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.
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| http://dx.doi.org/10.1021/acs.orglett.8b00036 | DOI Listing |
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Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis-Beirut Reaction.
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Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
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.
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Tetrahedron Lett
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Department of Chemistry, University of California, Davis, One Shields Ave., Davis, CA 95616.
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.
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Department of Chemistry , University of California Davis, 1 Shields Avenue , Davis , California 95616 , United States.
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.
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Acc Chem Res
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Department of Chemistry , University of California Davis, 1 Shields Avenue , Davis California 95616 , United States.
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View Article and Find Full Text PDFAccessing Multiple Classes of 2 H-Indazoles: Mechanistic Implications for the Cadogan and Davis-Beirut Reactions.
J Am Chem Soc
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Department of Chemistry , University of California Davis, 1 Shields Avenue , Davis , California 95616 , United States.
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.
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