Synthesis Of Phenazines Research Articles

Electrochemical Oxidative (4 + 2) Cyclization of Anilines and o-Phenylenediamines for the Synthesis of Phenazines.

Phenazines, crucial constituents of nitrogen-containing heterocycles, widely exist in functional compounds. Herein, we report an anodic oxidative (4 + 2) cyclization between anilines and o-phenylenediamines for the uniform construction of phenazines in a simple undivided cell. Dual C-H amination followed by oxidation represents an outstanding step and atom efficiency. A sequence of phenazines is produced with excellent functional group tolerance at room temperature.

Sustainable Synthesis of Phenazines: A Review of Green Approaches

Abstract: Owing to its momentous significance in the development of new medications, phenazine, and its analogues are successful heterocyclic scaffolds as well as essential building blocks for developing physiologically active chemicals. Traditionally, phenazine and its derivatives have been synthesized using chemical methods that involve toxic organic solvents, dangerous reagents, and the risk of hazardous metal contamination in the final products. These drawbacks have significantly limited the widespread application of phenazine derivatives in therapeutic treatments and the pharmaceutical industry. Consequently, there is a growing demand for environmentally friendly methods that can address these challenges with less environmental damage. As a result, it is now possible to employ green and highly efficient methods for the synthesis of phenazine and its derivatives. These methods include mechanosynthesis, solvent-free and catalyst-free synthesis, green solventbased synthesis, ultrasound-assisted synthesis, microwave-assisted synthesis, and other similar approaches. In light of the fact that the phenazine backbone is a widely present biologically active component and the growing need to decrease the use of hazardous solvents, catalysts, and energy, this review has provided a summary of various sustainable and facile synthetic strategies of phenazine derivatives.

Synthesis of Amino Phenazines through the Oxidative Cyclization of Anilines with o-Phenylenediamines

Key words phenazines - oxidative cyclization - anilines - o-phenylenediamine - C–H functionalization - cobalt catalysis

DMAP catalyzed one-pot multicomponent synthesis of benzo phenazine and pyrimidine tethered tri-substituted methanes and their DFT analysis

In this article, we reported an eco-friendly, quick, and practical one-pot ultrasound-mediated condensation method employing DMAP as an organo-catalyst in an aqueous medium for the production of benzophenazine and aminopyrimidine tethered trisubstituted methane derivatives (5a-f). The prominent characteristics of this approach are the utilization of readily available starting materials, simple experimental procedure, short reaction time, no column chromatography, high atom economy and moderate to good yields. Further, DFT calculations using B3LYP 6-311(d,p) basis set was done to study the structural characteristics of compound 5b, and it was observed that the theoretical findings supports the experimental results.

NaCl Micro-Crystal as a Molecular Mold for Enhanced Synthesis of Planar Phenazines and Their Applications on Chemosensing and a Full-Color Fluorescent Material.

NaCl has been successfully used as a template for the synthesis of 2D nanomaterials, but it is seldom used for the construction of flat small organic molecules. Herein, a simple, low-cost, and highly efficient synthesis of phenazines with planar main frames, such as 5-phenyl-5,14-dihydro-5,7,12,14-tetraazapentacene, in the presence of NaCl micro-crystal as a kind of molecular mold is described. The reactants were mixed with NaCl powder and heated to 320 °C for 5 min. Yields >90% were readily achieved after a simple precipitation in water. The effectiveness of NaCl crystal as a mold with HCl was confirmed by comparison with common inorganic salts, SiO2, and γ-Al2O3 with HCl together with combinations including NaNO3 + HNO3, Na2SO4 + H2SO4, NaH2PO4 + H3PO4, and NaH2PO4 + polyphosphoric acid. The mechanism was deduced with the aid of computer simulation, which confirms the stabilization of 5,14-dihydro-5,7,12,14-tetraazapentacene by the NaCl surface. DMSO solution of a product, 1,3-dihydro-imidazo[4,5-b]phenazin-2-one, showed enhanced fluorescence in H2O, and it was used as a fluorescent probe for pH and Hg2+. A full-color material was prepared by mixing precursors of epoxy resin and phenazines, and its fluorescent color could be adjusted by the ratio of phenazines.

