Nitrogen Heterocyclic Systems Research Articles

Application of LFER to the N(1)-H Acidities of Five-Membered Nitrogen Heterocyclic Ring Systems: A Review on Graduate Chemical Education Exercise

Abstract: An attempt is made for the first time in our laboratory to apply the Hammett and Taft equations to the five-membered heterocyclic ring systems pyrroles, pyrazoles, imidazole, and triazoles. It is shown that the pKa values of N(1)-H acidities of 3-X-pyrroles, 3-Xpyrazole, 4-X-pyrazole, 4-X-imidazole, 3-X-1,2,4-triazole and 4-X-1,2,3-triazole correlated well with Hammett σ values.

Five-Membered Hetarene N-Oxides: Recent Advances in Synthesis and Reactivity

AbstractFive-membered heterocyclic N-oxides attract special attention due to their significant potential applications in medicinal chemistry and advanced materials science. In this regard, novel methods for their synthesis and functionalization are in constant demand. In this short review, recent state-of-the-art achievements in the chemistry of isoxazoline N-oxides, 1,2,3-triazole 1-oxides and 1,2,5-oxadiazole 2-oxides are summarized. The main routes involving transition-metal-catalyzed and metal-free functionalization protocols along with mechanistic considerations are outlined. The transformations of these hetarene N-oxide rings as precursors to other nitrogen heterocyclic systems are also presented.1 Introduction2 Isoxazoline N-Oxides3 1,2,3-Triazole 1-Oxides4 1,2,5-Oxadiazole 2-Oxides5 Conclusion

From Alkynes to Heterocycles through Metal-Promoted Silylformylation and Silylcarbocyclization Reactions

Oxygen and nitrogen heterocyclic systems are present in a large number of natural and synthetic compounds. In particular, oxa- and aza-silacyclane, tetrahydrofuran, benzofuran, cycloheptadifuranone, cycloheptadipyrrolone, pyrrolidine, lactone, lactam, phthalan, isochromanone, tetrahydroisoquinolinone, benzoindolizidinone, indoline and indolizidine scaffolds are present in many classes of biologically active molecules. Most of these contain a C=O moiety which can be easily introduced using carbonylative reaction conditions. In this field, intramolecular silylformylation and silylcarbocyclization reactions may afford heterocyclic compounds containing a carbonyl functional group together with a vinylsilane moiety which can be further transformed. Considering these two aspects, in this review a detailed analysis of the literature data regarding the application of silylformylation and silylcarbocyclization reactions to the synthesis of several heterocyclic derivatives is reported.

Synthesis of a New Series of Nitrogen/Sulfur Heterocycles by Linking Four Rings: Indole; 1,2,4-Triazole; Pyridazine; and Quinoxaline.

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2–6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7–16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7–13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19–25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.

Heteroannulated Coumarins and Chromones from Chemical Transformations of 6,8‐Dimethylchromone‐3‐carbonitrile

A novel series of heterocyclic systems fused coumarins and chromones were efficiently synthesized from chemical transformations of 6,8‐dimethylchromone‐3‐carbonitrile (1) with a variety of carbon nucleophilic reagents. Ring opening ring closure reactions of carbonitrile 1 with cyanoacetohydrazide, malononitrile dimer (2‐aminoprop‐1‐ene‐1,1,3‐tricarbonitrile), and isomeric cyclohexanediones led to a diversity of coumarins and chromones fused nitrogen heterocyclic systems. Also, 1‐ethyl‐4‐hydroxyquinolin‐2(1H)‐one (13) and 6‐ethyl‐4‐hydroxypyrano[3,2‐c]quinoline‐2,5(6H)‐dione (14) are chemical equivalent towards carbonitrile 1 leading to benzo [h]chromeno[2,3‐b][1, 6] naphthyridine derivative 15. Structures of the new synthesized products were deduced on the basis of their analytical and spectral data.

Synthesis and chromatographic applications of polysiloxane-based stationary phase containing nitrogen heterocyclic system

In this work, a novel kind of stationary phase called 2,5-diphenyl-3,4-bis(pyridin-2-yl) phenyl grafted polysiloxane (DPPP, containing 16.0% 2,5-diphenyl-3,4-bis(pyridin-2-yl) phenyl group) was synthesized and statically coated inside fused-silica capillary column. The thermo-stability of DPPP was evaluated by thermogravimetric analysis (TGA) and the result indicated that DPPP did not decompose slightly until 380 °C. The chromatogram of the polyethylene pyrolysis products showed that the upper working temperature of the DPPP column was about 370 °C. The column efficiency of the DPPP column was 3500–3800 plates/m. McReynolds contants of the DPPP revealed that its polarity was moderate. Abraham system contants revealed that H-bond basicity was the major interaction of DPPP, followed by dipole-induced dipole interaction and dispersion force. In particular, compared to DB-17 column, the DPPP showed superiority on separating pyridine derivatives, aromatic aldehydes, and fatty alcohols.

