Preparation of 3-Substituted Isoindolin-1-one, Cinnoline, and 1,2,4-[]-Benzotriazine Derivatives.

Herein, we report a new approach to synthesize a series of 1,2,4-[]-benzotriazine and cinnoline derivatives from 3-substituted isoindolin-1-one. All the reported products are obtained through an economical two-step synthetic procedure resulting in fair-to-high yields. Cinnolines (a) and 1,2,4-[]-benzotriazines (b) result from an intramolecular cyclization of the corresponding 3-substituted isoindolin-1-ones, which, in turn, are prepared by an addition reaction from 2-cyanobenzaldehyde and 2-(2-nitrophenyl) acetonitrile (a) or 2-nitroaniline derivatives (b).

Davis-Beirut Reaction Inspired Nitroso Diels-Alder Reaction.

A Davis-Beirut reaction inspired nitroso Diels-Alder protocol is reported. The starting material for the procedure is a nitrophenyl moiety with the position appropriately substituted with a 2°-amine (see ) or 2°-alcohol (see ). Deprotonation at the benzylic position followed by concomitant oxidation of the benzylic position and reduction of the nitro moiety delivers a nitrosophenyl intermediate, which subsequently undergoes a nitroso Diels-Alder reaction.

A Redox Isomerization Strategy for Accessing Modular Azobenzene Photoswitches with Near Quantitative Bidirectional Photoconversion.

Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing -formylazobenzenes from -nitrobenzyl alcohol. The resulting azo-aldehydes can be readily converted to photoswitchable compounds with excellent photophysical properties using simple hydrazide click chemistry.

Davis-Beirut Reaction: A Photochemical Brønsted Acid Catalyzed Route to -Aryl 2-Indazoles.

The Davis-Beirut reaction provides access to 2-indazoles from aromatic nitro compounds. However, -aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate was generated under alkaline conditions, but as reported here, the photochemistry of -nitrobenzyl alcohols empowered Brønsted acid catalyzed conditions for accessing -aryl targets.

Davis-Beirut Reaction: Diverse Chemistries of Highly Reactive Nitroso Intermediates in Heterocycle Synthesis.

Indazoles are an important class of nitrogen heterocycles because of their excellent performance in biologically relevant applications, such as in chemical biology and medicinal chemistry. In these applications, convenient synthesis using commercially available and diverse building blocks is highly desirable. Within this broad class, 2-indazoles are relatively underexploited when compared to 1-indazole, perhaps because of regioselectivity issues associated with the synthesis of 2-indazoles.

Accessing Multiple Classes of 2 H-Indazoles: Mechanistic Implications for the Cadogan and Davis-Beirut Reactions.

The Cadogan cyclization is a robust but harsh method for the synthesis of 2 H-indazoles, a valuable class of nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously. Here, 2 H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis-Beirut reaction and are presented as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed.

Novel 2-(5-Imino-5-isoquinolones[3,4-]quinoxalin-7-ylmethyl)-benzonitrile () and Other Related Derivatives Targeting Colon Cancer Cells: Syntheses and in Vitro Models.

Chemotherapy has been shown to be effective in reducing the progression and development of cancer in metastatic patients. However, drug selectivity is still a major issue for most chemotherapeutics. In this study, we synthesized four novel heterocyclic compounds having similarity in structure with quinone systems whereby nitrogen atoms replace the oxygen atoms.

Photochemical Preparation of 1,2-Dihydro-3 H-indazol-3-ones in Aqueous Solvent at Room Temperature.

o-Nitrosobenzaldehyde is a reactive intermediate useful in the synthesis of nitrogen heterocycles. Previous strategies for using o-nitrosobenzaldehyde involve its isolation via chromatography and/or formation under harsh conditions. Herein, this intermediate was photochemically generated in situ from o-nitrobenzyl alcohols in a mild, efficient manner for the construction of 1,2-dihydro-3 H-indazol-3-ones using an aqueous solvent at room temperature.

N-N Bond Formation between Primary Amines and Nitrosos: Direct Synthesis of 2-Substituted Indazolones with Mechanistic Insights.

A concise, one-step route to indazolones from primary alkyl amines and o-nitrobenzyl alcohols is reported. The key step in this readily scalable indazolone forming process involves base-mediated in situ o-nitrobenzyl alcohol → o-nitrosobenzaldehyde conversion. Although this functional group interconversion is known to be useful for 2 H-indazole synthesis, its reactivity was modulated for indazolone formation.

Davis-Beirut Reaction: Alkoxide versus Hydroxide Addition to the Key o-Nitrosoimine Intermediate.

Reaction options, alkoxide vs hydroxide vs amine addition to the key intermediate (o-nitrosoimine) generated in the Davis-Beirut reaction of an o-nitrobenzylamine substrate, are reported to explain the nucleophilic addition selectivity of this one-pot indazole-forming process. The hydroxide addition/deprotection pathway as well as the fate of the resulting o-nitrosobenzaldehyde were both uncovered with several o-nitrobenzylamine substrates, and design elements required for an efficient double Davis-Beirut reaction, inspired by new mechanistic insights, were defined.

Retraction Note to: Quinoxaline 1,4-dioxides induce G/M cell cycle arrest and apoptosis in human colon cancer cells.

The authors have retracted this article because of overlap in images within the publication and with another previously published article. It was brought to our attention that there are inconsistencies in Figs. 3, 5 and 6.

Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis-Beirut Reaction.

The discovery of a new variation on the Davis-Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its expected reactivity-a potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described.

The photoprotective effects of 2-benzoyl-3-phenylquinoxaline 1,4-dioxide against UVB-induced damage in HaCaT cells.