Development of Artificial Synthetic Pathway of Endophenazines in Pseudomonas chlororaphis P3.

Simple SummaryTerpenoid phenazines generally produced in Streptomyces exhibit potential antitumor and antibacterial activities. In this study, we designed and constructed an artificial biosynthetic pathway for the synthesis of terpenoid phenazines in Pseudomonas chlororaphis P3. We successfully synthesized endophenazine A and endophenazine A1 for the first time in Pseudomonas by introducing the prenyltransferase PpzP. Moreover, we revealed the biosynthetic pathway of endophenazine A1 in P. chlororaphis P3. This study enriches the diversity of phenazines in P. chlororaphis P3 and provides a reference for the heterologous synthesis of terpenoid phenazines.Endophenazine A is a terpenoid phenazine with phenazine-1-carboxylic acid (PCA), and dimethylallyl diphosphate (DMAPP) derived from the 2-methyl-D-erythritol-4-phosphate (MEP) pathway as the precursor, which shows good antimicrobial activity against several Gram-positive bacteria and fungi. However, the highest yield of endophenazine A was about 20 mg/L in Streptomyces, limiting its large-scale industrial development. Pseudomonas chlororaphis P3, possessing an efficient PCA synthesis and MEP pathways, is a suitable chassis to synthesize endophenazine A. Herein, we designed an artificial biosynthetic pathway for the synthesis of endophenazine A in P. chlororaphis P3. Primarily, the prenyltransferase PpzP from Streptomyces anulatus 9663 was introduced into P. chlororaphis P3 and successfully synthesized endophenazine A. Another phenazine compound, endophenazine A1, was discovered and identified as a leakage of the intermediate 4-hydroxy-3-methyl-2-butene pyrophosphate (HMBPP). Finally, the yield of endophenazine A reached 279.43 mg/L, and the yield of endophenazine A1 reached 189.2 mg/L by metabolic engineering and medium optimization. In conclusion, we successfully synthesized endophenazine A and endophenazine A1 in P. chlororaphis P3 for the first time and achieved the highest titer, which provides a reference for the heterologous synthesis of terpenoid phenazines.

Synthesis of 1-substituted phenazines as novel antichlamydial agents

A novel series of 1-substituted phenazines 4a-4l were designed and synthesized via Palladium-catalyzed reactions from 1-phenazine trifluoromethanesulfonate. These phenazines showed antichlamydial activity with IC50 values from 1 to 10 μM. Among them, compounds 4c and 4i exhibited the best antichlamydial activity with IC50 values from 2.06 to 2.74 μM without apparent cytotoxicity to host cells.

One-pot synthesis of phenazines from 2-naphthols with 1, 2-diamines and its biological importance and binding studies

One-pot synthesis of phenazines from 2-naphthols with 1, 2-diamines and its biological importance and binding studies

Synthesis of phenazines from ortho-bromo azo compounds via sequential Buchwald-Hartwig amination under micellar conditions and acid promoted cyclization

Non-symmetric phenazines were synthesized via the Buchwald-Hartwig amination of ortho-bromoazobenzenes with anilines under micellar conditions, using the commercially available surfactant Kolliphor EL in water, followed by an acid-promoted 6π-electrocyclization-aromatization process. Two different synthetic pathways to obtain the ortho-bromo azo intermediates were explored, namely the palladium catalysed selective ortho bromination of azobenzenes and the diazo coupling of ortho-bromo diazonium salts with N,N-dimethylaniline, imidazole, phenol, sodium methanesulfinate and ethyl chloroformate.

Forest Tree Associated Bacterial Diffusible and Volatile Organic Compounds against Various Phytopathogenic Fungi.