Photochemistry of 1,4-Dihydropyridine Derivatives: Diradical Formation, Delocalization and Trapping as a Route to Novel Tricyclic and Tetracyclic Nitrogen Heterocyclic Ring Systems.

Irradiation of an acetonitrile solution of 4-aryl-3,5-dibenzoyl-1,4-dihydropyridine derivatives 1a–c and maleimides 2a–c using medium pressure Hg-arc lamp (λ > 290) nm afforded three different cycloadducts 4, 5, 6 in addition to the oxidation products 3. These results indicate that compounds 1a–c undergoes intermolecular cycloaddition reaction through three biradical intermediates and behave photochemically different than those reported previously for the analogous 3,5-diacetyl and 3,5-dicarboxylic acid derivatives. The present work also offers simple access to novel tricyclic and tetracyclic nitrogen heterocyclic ring systems of potential biological and synthetic applications. The structure of the photoproducts was established spectroscopically and by single crystal X-ray crystallography.

Synthesis and pharmacological evaluation of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles: A condensed bridgehead nitrogen heterocyclic system

A series of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a–j and 5a–d) were synthesized by condensation of 4-amino-5-diphenylmethyl-4H-1,2,4-triazole-3-thiol with various substituted aromatic acids and aryl/alkyl-isothiocyanates. The structures of synthesized compounds were characterized by elemental analysis, IR, 1H NMR, 13C NMR and mass spectroscopic studies. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic, lipid peroxidation and hepatotoxic effects. Compounds 6-(4-chlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (4a) and 6-(2,4-dichlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole(4c) emerged as the most active compounds of the series and were moderately more potent than the standard drug ibuprofen.

Facile Synthesis of Derivatives of 1,1,3‐Trioxo‐2H,4H‐pyrrolo[1,2‐b][1,2,4,6]thiatriazine: A New Heterocyclic System

ABSTRACTWe reported a facile and efficient methodology to synthesize derivatives of pyrrolo[1,2‐b][1,2,4,6]thiatriazine (PTTD): a new bridgehead nitrogen heterocyclic system. Treatment of methyl pyrrole‐2‐carboxylate with N‐benzylsulfamoyl chlorides followed by subsequent hydrolysis reaction afforded 1‐benzylsulfamoyl‐1H‐pyrrole‐2‐carboxylic acids, which underwent ring‐closing reaction by treatment with diphenyl phosphorazidate via Curtius rearrangement; subsequent alkylation reaction afforded the desired 2,4‐disubstituted‐1,1,3‐trioxo‐2H,4H‐PTTDs.

Three-Component Reaction: Synthesis, Characterization, and Biological Study of Some Fused Bridgehead Nitrogen Heterocyclic Systems Containing 4-Methylthiophenyl Moiety

Several substituted thiazolo-[3,2-b]-1,2,4-triazole derivatives 4 were synthesized by a one-pot, three-component reaction of 3-(4-methylthiobenzyl)-1,2,4-triazole-5-thiol 3, substituted 5-aryl-furan-2-carboxaldehydes/substituted aromatic aldehydes, and monochloroacetic acid in acetic acid using acetic anhydride and anhydrous sodium acetate. Compound 3 was obtained from 4-methylthiophenyl acetic acid by esterification followed by hydrazinolysis. All structures of the newly synthesized compounds were elucidated by elemental analysis and spectral data. The newly synthesized compounds were also screened for their antimicrobial and anti-inflammatory activities.Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.GRAPHICAL ABSTRACT

Synthesis of Polycyclic Benzofused Nitrogen Heterocycles via a Tandem Ynamide Benzannulation/Ring-Closing Metathesis Strategy. Application in a Formal Total Synthesis of (+)-FR900482

A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+)-FR66979 is described.

Synthesis and antimicrobial activity of chromone-linked 2-pyridone fused with 1,2,4-triazoles, 1,2,4-triazines and 1,2,4-triazepines ring systems

Three series of novel fused nitrogen heterocyclic systems such as 1,2,4-triazolo[1,5-α ] pyridines (5-7 and 9), pyrido[1,2-b][1,2,4]triazines (10, 11, 13 and 15), and pyrido[1,2-b][1,2,4]triazepines (17, 18, 20 and 22) linked with a chromone moiety were synthesized from the key intermediate 1,6-diamino-(6-chloro-4-oxo-4H-chromen-3-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4) with some electrophilic reagents. The structures of the novel compounds were established by elemental analyses and spectral data. All the products were also screened invitro for their antimicrobial activity. Compounds 7, 9 and 15 showed the highest activities when compared with the reference drugs.