With the increasing levels of atmospheric ozone depletion, there has been much concern about the causal effects of high levels of ultraviolet radiation reaching the Earth's surface on skin cancer. This has led to growing interest in identifying new active ingredients for use in commercial sunscreens. In our study, the chemical compound 2-benzoyl-3-phenylquinoxaline 1,4-dioxide (BPQ) prepared by the Beirut reaction was tested for its ability to protect a human keratinocyte cell line (HaCaT) against ultraviolet B radiation (280-315 nm).

One-Pot Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines and Isoquinolino[3,4-b]quinoxalines via Tandem Cyclization Strategies.

Two operationally simple one-pot protocols have been developed for the synthesis of amino-functionalized benzo[4,5]imidazo[2,1-a]isoquinolines and isoquinolino[3,4-b]quinoxalines. Optimization data and substrate scope for these atom-economical transformations, which engage commercially available o-phenylenediamines and o-cyanobenzaldehydes, are discussed.

Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic Strategies and Photophysical Studies.

A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λ(max) of excitation for DBNs with varying electronic character.

Expedient one-pot synthesis of indolo[3,2-]isoquinolines via a base-promoted -alkylation/tandem cyclization.

A transition metal-free, one-pot protocol has been developed for the synthesis of 11-indolo[3,2-]isoquinolin-5-amines via the atom economical annulation of ethyl (2-cyanophenyl)carbamates and 2-cyanobenzyl bromides. This method proceeds via sequential -alkylation and base-promoted cyclization. Optimization data, substrate scope, mechanistic insights, and photoluminescence properties are discussed.

Inhibition of myeloperoxidase: evaluation of 2H-indazoles and 1H-indazolones.

Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays.

Davis-Beirut reaction: route to thiazolo-, thiazino-, and thiazepino-2H-indazoles.

Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitrobenzaldehydes or o-nitrobenzyl bromides and S-trityl-protected 1°-aminothioalkanes are reported. The process consists of formation of the requisite N-(2-nitrobenzyl)(tritylthio)alkylamine, subsequent deprotection of the trityl moiety with TFA, and immediate treatment with aq. KOH in methanol under Davis-Beirut reaction conditions to deliver the target thiazolo-, thiazino-, or thiazepino-2H-indazole in good overall yield.

Cyclic azacyanines: experimental and computational studies on spectroscopic properties and unique reactivity.

The absorption and fluorescence properties of cyclic azacyanine (CAC) derivatives were examined in several solvents. The presence of electron donating or withdrawing groups on the CAC impacts spectroscopic properties. The general solvent relaxation displayed by azacyanine derivatives is in accordance with Lippert-Mataga's prediction but exception is noted in the case of protic solvent due to specific hydrogen bonding interactions.

The quinoxaline di-N-oxide DCQ blocks breast cancer metastasis in vitro and in vivo by targeting the hypoxia inducible factor-1 pathway.

Background: Although tumor hypoxia poses challenges against conventional cancer treatments, it provides a therapeutic target for hypoxia-activated drugs. Here, we studied the effect of the hypoxia-activated synthetic quinoxaline di-N-oxide DCQ against breast cancer metastasis and identified the underlying mechanisms.

Methods: The human breast cancer cell lines MCF-7 (p53 wildtype) and MDA-MB-231 (p53 mutant) were treated with DCQ under normoxia or hypoxia.

Acid and base catalyzed Davis-Beirut reaction: experimental and theoretical mechanistic studies and synthesis of novel 3-amino-2H-indazoles.

The Davis-Beirut reaction, which provides an efficient synthesis of 2H-indazoles and, subsequently, indazolones, is shown to proceed rapidly from o-nitrosobenzaldehyde and primary amines under both acid or base catalysis. Experimental and theoretical evidence in support of a reaction mechanism is provided in which o-nitrosobenzylidine imine is a pivotal intermediate in this N,N-bond forming heterocyclization reaction. The Davis-Beirut reaction is also shown to effectively synthesize a number of novel 3-amino-2H-indazole derivatives.

The Davis-Beirut Reaction: a novel entry into 2H-indazoles and indazolones. Recent biological activity of indazoles.

A novel, easy method for the syntheses of richly diversified 2H-indazoles and indazolones, called the Davis-Beirut reaction, and other recent 2H-indazole synthetic routes are briefly reviewed. An update on the biological activity of indazoles is also surveyed.

A one-pot-three-step route to triazolotriazepinoindazolones from oxazolino-2H-indazoles.

A one-pot-three-step method has been developed for the conversion of oxazolino-2H-indazoles into triazolotriazepinoindazolones with three points of diversity. Step one of this process involves a propargyl bromide-initiated ring opening of the oxazolino-2H-indazole (available by the Davis-Beirut reaction) to give an N(1)-(propargyl)-N(2)-(2-bromoethyl)-disubstituted indazolone, which then undergoes -CH(2)Br → -CH(2)N(3) displacement (step two) followed by an uncatalyzed intramolecular azide-alkyne 1,3-dipolar cycloaddition (step three) to form the target heterocycle. Employing 7-bromooxazolino-2H-indazole allows for further diversification through, for example, palladium-catalyzed coupling chemistry, as reported here.

Unusual Friedlander reactions: a route to novel quinoxaline-based heterocycles.

Acid catalyzed Friedlander reactions of a number of 2,3-dihydro-1H-cyclopenta[b]quinoxaline-1-ones with 2-aminobenzaldehyde yield, unexpectedly, 8H-indolo[3,2-a]phenazine and quinolino[2,3-c]cyclopentadienone[2,3-b]quinoxalines, the structures of derivatives of which were confirmed by X-ray crystallography. Easy routes to novel quinoxaline-based indoles, quinolones, and quinoxaline-1,4-dioxides are reported, and proposed mechanisms for the unexpected products are discussed.