Plant growth-promoting rhizobacteria (PGPR) can potentially be used as an alternative strategy to control plant diseases. In this study, strain ST–TJ4 isolated from the rhizosphere soil of a healthy poplar was found to have a strong antifungal activity against 11 phytopathogenic fungi in agriculture and forestry. Strain ST–TJ4 was identified as Pseudomonas sp. based on 16S rRNA-encoding gene sequences. The bacterium can produce siderophores, cellulase, and protease, and has genes involved in the synthesis of phenazine, 1–phenazinecarboxylic acid, pyrrolnitrin, and hydrogen cyanide. Additionally, the volatile compounds released by strain ST–TJ4 can inhibit the mycelial growth of plant pathogenic fungi more than diffusible substances can. Based on volatile compound profiles of strain ST–TJ4 obtained from headspace collection and GC–MS/MS analysis, 1-undecene was identified. In summary, the results suggested that Pseudomonas sp. ST–TJ4 can be used as a biocontrol agent for various plant diseases caused by phytopathogenic fungi.

Synthesis and Assessment of 3-Substituted Phenazines as Novel Antichlamydial Agents.

In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activities. We found that a few of the synthesized 4-substituted phenazines could block the infectivity of chlamydiae without host cell toxicity. The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents. The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by the treatment of uninfected HeLa cells using WST-1 method. Most of the 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 μM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 μM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle. Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through further chemical modification on C-3 position rather than C-4 position of phenazine.

Recent Advances in the Synthesis of Acridines and Phenazines

Acridines and phenazines are common motifs in bioactive compounds and natural products. Many excellent works on the synthesis of these skeletons starting from diaryliodonium salts, benzaldehydes, anthranils, azobenzenes, and nitrosobenzenes have been reported. In this overview, we highlight several recent elegant works on the synthesis of acridines and phenazines.1 Introduction2 Synthesis of Acridines3 Synthesis of Phenazines4 Conclusion

Theophylline Supported on Modified Silica‐Coated Magnetite Nanoparticles as a Novel, Efficient, Reusable Catalyst in Green One‐Pot Synthesis of Spirooxindoles and Phenazines

AbstractIn the present work, theophylline immobilized on superparamagnetic Fe3O4@SiO2 nanoparticles were prepared via a multistep method and was fully characterized by means of fourier transform infrared (FT‐IR) spectroscopy, X‐ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE‐SEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA), energy dispersive X‐ray analysis (EDX), vibration sample magnetometry (VSM), N2 adsorption‐desorption isotherm analysis, temperature‐programmed desorption of carbon dioxide (CO2‐TPD) and elemental analysis. The catalytic performance of this novel nanomagnetic catalyst has been studied in the synthesis of spirooxindole derivatives via a one‐pot three‐component reaction of isatin derivatives, malononitrile or ethyl 2‐cyanoacetate, and 5‐amino‐1,3‐dimethyluracil in excellent yields under reflux conditions in water. Also, the highly efficient, green and economical synthesis of poly‐substituted benzo[a]pyrano‐[2, 3‐c]phenazine derivatives from four component reaction of 2‐hydroxynaphthalene‐1,4‐dione, diamines, aldehydes, and malononitrile in the presence of this basic magnetic catalyst has been developed. In addition, the used catalyst could be separated conveniently from the reaction system for up to 6 runs without significant loss of its catalytic efficiency.

Synthesis of Cyclobutadienoid-Fused Phenazines with Strongly Modulated Degrees of Antiaromaticity.

The streamlined synthesis of a series of regioisomeric azaacene analogues containing fused phenazine and antiaromatic cyclobutadienoids (CBDs), using a catalytic arene-oxanorbornene annulation, followed by aromatization is reported. Controlling the fusion patterns allowed strong modulation of local antiaromaticity. Enhancing antiaromaticity in these regioisomeric azaacenes led to stabilized LUMO, reduced band gap, and quenched fluorescence. This synthetic strategy provides a facile means to fuse CBDs with variable degrees of antiaromaticity onto N-heteroarenes to tune their optoelectronic properties.

An Efficient Buchwald-Hartwig/Reductive Cyclization for the Scaffold Diversification of Halogenated Phenazines: Potent Antibacterial Targeting, Biofilm Eradication, and Prodrug Exploration.