Recent CB1 cannabinoid receptor antagonists and inverse agonists

AbstractAntagonists or inverse agonists of the cannabinoid CB1 receptor (CB1R) reported from the 2006–2007 period are reviewed. The compounds are either variations of the archetypical cannabinoid CB1 inverse agonist rimonabant (SR141716) or are other structures less obviously related to the archetype. Many of the former class replace the core pyrazole ring of rimonabant with other ring systems to display/arrange the appended binding/activity elements. A structure‐activity relationship evolves from bioassays of these compounds that also provides a more detailed understanding of the molecular mechanism of the binding to and stabilization of the active and inactive states of the constitutively active CB1R. In addition to diverse variations of the core ring and appended substituents, conformationally constrained analogs with high affinity were revealed, a number of which do not fit a one‐to‐one atom correspondence with the putatively active conformations of the rimonabant template and other active analogs. Diphenylmethyl analogs were a repeated motif in structures where core rings were either absent or played less restrictive roles in structures pursuing higher conformational freedom. Bicyclic nitrogen heterocyclic ring systems as the central core structures were reported, as were linear structures including phenyl ureas and taranabant analogs. Finally, peptides in the hemopressin class were presented as CB1 antagonists. Drug Dev Res 70:601–615, 2009. © 2009 Wiley‐Liss, Inc.

ChemInform Abstract: Condensed Bridgehead Nitrogen Heterocyclic System: Synthesis and Pharmacological Activities of 1,2,4‐Triazolo‐[3,4‐b]‐1,3,5‐thiadiazole Derivatives of Ibuprofen and Biphenyl‐4‐yloxy Acetic Acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Chemistry of the Pseudobasic Amino Alcohols. Part 40. Synthesis of Three New Condensed Nitrogen Heterocyclic Systems.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

New heterocycles from tetrazines and oxadiazoles

Abstract magnified imageThe reactivity of 3,4‐diamino‐1,2,5‐oxadiazole (2) toward nucleophilic substitution of 3,6‐bis(3,5‐dimethylpyrazol‐1yl)‐1,2,4,5‐tetrazine (1) was studied. A new class of high nitrogen heterocyclic systems was prepared. It was determined that 3,4‐diamino‐1,2,5‐oxadiazole did not display the required nucleophilicity to be reactive. However, the anion of 3,4‐diamino‐1,2,5‐oxadiazole, prepared by treatment with strong base, was sufficiently reactive to act as a nucleophile. J. Heterocyclic Chem., (2009).

Chemistry of the Pseudobasic Amino Alcohols. Part 40. Synthesis of Three New Condensed Nitrogen Heterocyclic Systems

Replacement of the central oxygen atom of the heptacyclic condensed diisoquinoline 3 by reaction with hydrazine, hydroxylamine or thiourea in a simple method gave three new heterocyclic ring systems involving 1,2,4,5-tetrazine (7), 1,2,4,5-oxatriazine (8) and 1,2,4,6-tetrazepine (9) central rings.

Surface active properties and biological activity of novel nonionic surfactants containing pyrimidines and related nitrogen heterocyclic ring systems

A series of annelated pyrimidine derivatives has been synthesized via different heterocyclization reactions of suitably functionalized 6-(4-octadecyloxyphenyl)-4-oxo-2- thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4) with different electrophiles and nucleophiles. These heterocycles bear an active hydrogen atom (NH, OH or COOH) which could be propoxylated using propylene oxide with different moles, 5, 10 and 15, to produce nonionic surfactant having a long alkyl chain with molecular weight suitable for becoming an amphiphilic molecule with correct hydrophilic-lypophilic balance which enhances solubility, biodegradability and hence lowers the toxicity to human beings and becomes environmentally friendly. In addition, the antimicrobial activities of these compounds were screened and it was found that some of these compounds have similar or higher activity compared with commercial antibiotic drugs (sulphadiazine), which make them suitable for diverse applications like the manufacturing of drugs, pesticides, emulsifiers, cosmetics, etc.

Synthesis of new condensed nitrogen heterocyclic systems

A cotarnine alkaloid-based synthesis was developed for new heptacyclic condensed diisoquinolines via the double intramolecular pseudosalt bis[1,3]dioxolo[4,5- g;4′,5′- g′][1,3,4]oxadiazolo[2,3- a;5,4- a′]diisoquinoline 6. Substitution of the central O atom in 6 by C, S, or N nucleophiles afforded the first representatives of the new ring systems bis[1,3]dioxolo[4,5- g:4,5- g′]pyrazolo[3,2- a:5,1- a′]diisoquinoline ( 7a– d), bis[1,3]dioxolo[4,5- g:4,5- g′][1,3,4]thiadiazolo[2,3- a:5,4- a′]diisoquinoline ( 8), and bis[1,3]dioxolo[4,5- g:4,5- g′][1,2,4]triazolo[3,2- a:5,1- a′]diisoquinoline ( 9a– d) under simple reaction conditions.

Condensed bridgehead nitrogen heterocyclic system: Synthesis and pharmacological activities of 1,2,4-triazolo-[3,4- b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid

Several 3,6-disubstituted-1,2,4-triazolo-[3,4- b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4 H)-1,2,4-triazoles ( 3a, b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, antibacterial and antifungal activities. Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains.