Davis-Beirut Reaction Research Articles

Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis-Beirut Reaction.

Herein, we report the structure and synthesis of the potent MDM2-p53 inhibitor BI-0282. The complex spirooxindole scaffold bearing four stereocenters embedded in a rigid polycyclic ring-system was effectively prepared on a multi-gram scale in only five synthesis steps employing a three-component 1,3-dipolar cycloaddition and a late-stage Davis–Beirut reaction as key steps.

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 para position appropriately substituted with a 2°-amine (see 5) or 2°-alcohol (see 6). 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. This one-pot procedure delivers aryldihydro-1,2-oxazines in moderate yields.

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

The Davis-Beirut reaction provides access to 2H-indazoles from aromatic nitro compounds. However, N-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 o-nitrobenzyl alcohols empowered Brønsted acid catalyzed conditions for accessing N-aryl targets. Anilines and alkyl amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical calculations.

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, 2H-indazoles are relatively underexploited when compared to 1H-indazole, perhaps because of regioselectivity issues associated with the synthesis of 2H-indazoles. This Account describes our unfolding of the synthetic utility of the Davis-Beirut reaction (DBR) for the construction of 2H-indazoles and their derivatives; parallel unfoldings of mechanistic models for these interrelated N-N bond forming reactions are also summarized. The Davis-Beirut reaction is a robust method that exploits the diverse chemistries of a key nitroso imine or nitroso benzaldehyde intermediate generated in situ under redox neutral conditions. The resulting N-N bond-forming heterocyclization between nucleophilic and electrophilic nitrogens can be leveraged for the synthesis of multiple classes of indazoles and their derivatives, such as simple or fused indazolones, thiazolo-indazoles, 3-alkoxy-2H-indazoles, 2H-indazole N-oxides, and 2H-indazoles with various substitutions on the ring system or the nitrogens. These diverse products can all be synthesized under alkaline conditions and the various strategies for accessing these heterocycles are discussed. Alternatively, we have also developed methods involving mild photochemical conditions for the nitrobenzyl → aci-nitro → nitroso imine sequence. Solvent consideration is especially important for modulating the chemistry of the reactive intermediates in these reactions; the presence of water is critically important in some cases, but water's beneficial effect has a ceiling because of the alternative reaction pathways it enables. Fused 2H-indazoles readily undergo ring opening reactions to give indazolones when treated with nucleophiles or electrophiles. Furthermore, palladium-catalyzed cross coupling, the Sonagashira reaction, EDC amide coupling, 1,3-dipolar cycloadditions with nitrile oxides, copper-catalyzed alkyne-azide cycloadditions (click reaction), as well as copper-free click reactions, can all be used late-stage to modify 2H-indazoles and indazolones. The continued development and applications of the Davis-Beirut reaction has provided many insights for taming the reactivity of highly reactive nitro and nitroso groups, which still has a plethora of underexplored chemistries and challenges. For example, there is currently a limited number of nonfused 2H-indazole examples containing an aryl substitution at nitrogen. This is caused by relatively slow N-N bond formation between N-aryl imine and nitroso reactants, which allows water to add to the key nitroso imine intermediate causing imine bond cleavage to be a competitive reaction pathway rather than proceeding through the desired N-N bond-forming heterocyclization.

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.

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

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to “Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis–Beirut Reaction”Jie S. Zhu, Jung-Ho Son, Andrew P. Teuthorn, Makhluf J. Haddadin, Mark J. Kurth*, and Dean J. Tantillo*Cite this: J. Org. Chem. 2017, 82, 23, 12946Publication Date (Web):November 1, 2017Publication History Published online1 November 2017Published inissue 1 December 2017https://doi.org/10.1021/acs.joc.7b02695Copyright © 2017 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views704Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (181 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

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.

Synthesis of novel 2H-indazole analogues via the Davis-Beirut reaction and conjugation onto magnetic nanoparticles

Methods for the construction of C3-amino substituted 2H-indazole motifs are scarce. While the Davis-Beirut reaction proved useful and versatile in the construction of alkoxy- and thia- C3-substituted 2H-indazoles under mild basic conditions, the same success was not enjoyed when confronted with nitrogen-based nucleophiles. Therefore, we set out to expand the scope of the Davis-Beirut reaction and investigated the ability of amine nucleophiles to prompt the heterocyclization. In addition, a model 2H-indazole analogue was successfully conjugated onto magnetic nanoparticles for the first time. The toxicity of the synthesized analogues was estimated using in silico T.E.S.T software. This report provides a reliable approach for the synthesis of indazole-loaded nanoparticles whose applications have not been investigated before.

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. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system.

Synthesis of Various Thia-2H-indazoles via the Davis–Beirut Reaction

Key words Davis–Beirut reaction - indazoles - sulfur-containing heterocycles

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. Subsequent S-oxidation gives the corresponding sulfone.

ChemInform Abstract: The Davis—Beirut Reaction: A Novel Entry into 2H‐Indazoles and Indazolones. Recent Biological Activity of Indazoles

AbstractReview: 39 refs.

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 and 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.

The Davis–Beirut Reaction: N1,N2-Disubstituted-1H-Indazolones via 1,6-Electrophilic Addition to 3-Alkoxy-2H-Indazoles

A variety of electrophiles (anhydrides, acid chlorides, carbonochloridates, sulfonyl chlorides, and alkyl bromides) react with 3-methoxy-2H-indazole (1a), benzoxazin[3,2-b]indazole (1d), and oxazolino[3,2-b]indazole (1e) - substrates available by the Davis-Beirut reaction - to yield a diverse set of N(1),N(2)-disubstituted-1H-indazolones. With certain electrophiles, an AERORC (Addition of the Electrophile, Ring Opening, and Ring Closure) process on indazole 1d results in indazoloindazolone formation. An intriguing aspect of these N(1),N(2)-disubstituted-1H-indazolones is that they are poised for diversification through, for example, azide-alkyne cycloaddition chemistry reported here.