Bacterial biofilms are surface-attached communities comprised of nonreplicating persister cells housed within a protective extracellular matrix. Biofilms display tolerance toward conventional antibiotics, occur in ∼80% of infections, and lead to >500000 deaths annually. We recently identified halogenated phenazine (HP) analogues which demonstrate biofilm-eradicating activities against priority pathogens; however, the synthesis of phenazines presents limitations. Herein, we report a refined HP synthesis which expedited the identification of improved biofilm-eradicating agents. 1-Methoxyphenazine scaffolds were generated through a Buchwald-Hartwig cross-coupling (70% average yield) and subsequent reductive cyclization (68% average yield), expediting the discovery of potent biofilm-eradicating HPs (e.g., 61: MRSA BAA-1707 MBEC = 4.69 μM). We also developed bacterial-selective prodrugs (reductively activated quinone-alkyloxycarbonyloxymethyl moiety) to afford HP 87, which demonstrated excellent antibacterial and biofilm eradication activities against MRSA BAA-1707 (MIC = 0.15 μM, MBEC = 12.5 μM). Furthermore, active HPs herein exhibit negligible cytotoxic or hemolytic effects, highlighting their potential to target biofilms.

Synthesis of Push-Pull Phenazines Possessing pH-Responsive Absorption Spectra and their Application in Selective Detection of Fe3+ Ions and Aromatics

Phenazines bearing electron-donor and electron-acceptor groups with high pH-sensing behavior were synthesized in moderate to good yields. Theoretical calculations on the frontier molecular orbitals and experimental oxidation potential measurements under variable pH values provide evidence for extensive internal charge transfer at high pH value. The well-known strong affinity of the catecholate moiety present in our phenazines is utilized for spectrophotometric detection of Fe3+ ion. Fluorescence-quenching behavior of the prepared phenazines is utilized for detection and distinction of electron-rich and electron-poor aromatics.

Synthetic routes for phenazines: an overview

Phenazines are known to exhibit a diverse range of biological properties, such as antimicrobial, antitumor, antioxidant, antimalarial, neuroprotectant, etc. Owing to their significant applications in both medicinal and industrial fields, the phenazine framework has emerged as a remarkable synthetic target. The most general approaches for synthesis of phenazines include the Wohl–Aue method, Beirut method, condensation of 1,2-diaminobenzenes with 2C-units, reductive cyclization of diphenylamines, oxidative cyclization of 1,2-diaminobenzene/diphenylamines, Pd-catalyzed N-arylation, multicomponent approaches, etc. Advances in the exploitation of synthetic routes for assembly of this scaffold are reported in this review.

A Sustainable Synthesis of Asymmetric Phenazines and Phenoxazinones Mediated by CotA‐Laccase

AbstractAn efficient and sustainable one‐step procedure for the synthesis of new asymmetric phenazines and phenoxazinones from commercially available ortho‐substituted diamines and ortho‐substituted hydroxyamines is reported. In this study we have expanded the substrate scope of CotA‐laccase‐catalyzed aerobic oxidations through the use of aromatic amines presenting variable functional groups, including N‐substitution, contributing to the rational synthesis of different heterocyclic scaffolds. The transformations proceed smoothly through a cascade of oxidative reactions to the benzoquinonediimine intermediates followed by nucleophilic addition, intramolecular cyclization and aromatization, all performed in mild conditions.magnified image

Microwave Assisted Synthesis of Phenazines from β-Lapachones and Their Tuberculostatic Activity

Microwave Assisted Synthesis of Phenazines from β-Lapachones and Their Tuberculostatic Activity

ChemInform Abstract: A Mild and Simple Method for the Synthesis of Substituted Phenazines.

A mild, simple, and general method has been developed for the synthesis of phenazines by cross-coupling of benzoquinones with o-phenylenediamines. Benzoquinones and o-phenylenediamines reacted smoothly to give the corresponding cross-coupled products in good to excellent yields. 1,4-Naphthoquinone also coupled with o-phenylenediamines in the presence of copper acetate at 50 °C to give the corresponding benzo[a]phenazines. All reactions could be carried out under air.