring) undergo further aromatization [15]. For instance, 2-methoxy-6-(methylsulfanyl)-2,3dihydropyridines are quantitatively transformed into 2-(methylsulfanyl)pyridines via elimination of methanol molecule in the presence of aqueous HCl under mild conditions (Et2O, ~35°C, 1.5–2 h) [16]. While developing studies in this line, we have found that the reaction of 1,3-dilithiated 1-methyl-2(prop-2-ynyl)-1H-pyrrole (1) with isothiocyanates, namely methoxymethyl isothiocyanate, offers a simple and convenient synthetic approach to previously unknown and difficultly accessible via conventional methods 2-methoxy-5-(1-methyl-1H-pyrrol-2-yl)-6-(methylsulfanyl)-2,3-dihydropyridine (2) and 3-(1-methyl-1Hpyrrol-2-yl)-2-(methylsulfanyl)pyridine (3). The primary adduct, methyl N-methoxymethyl-2-(1-methyl1H-pyrrol-2-yl)buta-2,3-dienimidothioate (4, 1-aza1,3,4-triene) at ~30°C undergoes isomerization through [1,5]-H shift into methyl N-[2-(1-methyl-1Hpyrrol-2-yl)-1-(methylsulfanyl)buta-1,3-dien-1-yl]methanimidate (5, 2-aza-1,3,5-triene), and electrocyclization of the latter yields 2,3-dihydropyridine 2. Distillation of 2 was accompanied by its partial thermally induced aromatization with elimination of methanol to give a mixture of dihydropyridine 2 and pyridine 3 at a ratio of 6 : 4 to 3 : 7. It was surprising that 2,3-dihydropyridine 2 was readily transformed into pyridine 3 at room temperature in the presence of a strong base, t-BuOK, in DMSO (10 min). The reaction was characterized by a slight heat evolution (the mixture spontaneously warmed up to 30°C). 3-(1-Methyl-1H-pyrrol-2-yl)pyridine (3) was isolated in 24% yield (calculated on the initial pyrrole 1; the conditions were not optimized). It should be noted that most known syntheses of pyridines from dihydropyridines refer to 1,2and 1,4-dihydropyridines whose aromatization is generally achieved via oxidation [17]. Except for a few our early publications [13–16], there are almost no published data on the synthesis and reactivity of 2,3-dihydropyridines, including their aromatization [18, 19]. 2-Methoxy-5-(1-methyl-1H-pyrrol-2-yl)-6-(methylsulfanyl)-2,3-dihydropyridine (2). a. A solution of 100 mmol of butyllithium in 40 mL of hexane was added under vigorous stirring at –100°C in an argon atmosphere to a solution of 5.96 g (46.7 mmol, with account taken of 93.4% purity) of 1-methyl-2-(prop2-ynyl)-1H-pyrrole (1) in 110 mL of THF. The cooling ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 1, pp. 132–135. © Pleiades Publishing, Ltd., 2015. Original Russian Text © N.A. Nedolya, O.A. Tarasova, A.I. Albanov, B.A. Trofimov, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 1, pp. 134–136.

ChemInform Abstract: Stereoselective Domino Azidation and [3 + 2] Cycloaddition: A Facile Route to Chiral Heterocyclic Scaffolds from Carbohydrate Derived Synthons.

A rapid one pot intermolecular aryl azidation and intramolecular azide-olefin cycloaddition protocol has been designed using carbohydrate precursors to generate optically active, aziridine fused oxa–aza heterocycles, related to DNA targeting anti-tumour agents which on further functionalization stereoselectively produce eight membered heterocyclic scaffolds. The structural conclusions were fully supported by a molecular modelling study based on density functional theory.

Intramolecular Schmidt reaction of tert-butyl 3-(3-azidopropyl)-4-oxopiperidine-1-carboxylate as a synthetic route to saturated fused aza heterocycles

Treatment of the title compound with trifluoroacetic acid induced intramolecular Schmidt reaction with formation of a saturated fused heterocyclic system, tert-butyl 5-oxo-2,3,4,5,7,8,9,9a-octahydro-1H-pyrrolo[1,2-a][1,4]-diazepine-2-carboxylate. The latter was reduced with lithium tetrahydridoaluminate, and subsequent treatment with hydrogen chloride in dioxane gave 2,3,4,5,7,8,9,9a-octahydro-1H-pyrrolo[1,2-a][1,4]-diazepine dihydrochloride which is a promising intermediate product for the synthesis of N-substituted diazepines with a fused pyrrole ring.

Tautomerism of Aza heterocycles: V. Structure of the spontaneous transformation products of 5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo-[4,3-c]pyridin-3-one in crystal and solution

5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one exists as zwitterion with a proton localized on the nitrogen atom of the piperidine ring and negative charge delocalized over the pyrazololate fragment. The compound is stable in crystal but ustable in solution. Its chromatographic purification and attempts to recrystallize or synthesize by condensation of phenylhydrazine with alkyl 1-methyl-4-oxopiperidin-3-carboxylate on heating in alcohols or benzene lead to the formation of a complex mixture of products. Among these products, we isolated and identified 3a,3a′-methylenebis(5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one), 1-methyl-3-(2-phenylhydrazinylidene)pyrrolidin-2-one, and 5-methyl-2-phenyl-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. The structure of methyl 3-(2-phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-carboxylate and 3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was proved by NMR spectroscopy. 3a,5-Dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was isolated as hydrochloride hydrate whose structure was determined by X-ray analysis.

Aza-Diels-Alder Reaction: An Efficient Approach for Construction of Heterocycles

Aza heterocycles comprise some rousing structures in biological systems. The aza-Diels-Alder reaction is a [4Π +2Π] cycloaddition, involving a nitrogen atom in either diene or dienophile or both for the generation of unsaturated N-hexacycles. Although aza- Diels-Alder reaction has made a wonderful journey through different stages of development it is still considered as one of the hot topics of research because of procedural simplicity, high atom economy, regio- and stereoselectivity. Building blocks of many pharmaceutically as well as pharmacologically vital heterocycles have come out as a result of application of aza-Diels-Alder protocol in numerous chemical reactions. This review article describes the state of the art of the aza-Diels-Alder reactions highlighting some of the very first discovery of this pericyclic reaction to most important modern developments. Our discussion is highly focused on awesome versions of aza- Diels-Alder reaction under selected and magnificent catalytic systems and, will provide readers an overview on versatility of this special branch of Diels-Alder reaction towards the creation of a flood of N-containing molecules.

ChemInform Abstract: Nucleophilic Substitution of Azide Acting as a Pseudo Leaving Group: One‐Step Synthesis of Various Aza Heterocycles.

AbstractIt is found that 3‐azidopropanoic acid reacts with carbodiimides to afford a six‐membered ring intermediate.